RBCC

Full text data of NF1

NF1 [Confidence: low (only semi-automatic identification from reviews)]
Neurofibromin (Neurofibromatosis-related protein NF-1; Neurofibromin truncated)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P21359
ID NF1_HUMAN Reviewed; 2839 AA.
AC P21359; O00662; Q14284; Q14930; Q14931; Q9UMK3;
DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 2.
DT 22-JAN-2014, entry version 173.
DE RecName: Full=Neurofibromin;
DE AltName: Full=Neurofibromatosis-related protein NF-1;
DE Contains:
DE RecName: Full=Neurofibromin truncated;
GN Name=NF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX PubMed=1457041; DOI=10.1089/dna.1992.11.727;
RA Bernards A., Haase V.H., Murthy A.E., Menon A., Hannigan G.E.,
RA Gusella J.F.;
RT "Complete human NF1 cDNA sequence: two alternatively spliced mRNAs and
RT absence of expression in a neuroblastoma line.";
RL DNA Cell Biol. 11:727-734(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2134734; DOI=10.1126/science.2134734;
RA Wallace M.R., Marchuk D.A., Andersen L.B., Letcher R., Odeh H.M.,
RA Saulino A.M., Fountain J.W., Brereton A., Nicholson J., Mitchell A.L.,
RA Brownstein B.H., Collins F.S.;
RT "Type 1 neurofibromatosis gene: identification of a large transcript
RT disrupted in three NF1 patients.";
RL Science 249:181-186(1990).
RN [3]
RP ERRATUM.
RX PubMed=2125369;
RA Wallace M.R., Marchuk D.A., Andersen L.B., Letcher R., Odeh H.M.,
RA Saulino A.M., Fountain J.W., Brereton A., Nicholson J., Mitchell A.L.,
RA Brownstein B.H., Collins F.S.;
RL Science 250:1749-1749(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1783401; DOI=10.1016/0888-7543(91)90017-9;
RA Marchuk D.A., Saulino A.M., Tavakkol R., Swaroop M., Wallace M.R.,
RA Andersen L.B., Mitchell A.L., Gutmann D.H., Boguski M.S.,
RA Collins F.S.;
RT "cDNA cloning of the type 1 neurofibromatosis gene: complete sequence
RT of the NF1 gene product.";
RL Genomics 11:931-940(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND ALTERNATIVE SPLICING.
RC TISSUE=Placenta;
RX PubMed=1339276; DOI=10.1016/0006-291X(92)91294-Z;
RA Suzuki H., Takahashi K., Kubota Y., Shibahara S.;
RT "Molecular cloning of a cDNA coding for neurofibromatosis type 1
RT protein isoform lacking the domain related to ras GTPase-activating
RT protein.";
RL Biochem. Biophys. Res. Commun. 187:984-990(1992).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RC TISSUE=Kidney;
RX PubMed=7570581; DOI=10.1620/tjem.175.225;
RA Suzuki H., Takahashi K., Shibahara S.;
RT "Evidence for the presence of two amino-terminal isoforms of
RT neurofibromin, a gene product responsible for neurofibromatosis type
RT 1.";
RL Tohoku J. Exp. Med. 175:225-233(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-80; LEU-678;
RP HIS-1422 AND LEU-2511.
RG NIEHS SNPs program;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 335-2839 (ISOFORM 1), AND
RP VARIANT NF1 PRO-1953.
RX PubMed=2114220; DOI=10.1016/0092-8674(90)90253-B;
RA Cawthon R.M., Weiss R., Xu G., Viskochil D., Culver M., Stevens J.,
RA Robertson M., Dunn D., Gesteland R., O'Connell P., White R.;
RT "A major segment of the neurofibromatosis type 1 gene: cDNA sequence,
RT genomic structure, and point mutations.";
RL Cell 62:193-201(1990).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 335-2839 (ISOFORMS 1 AND 6).
RX PubMed=2116237; DOI=10.1016/0092-8674(90)90024-9;
RA Xu G., O'Connell P., Viskochil D., Cawthon R.M., Robertson M.,
RA Culver M., Dunn D., Stevens J., Gesteland R., White R., Weiss R.;
RT "The neurofibromatosis type 1 gene encodes a protein related to GAP.";
RL Cell 62:599-608(1990).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 707-782.
RX PubMed=9002664; DOI=10.1093/hmg/6.1.9;
RA Regnier V., Meddeb M., Lecointre G., Richard F., Duverger A.,
RA Nguyen V.C., Dutrillaux B., Bernheim A., Danglot G.;
RT "Emergence and scattering of multiple neurofibromatosis (NF1)-related
RT sequences during hominoid evolution suggest a process of
RT pericentromeric interchromosomal transposition.";
RL Hum. Mol. Genet. 6:9-16(1997).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 751-1611 (ISOFORMS 1 AND 2).
RX PubMed=7774960; DOI=10.1016/0888-7543(95)80104-T;
RA Li Y., O'Connell P., Breidenbach H.H., Cawthon R.M., Stevens J.,
RA Xu G., Neil S., Robertson M., White R., Viskochil D.;
RT "Genomic organization of the neurofibromatosis 1 gene (NF1).";
RL Genomics 25:9-18(1995).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1090-1598 (ISOFORM 4).
RX PubMed=2121370; DOI=10.1016/0092-8674(90)90150-D;
RA Martin G.A., Viskochil D., Bollag G., McCabe P.C., Crosier W.J.,
RA Haubruck H., Conroy L., Clark R., O'Connell P., Cawthon R.M.,
RA Innis M., McCormick F.;
RT "The GAP-related domain of the neurofibromatosis type 1 gene product
RT interacts with ras p21.";
RL Cell 63:843-849(1990).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1168-1566 (ISOFORMS 1 AND 2).
RX PubMed=1923522;
RA Nishi T., Lee P.S., Oka K., Levin V.A., Tanase S., Morino Y., Saya H.;
RT "Differential expression of two types of the neurofibromatosis type 1
RT (NF1) gene transcripts related to neuronal differentiation.";
RL Oncogene 6:1555-1559(1991).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1371-1391 (ISOFORM 2), FUNCTION, AND
RP TISSUE SPECIFICITY.
RX PubMed=8417346;
RA Andersen L.B., Ballester R., Marchuk D.A., Chang E., Gutmann D.H.,
RA Saulino A.M., Camonis J., Wigler M., Collins F.S.;
RT "A conserved alternative splice in the von Recklinghausen
RT neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both
RT of which have GTPase-activating protein activity.";
RL Mol. Cell. Biol. 13:487-495(1993).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1371-1391 (ISOFORM 2).
RX PubMed=1662505; DOI=10.1016/0006-291X(91)92029-J;
RA Suzuki Y., Suzuki H., Kayama T., Yoshimoto T., Shibahara S.;
RT "Brain tumors predominantly express the neurofibromatosis type 1 gene
RT transcripts containing the 63 base insert in the region coding for
RT GTPase activating protein-related domain.";
RL Biochem. Biophys. Res. Commun. 181:955-961(1991).
RN [18]
RP FUNCTION.
RX PubMed=2121371; DOI=10.1016/0092-8674(90)90151-4;
RA Ballester R., Marchuk D.A., Boguski M.S., Saulino A.M., Letcher R.,
RA Wigler M., Collins F.S.;
RT "The NF1 locus encodes a protein functionally related to mammalian GAP
RT and yeast IRA proteins.";
RL Cell 63:851-859(1990).
RN [19]
RP RNA EDITING.
RX PubMed=8602361; DOI=10.1093/nar/24.3.478;
RA Skuse G.R., Cappione A.J., Sowden M., Metheny L.J., Smith H.C.;
RT "The neurofibromatosis type I messenger RNA undergoes base-
RT modification RNA editing.";
RL Nucleic Acids Res. 24:478-485(1996).
RN [20]
RP RNA EDITING.
RX PubMed=11727199; DOI=10.1086/337952;
RA Mukhopadhyay D., Anant S., Lee R.M., Kennedy S., Viskochil D.,
RA Davidson N.O.;
RT "C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that
RT express both the type II transcript and apobec-1, the catalytic
RT subunit of the apolipoprotein B mRNA-editing enzyme.";
RL Am. J. Hum. Genet. 70:38-50(2002).
RN [21]
RP REVIEW ON VARIANTS.
RX PubMed=7981724; DOI=10.1002/humu.1380040202;
RA Upadhyaya M., Shaw D.J., Harper P.S.;
RT "Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis
RT and polymorphisms in the NF1 gene.";
RL Hum. Mutat. 4:83-101(1994).
RN [22]
RP REVIEW ON VARIANTS.
RX PubMed=8825042;
RA Shen M.H., Harper P.S., Upadhyaya M.;
RT "Molecular genetics of neurofibromatosis type 1 (NF1).";
RL J. Med. Genet. 33:2-17(1996).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864; SER-2188; SER-2515;
RP SER-2521 AND SER-2543, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864; SER-876 AND
RP SER-2515, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864 AND SER-2817, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [30]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2543 AND SER-2817, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 1198-1551.
RX PubMed=9687500; DOI=10.1093/emboj/17.15.4313;
RA Scheffzek K., Ahmadian M.R., Wiesmuller L., Kabsch W., Stege P.,
RA Schmitz F., Wittinghofer A.;
RT "Structural analysis of the GAP-related domain from neurofibromin and
RT its implications.";
RL EMBO J. 17:4313-4327(1998).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1581-1837, LIPID-BINDING,
RP DOMAIN, AND MUTAGENESIS OF LYS-1691; ARG-1695; ARG-1769 AND LYS-1771.
RX PubMed=16397625; DOI=10.1038/sj.embor.7400602;
RA D'Angelo I., Welti S., Bonneau F., Scheffzek K.;
RT "A novel bipartite phospholipid-binding module in the
RT neurofibromatosis type 1 protein.";
RL EMBO Rep. 7:174-179(2006).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 1566-1837 IN COMPLEX WITH
RP PHOSPHOLIPID, LIPID-BINDING, AND DOMAIN.
RX PubMed=17187824; DOI=10.1016/j.jmb.2006.11.055;
RA Welti S., Fraterman S., D'Angelo I., Wilm M., Scheffzek K.;
RT "The sec14 homology module of neurofibromin binds cellular
RT glycerophospholipids: mass spectrometry and structure of a lipid
RT complex.";
RL J. Mol. Biol. 366:551-562(2007).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 1581-1837 OF VARIANT NF1
RP VAL-1605 AND MUTANT LYS-1771 DEL IN COMPLEX WITH LIPID,
RP CHARACTERIZATION OF VARIANT NF1 VAL-1605, MUTAGENESIS OF LYS-1771,
RP LIPID-BINDING, AND DOMAIN.
RX PubMed=21089070; DOI=10.1002/humu.21405;
RA Welti S., Kuhn S., D'Angelo I., Brugger B., Kaufmann D., Scheffzek K.;
RT "Structural and biochemical consequences of NF1 associated
RT nontruncating mutations in the Sec14-PH module of neurofibromin.";
RL Hum. Mutat. 32:191-197(2011).
RN [36]
RP VARIANT GLU-1444.
RX PubMed=1568247; DOI=10.1016/0092-8674(92)90408-5;
RA Li Y., Bollag G., Clark R., Stevens J., Conroy L., Fults D., Ward K.,
RA Friedman E., Samowitz W., Robertson M., Bradley P., McCormick F.,
RA White R., Cawthon R.M.;
RT "Somatic mutations in the neurofibromatosis 1 gene in human tumors.";
RL Cell 69:275-281(1992).
RN [37]
RP VARIANTS NF1 MET-2164 AND ASN-2192.
RX PubMed=1302608; DOI=10.1093/hmg/1.9.735;
RA Upadhyaya M., Shen M.H., Cherryson A., Farnham J., Maynard J.,
RA Huson S.M., Harper P.S.;
RT "Analysis of mutations at the neurofibromatosis 1 (NF1) locus.";
RL Hum. Mol. Genet. 1:735-740(1992).
RN [38]
RP VARIANT GLY-HIS-GLU-GLN-GLN-LYS-LEU-PRO-ALA-ALA-THR-LEU-ALA-LEU-1733
RP INS.
RX PubMed=8317503;
RA Tassabehji M., Strachan T., Sharland M., Colley A., Donnai D.,
RA Harris R., Thakker N.;
RT "Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon
RT in a family with features of Watson syndrome and Noonan syndrome.";
RL Am. J. Hum. Genet. 53:90-95(1993).
RN [39]
RP VARIANT MET-991 DEL.
RX PubMed=7904209; DOI=10.1093/hmg/2.11.1861;
RA Shen M.H., Harper P.S., Upadhyaya M.;
RT "Neurofibromatosis type 1 (NF1): the search for mutations by PCR-
RT heteroduplex analysis on Hydrolink gels.";
RL Hum. Mol. Genet. 2:1861-1864(1993).
RN [40]
RP VARIANTS NF1 ASP-1166 AND ARG-1440.
RX PubMed=7981679; DOI=10.1093/hmg/3.7.1109;
RA Purandare S.M., Lanyon W.G., Connor J.M.;
RT "Characterisation of inherited and sporadic mutations in
RT neurofibromatosis type-1.";
RL Hum. Mol. Genet. 3:1109-1115(1994).
RN [41]
RP VARIANT NF1 2387-ASN-PHE-2388 DEL.
RX PubMed=8081387; DOI=10.1002/humu.1380030404;
RA Abernathy C.R., Colman S.D., Kousseff B.G., Wallace M.R.;
RT "Two NF1 mutations: frameshift in the GAP-related domain, and loss of
RT two codons toward the 3' end of the gene.";
RL Hum. Mutat. 3:347-352(1994).
RN [42]
RP VARIANT NF1 ALA-2631.
RX PubMed=8544190;
RA Upadhyaya M., Maynard J., Osborn M.J., Huson S.M., Ponder M.,
RA Ponder B.A.J., Harper P.S.;
RT "Characterisation of germline mutations in the neurofibromatosis type
RT 1 (NF1) gene.";
RL J. Med. Genet. 32:706-710(1995).
RN [43]
RP VARIANT NF1 ARG-629.
RX PubMed=8834249; DOI=10.1007/s004390050079;
RA Gasparini P., D'Agruma L., de Cillis G.P., Balestrazzi P.,
RA Mingarelli R., Zelante L.;
RT "Scanning the first part of the neurofibromatosis type 1 gene by RNA-
RT SSCP: identification of three novel mutations and of two new
RT polymorphisms.";
RL Hum. Genet. 97:492-495(1996).
RN [44]
RP VARIANT NF1 ARG-1035.
RX PubMed=8807336;
RX DOI=10.1002/(SICI)1098-1004(1996)8:1<51::AID-HUMU7>3.3.CO;2-Z;
RA Wu R., Legius E., Robberecht W., Dumoulin M., Cassiman J.-J.,
RA Fryns J.-P.;
RT "Neurofibromatosis type I gene mutation in a patient with features of
RT LEOPARD syndrome.";
RL Hum. Mutat. 8:51-56(1996).
RN [45]
RP VARIANTS NF1 SER-1412; GLN-1440; GLU-1444 AND GLY-1489.
RX PubMed=9003501; DOI=10.1007/s004390050317;
RA Upadhyaya M., Osborn M.J., Maynard J., Kim M.R., Tamanoi F.,
RA Cooper D.N.;
RT "Mutational and functional analysis of the neurofibromatosis type 1
RT (NF1) gene.";
RL Hum. Genet. 99:88-92(1997).
RN [46]
RP VARIANTS NF1 ARG-844 AND PRO-898.
RX PubMed=9150739; DOI=10.1007/s004390050427;
RA Maynard J., Krawczak M., Upadhyaya M.;
RT "Characterization and significance of nine novel mutations in exon 16
RT of the neurofibromatosis type 1 (NF1) gene.";
RL Hum. Genet. 99:674-676(1997).
RN [47]
RP VARIANT NF1 ARG-1952.
RX PubMed=9101300;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<366::AID-HUMU12>3.3.CO;2-O;
RA Hudson J., Wu C.L., Tassabehji M., Summers E.M., Simon S., Super M.,
RA Donnai D., Thakker N.;
RT "Novel and recurrent mutations in the neurofibromatosis type 1 (NF1)
RT gene.";
RL Hum. Mutat. 9:366-367(1997).
RN [48]
RP VARIANTS NF1 GLY-338 AND TRP-1611.
RX PubMed=9298829;
RX DOI=10.1002/(SICI)1098-1004(1997)10:3<248::AID-HUMU14>3.3.CO;2-D;
RA Upadhyaya M., Maynard J., Osborn M.J., Harper P.S.;
RT "Six novel mutations in the neurofibromatosis type 1 (NF1) gene.";
RL Hum. Mutat. 10:248-250(1997).
RN [49]
RP VARIANT NF1 PRO-1276.
RX PubMed=9668168; DOI=10.1093/hmg/7.8.1261;
RA Klose A., Ahmadian M.R., Schuelke M., Scheffzek K., Hoffmeyer S.,
RA Gewies A., Schmitz F., Kaufmann D., Peters H., Wittinghofer A.,
RA Nuernberg P.;
RT "Selective disactivation of neurofibromin GAP activity in
RT neurofibromatosis type 1 (NF1).";
RL Hum. Mol. Genet. 7:1261-1268(1998).
RN [50]
RP VARIANT NF1 GLY-1204, AND VARIANT HIS-765.
RX PubMed=10336779;
RX DOI=10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.3.CO;2-U;
RA Krkljus S., Abernathy C.R., Johnson J.S., Williams C.A.,
RA Driscoll D.J., Zori R., Stalker H.J., Rasmussen S.A., Collins F.S.,
RA Kousseff B.G., Baumbach L., Wallace M.R.;
RT "Analysis of CpG C-to-T mutations in neurofibromatosis type 1.";
RL Hum. Mutat. 11:411-411(1998).
RN [51]
RP VARIANT NF1 PRO-508.
RX PubMed=11258625;
RA Messiaen L.M., Callens T., Roux K.J., Mortier G.R., De Paepe A.,
RA Abramowicz M., Pericak-Vance M.A., Vance J.M., Wallace M.R.;
RT "Exon 10b of the NF1 gene represents a mutational hotspot and harbors
RT a recurrent missense mutation Y489C associated with aberrant
RT splicing.";
RL Genet. Med. 1:248-253(1999).
RN [52]
RP VARIANT NF1 PRO-1446.
RX PubMed=10220149;
RX DOI=10.1002/(SICI)1098-1004(1999)13:4<337::AID-HUMU12>3.0.CO;2-F;
RA Peters H., Hess D., Fahsold R., Schuelke M.;
RT "A novel mutation L1425P in the GAP-region of the NF1 gene detected by
RT temperature gradient gel electrophoresis (TGGE).";
RL Hum. Mutat. 13:337-337(1999).
RN [53]
RP VARIANTS NF1 PRO-216; PRO-357; CYS-491; PRO-549; THR-581; ARG-583;
RP PHE-665; PRO-695; PRO-763; SER-777; LYS-780; PRO-781; PRO-847;
RP SER-1156; PRO-1250; GLN-1276; PRO-1276; PRO-1446; VAL-1605 AND
RP ILE-2507, AND VARIANT GLU-176.
RX PubMed=10712197; DOI=10.1086/302809;
RA Fahsold R., Hoffmeyer S., Mischung C., Gille C., Ehlers C.,
RA Kuecuekceylan N., Abdel-Nour M., Gewies A., Peters H., Kaufmann D.,
RA Buske A., Tinschert S., Nuernberg P.;
RT "Minor lesion mutational spectrum of the entire NF1 gene does not
RT explain its high mutability but points to a functional domain upstream
RT of the GAP-related domain.";
RL Am. J. Hum. Genet. 66:790-818(2000).
RN [54]
RP VARIANTS NF1 SER-117; TRP-1204; PRO-1446 AND 2387-ASN-PHE-2388 DEL.
RX PubMed=10607834; DOI=10.1093/hmg/9.2.237;
RA Ars E., Serra E., Garcia J., Kruyer H., Gaona A., Lazaro C.,
RA Estivill X.;
RT "Mutations affecting mRNA splicing are the most common molecular
RT defects in patients with neurofibromatosis type 1.";
RL Hum. Mol. Genet. 9:237-247(2000).
RN [55]
RP ERRATUM.
RA Ars E., Serra E., Garcia J., Kruyer H., Gaona A., Lazaro C.,
RA Estivill X.;
RL Hum. Mol. Genet. 9:659-659(2000).
RN [56]
RP VARIANT NF1 PHE-844.
RX PubMed=10980545;
RX DOI=10.1002/1098-1004(200009)16:3<274::AID-HUMU21>3.3.CO;2-6;
RA Boulandet E.G., Pantel J., Cazeneuve C., Van Gijn M., Vidaud D.,
RA Lemay S., Martin J., Zeller J., Revuz J., Goossens M., Amselem S.,
RA Wolkenstein P.;
RT "NF1 gene analysis focused on CpG-rich exons in a cohort of 93
RT patients with neurofibromatosis type 1.";
RL Hum. Mutat. 16:274-275(2000).
RN [57]
RP VARIANT SPINAL FSNF PRO-2088.
RX PubMed=11704931; DOI=10.1086/324648;
RA Kaufmann D., Mueller R., Bartelt B., Wolf M., Kunzi-Rapp K.,
RA Hanemann C.O., Fahsold R., Hein C., Vogel W., Assum G.;
RT "Spinal neurofibromatosis without cafe-au-lait macules in two families
RT with null mutations of the NF1 gene.";
RL Am. J. Hum. Genet. 69:1395-1400(2001).
RN [58]
RP VARIANTS NF1 LYS-780; CYS-784; PRO-1147; CYS-1193; ARG-1444; SER-1785;
RP ASN-2012 AND LYS-2357.
RX PubMed=11735023; DOI=10.1007/s004390100594;
RA Han S.S., Cooper D.N., Upadhyaya M.N.;
RT "Evaluation of denaturing high performance liquid chromatography
RT (DHPLC) for the mutational analysis of the neurofibromatosis type 1 (
RT NF1) gene.";
RL Hum. Genet. 109:487-497(2001).
RN [59]
RP VARIANTS NF1 PHE-82; ARG-784 AND GLU-1444.
RX PubMed=11857752; DOI=10.1002/humu.9018;
RA Kluwe L., Friedrich R.E., Korf B., Fahsold R., Mautner V.-F.;
RT "NF1 mutations in neurofibromatosis 1 patients with plexiform
RT neurofibromas.";
RL Hum. Mutat. 19:309-309(2002).
RN [60]
RP VARIANT NFNS GLU-1459 DEL.
RX PubMed=12707950; DOI=10.1002/ajmg.a.20023;
RA Baralle D., Mattocks C., Kalidas K., Elmslie F., Whittaker J.,
RA Lees M., Ragge N., Patton M.A., Winter R.M., ffrench-Constant C.;
RT "Different mutations in the NF1 gene are associated with
RT neurofibromatosis-Noonan syndrome (NFNS).";
RL Am. J. Med. Genet. A 119:1-8(2003).
RN [61]
RP VARIANTS NF1 TYR-93; VAL-604; ARG-844 AND PRO-898, AND VARIANTS
RP ASP-74; GLU-176; ARG-712 AND GLN-1276.
RX PubMed=12522551; DOI=10.1007/s00439-002-0858-4;
RA Wang Q., Montmain G., Ruano E., Upadhyaya M., Dudley S., Liskay R.M.,
RA Thibodeau S.N., Puisieux A.;
RT "Neurofibromatosis type 1 gene as a mutational target in a mismatch
RT repair-deficient cell type.";
RL Hum. Genet. 112:117-123(2003).
RN [62]
RP VARIANTS NF1 LYS-780; PRO-847; GLU-848 AND ARG-968; ASN-1444; LEU-1953
RP DEL AND ARG-2001.
RX PubMed=12552569; DOI=10.1002/humu.9111;
RA De Luca A., Buccino A., Gianni D., Mangino M., Giustini S.,
RA Richetta A., Divona L., Calvieri S., Mingarelli R., Dallapiccola B.;
RT "NF1 gene analysis based on DHPLC.";
RL Hum. Mutat. 21:171-172(2003).
RN [63]
RP VARIANTS NF1 ARG-578; PRO-920 AND ALA-2221.
RX PubMed=12746402; DOI=10.1136/jmg.40.5.368;
RA Kluwe L., Tatagiba M., Fuensterer C., Mautner V.F.;
RT "NF1 mutations and clinical spectrum in patients with spinal
RT neurofibromas.";
RL J. Med. Genet. 40:368-371(2003).
RN [64]
RP VARIANT NF1 VAL-186, AND CHARACTERIZATION OF VARIANT NF1 VAL-186.
RX PubMed=15523642; DOI=10.1002/humu.20103;
RA Zatkova A., Messiaen L., Vandenbroucke I., Wieser R., Fonatsch C.,
RA Krainer A.R., Wimmer K.;
RT "Disruption of exonic splicing enhancer elements is the principal
RT cause of exon skipping associated with seven nonsense or missense
RT alleles of NF1.";
RL Hum. Mutat. 24:491-501(2004).
RN [65]
RP VARIANTS NF1 ASN-157; ARG-629; SER-777; LYS-780; ARG-784; PRO-847;
RP GLU-848; ARG-968; ASN-1444; LEU-1953 DEL AND ARG-2001, AND VARIANT
RP GLU-176.
RX PubMed=15146469; DOI=10.1002/humu.9245;
RA De Luca A., Schirinzi A., Buccino A., Bottillo I., Sinibaldi L.,
RA Torrente I., Ciavarella A., Dottorini T., Porciello R., Giustini S.,
RA Calvieri S., Dallapiccola B.;
RT "Novel and recurrent mutations in the NF1 gene in Italian patients
RT with neurofibromatosis type 1.";
RL Hum. Mutat. 23:629-629(2004).
RN [66]
RP VARIANTS NF1 ARG-31; PRO-145; ARG-324; VAL-337; CYS-489; PRO-532;
RP ARG-574; ARG-629; PHE-665; PHE-844; PRO-844; MET-991 DEL; VAL-1073;
RP ARG-1196; GLY-1276; GLN-1276; GLU-1430; GLU-1459 DEL AND GLY-1489, AND
RP VARIANTS GLU-176 AND CYS-873.
RX PubMed=15060124; DOI=10.1136/jmg.2003.011890;
RA Mattocks C., Baralle D., Tarpey P., ffrench-Constant C., Bobrow M.,
RA Whittaker J.;
RT "Automated comparative sequence analysis identifies mutations in 89%
RT of NF1 patients and confirms a mutation cluster in exons 11-17
RT distinct from the GAP related domain.";
RL J. Med. Genet. 41:E48-E48(2004).
RN [67]
RP VARIANT NF1 PRO-1243.
RX PubMed=15520408; DOI=10.1136/jmg.2004.021683;
RA Ferner R.E., Hughes R.A.C., Hall S.M., Upadhyaya M., Johnson M.R.;
RT "Neurofibromatous neuropathy in neurofibromatosis 1 (NF1).";
RL J. Med. Genet. 41:837-841(2004).
RN [68]
RP VARIANT NF1 ARG-844.
RX PubMed=15948193; DOI=10.1002/ajmg.a.30813;
RA Bertola D.R., Pereira A.C., Passetti F., de Oliveira P.S.L.,
RA Messiaen L., Gelb B.D., Kim C.A., Krieger J.E.;
RT "Neurofibromatosis-Noonan syndrome: molecular evidence of the
RT concurrence of both disorders in a patient.";
RL Am. J. Med. Genet. A 136:242-245(2005).
RN [69]
RP VARIANTS NFNS ARG-194; GLU-1444; THR-1451; LEU-1453 AND GLU-1459 DEL.
RX PubMed=16380919; DOI=10.1086/498454;
RA De Luca A., Bottillo I., Sarkozy A., Carta C., Neri C., Bellacchio E.,
RA Schirinzi A., Conti E., Zampino G., Battaglia A., Majore S.,
RA Rinaldi M.M., Carella M., Marino B., Pizzuti A., Digilio M.C.,
RA Tartaglia M., Dallapiccola B.;
RT "NF1 gene mutations represent the major molecular event underlying
RT neurofibromatosis-Noonan syndrome.";
RL Am. J. Hum. Genet. 77:1092-1101(2005).
RN [70]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-1187; LEU-1951 AND ARG-2745.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [71]
RP VARIANT NFNS PHE-1411.
RX PubMed=19845691; DOI=10.1111/j.1399-0004.2009.01233.x;
RA Nystrom A.M., Ekvall S., Allanson J., Edeby C., Elinder M.,
RA Holmstrom G., Bondeson M.L., Anneren G.;
RT "Noonan syndrome and neurofibromatosis type I in a family with a novel
RT mutation in NF1.";
RL Clin. Genet. 76:524-534(2009).
RN [72]
RP VARIANTS GLU-176; THR-330; ASP-393; LEU-393; PRO-519; THR-776 AND
RP PHE-1484.
RX PubMed=22108604; DOI=10.1038/ejhg.2011.207;
RA Thomas L., Spurlock G., Eudall C., Thomas N.S., Mort M., Hamby S.E.,
RA Chuzhanova N., Brems H., Legius E., Cooper D.N., Upadhyaya M.;
RT "Exploring the somatic NF1 mutational spectrum associated with NF1
RT cutaneous neurofibromas.";
RL Eur. J. Hum. Genet. 20:411-419(2012).
RN [73]
RP VARIANT NF1 THR-160.
RX PubMed=21838856; DOI=10.1186/1897-4287-9-6;
RA Ponti G., Losi L., Martorana D., Priola M., Boni E., Pollio A.,
RA Neri T.M., Seidenari S.;
RT "Clinico-pathological and biomolecular findings in Italian patients
RT with multiple cutaneous neurofibromas.";
RL Hered. Cancer Clin. Pract. 9:6-6(2011).
CC -!- FUNCTION: Stimulates the GTPase activity of Ras. NF1 shows greater
CC affinity for Ras GAP, but lower specific activity. May be a
CC regulator of Ras activity.
CC -!- INTERACTION:
CC P05067:APP; NbExp=3; IntAct=EBI-1172917, EBI-77613;
CC P34741:SDC2; NbExp=4; IntAct=EBI-1172917, EBI-1172957;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Comment=Experimental confirmation may be lacking for some
CC isoforms;
CC Name=2; Synonyms=Type II;
CC IsoId=P21359-1; Sequence=Displayed;
CC Name=1; Synonyms=Type I;
CC IsoId=P21359-2; Sequence=VSP_001628;
CC Name=3;
CC IsoId=P21359-3; Sequence=VSP_001629, VSP_001630;
CC Name=4;
CC IsoId=P21359-4; Sequence=VSP_001631, VSP_001632;
CC Name=5;
CC IsoId=P21359-5; Sequence=VSP_043467, VSP_043468;
CC Name=6;
CC IsoId=P21359-6; Sequence=VSP_001628, VSP_053587;
CC -!- TISSUE SPECIFICITY: Detected in brain, peripheral nerve, lung,
CC colon and muscle.
CC -!- DOMAIN: Binds phospholipids via its C-terminal CRAL-TRIO domain.
CC Binds primarily glycerophospholipids with monounsaturated C18:1
CC and/or C16:1 fatty acid moieties and a phosphatidylethanolamine or
CC phosphatidylcholine headgroup. Has lesser affinity for lipids
CC containing phosphatidylserine and phosphatidylinositol.
CC -!- RNA EDITING: Modified_positions=1306; Note=The stop codon (UGA) at
CC position 1306 is created by RNA editing. Various levels of RNA
CC editing occurs in peripheral nerve-sheath tumor samples (PNSTs)
CC from patients with NF1. Preferentially observed in transcripts
CC containing exon 23A.
CC -!- DISEASE: Neurofibromatosis 1 (NF1) [MIM:162200]: A disease
CC characterized by patches of skin pigmentation (cafe-au-lait
CC spots), Lisch nodules of the iris, tumors in the peripheral
CC nervous system and fibromatous skin tumors. Individuals with the
CC disorder have increased susceptibility to the development of
CC benign and malignant tumors. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the
CC hematopoietic stem cell compartment with proliferation of
CC differentiated progeny. Patients have splenomegaly, enlarged lymph
CC nodes, rashes, and hemorrhages. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Watson syndrome (WS) [MIM:193520]: A syndrome
CC characterized by the presence of pulmonary stenosis, cafe-au-lait
CC spots, and mental retardation. It is considered as an atypical
CC form of neurofibromatosis. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Familial spinal neurofibromatosis (FSNF) [MIM:162210]:
CC Considered to be an alternative form of neurofibromatosis, showing
CC multiple spinal tumors. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321]:
CC Characterized by manifestations of both NF1 and Noonan syndrome
CC (NS). NS is a disorder characterized by dysmorphic facial
CC features, short stature, hypertelorism, cardiac anomalies,
CC deafness, motor delay, and a bleeding diathesis. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of
CC the large intestine (the colon) and the rectum. Genetic
CC alterations are often associated with progression from
CC premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
CC factors for cancer of the colon and rectum include colon polyps,
CC long-standing ulcerative colitis, and genetic family history.
CC Note=The gene represented in this entry may be involved in disease
CC pathogenesis.
CC -!- SIMILARITY: Contains 1 CRAL-TRIO domain.
CC -!- SIMILARITY: Contains 1 Ras-GAP domain.
CC -!- CAUTION: Was originally (PubMed:8807336) thought to be associated
CC with LEOPARD (LS), an autosomal dominant syndrome.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA59923.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=NF1 Genetic Mutation Analysis Consortium;
CC URL="http://www.upmc.edu/Neurofibro/NNFFconsortium.htm";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NF1ID134.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NF1";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nf1/";
CC -!- WEB RESOURCE: Name=Mendelian genes neurofibromin 1 (NF1);
CC Note=Leiden Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/NF1";
CC -----------------------------------------------------------------------
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DR EMBL; M89914; AAA59925.1; -; mRNA.
DR EMBL; M82814; AAA59924.1; -; mRNA.
DR EMBL; M60496; AAA59928.1; -; mRNA.
DR EMBL; D12625; BAA02150.1; -; mRNA.
DR EMBL; M38106; AAA74897.1; -; mRNA.
DR EMBL; M38107; AAB59558.1; -; mRNA.
DR EMBL; D42072; BAA07669.1; -; mRNA.
DR EMBL; AY796305; AAV50004.1; -; Genomic_DNA.
DR EMBL; AC004222; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC079915; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC134669; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135724; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC138207; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC139072; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471147; EAW80272.1; -; Genomic_DNA.
DR EMBL; CH471147; EAW80275.1; -; Genomic_DNA.
DR EMBL; AH000834; AAA18483.1; -; Genomic_DNA.
DR EMBL; Y07853; CAA69179.1; -; Genomic_DNA.
DR EMBL; U17690; AAB48380.1; -; Genomic_DNA.
DR EMBL; U17680; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17681; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17682; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17683; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17684; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17685; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17686; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17687; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17688; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17689; AAB48380.1; JOINED; Genomic_DNA.
DR EMBL; U17690; AAB48379.1; -; Genomic_DNA.
DR EMBL; U17680; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17681; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17682; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17683; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17684; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17685; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17687; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17688; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17689; AAB48379.1; JOINED; Genomic_DNA.
DR EMBL; U17656; AAB48373.1; -; Genomic_DNA.
DR EMBL; U17659; AAB48374.1; -; Genomic_DNA.
DR EMBL; U17662; AAB48375.1; -; Genomic_DNA.
DR EMBL; U17668; AAB48376.1; -; Genomic_DNA.
DR EMBL; U17667; AAB48376.1; JOINED; Genomic_DNA.
DR EMBL; U17673; AAB48377.1; -; Genomic_DNA.
DR EMBL; U17677; AAB48378.1; -; Genomic_DNA.
DR EMBL; U17676; AAB48378.1; JOINED; Genomic_DNA.
DR EMBL; M60915; AAA59921.1; -; mRNA.
DR EMBL; M60915; AAA59922.1; -; mRNA.
DR EMBL; M61213; AAA59923.1; ALT_INIT; mRNA.
DR EMBL; S51751; AAB24636.1; -; mRNA.
DR EMBL; D10490; BAA01371.1; -; mRNA.
DR PIR; B55282; B55282.
DR PIR; I78852; I78852.
DR RefSeq; NP_000258.1; NM_000267.3.
DR RefSeq; NP_001035957.1; NM_001042492.2.
DR RefSeq; NP_001121619.1; NM_001128147.2.
DR UniGene; Hs.113577; -.
DR PDB; 1NF1; X-ray; 2.50 A; A=1198-1551.
DR PDB; 2D4Q; X-ray; 2.30 A; A/B=1581-1837.
DR PDB; 2E2X; X-ray; 2.50 A; A/B=1566-1837.
DR PDB; 3P7Z; X-ray; 2.65 A; A/B=1566-1837.
DR PDB; 3PEG; X-ray; 2.52 A; A=1566-1837.
DR PDB; 3PG7; X-ray; 2.19 A; A/B=1581-1837.
DR PDBsum; 1NF1; -.
DR PDBsum; 2D4Q; -.
DR PDBsum; 2E2X; -.
DR PDBsum; 3P7Z; -.
DR PDBsum; 3PEG; -.
DR PDBsum; 3PG7; -.
DR ProteinModelPortal; P21359; -.
DR SMR; P21359; 1206-1550, 1568-1837.
DR IntAct; P21359; 12.
DR MINT; MINT-1504522; -.
DR STRING; 9606.ENSP00000351015; -.
DR PhosphoSite; P21359; -.
DR DMDM; 548350; -.
DR PaxDb; P21359; -.
DR PRIDE; P21359; -.
DR Ensembl; ENST00000356175; ENSP00000348498; ENSG00000196712.
DR Ensembl; ENST00000358273; ENSP00000351015; ENSG00000196712.
DR Ensembl; ENST00000431387; ENSP00000412921; ENSG00000196712.
DR GeneID; 4763; -.
DR KEGG; hsa:4763; -.
DR UCSC; uc002hgg.3; human.
DR CTD; 4763; -.
DR GeneCards; GC17P029421; -.
DR HGNC; HGNC:7765; NF1.
DR HPA; CAB004786; -.
DR MIM; 114500; phenotype.
DR MIM; 162200; phenotype.
DR MIM; 162210; phenotype.
DR MIM; 193520; phenotype.
DR MIM; 601321; phenotype.
DR MIM; 607785; phenotype.
DR MIM; 613113; gene.
DR neXtProt; NX_P21359; -.
DR Orphanet; 97685; 17q11 microdeletion syndrome.
DR Orphanet; 139474; 17q11.2 microduplication syndrome.
DR Orphanet; 79428; Familial segmental neurofibromatosis.
DR Orphanet; 79429; Familial spinal neurofibromatosis.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 636; Neurofibromatosis type 1.
DR Orphanet; 648; Noonan syndrome.
DR Orphanet; 3444; Watson syndrome.
DR PharmGKB; PA31572; -.
DR eggNOG; COG5261; -.
DR HOGENOM; HOG000047020; -.
DR HOVERGEN; HBG006486; -.
DR InParanoid; P21359; -.
DR KO; K08052; -.
DR OMA; IDFTHTC; -.
DR OrthoDB; EOG74J96W; -.
DR PhylomeDB; P21359; -.
DR SignaLink; P21359; -.
DR ChiTaRS; NF1; human.
DR EvolutionaryTrace; P21359; -.
DR GeneWiki; Neurofibromin_1; -.
DR GenomeRNAi; 4763; -.
DR NextBio; 18348; -.
DR PRO; PR:P21359; -.
DR ArrayExpress; P21359; -.
DR Bgee; P21359; -.
DR CleanEx; HS_NF1; -.
DR Genevestigator; P21359; -.
DR GO; GO:0030424; C:axon; IDA:HGNC.
DR GO; GO:0005737; C:cytoplasm; ISS:HGNC.
DR GO; GO:0030425; C:dendrite; IDA:HGNC.
DR GO; GO:0031235; C:intrinsic to cytoplasmic side of plasma membrane; IBA:RefGenome.
DR GO; GO:0005634; C:nucleus; ISS:HGNC.
DR GO; GO:0005099; F:Ras GTPase activator activity; IDA:HGNC.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:HGNC.
DR GO; GO:0030325; P:adrenal gland development; ISS:HGNC.
DR GO; GO:0048844; P:artery morphogenesis; ISS:HGNC.
DR GO; GO:0048593; P:camera-type eye morphogenesis; ISS:HGNC.
DR GO; GO:0021987; P:cerebral cortex development; ISS:HGNC.
DR GO; GO:0030199; P:collagen fibril organization; ISS:HGNC.
DR GO; GO:0021897; P:forebrain astrocyte development; ISS:HGNC.
DR GO; GO:0048853; P:forebrain morphogenesis; ISS:HGNC.
DR GO; GO:0007507; P:heart development; ISS:HGNC.
DR GO; GO:0001889; P:liver development; ISS:HGNC.
DR GO; GO:0000165; P:MAPK cascade; ISS:HGNC.
DR GO; GO:0001656; P:metanephros development; ISS:HGNC.
DR GO; GO:0022011; P:myelination in peripheral nervous system; ISS:HGNC.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0048712; P:negative regulation of astrocyte differentiation; IEA:Ensembl.
DR GO; GO:0030336; P:negative regulation of cell migration; IMP:MGI.
DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IMP:HGNC.
DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; ISS:UniProtKB.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISS:HGNC.
DR GO; GO:0007406; P:negative regulation of neuroblast proliferation; ISS:HGNC.
DR GO; GO:0046929; P:negative regulation of neurotransmitter secretion; IEA:Ensembl.
DR GO; GO:0048715; P:negative regulation of oligodendrocyte differentiation; ISS:HGNC.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0035021; P:negative regulation of Rac protein signal transduction; IEA:Ensembl.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IBA:RefGenome.
DR GO; GO:0042992; P:negative regulation of transcription factor import into nucleus; ISS:HGNC.
DR GO; GO:0021915; P:neural tube development; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; ISS:HGNC.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase cascade; ISS:HGNC.
DR GO; GO:0043473; P:pigmentation; ISS:HGNC.
DR GO; GO:0045762; P:positive regulation of adenylate cyclase activity; ISS:HGNC.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:HGNC.
DR GO; GO:0007265; P:Ras protein signal transduction; ISS:HGNC.
DR GO; GO:0045765; P:regulation of angiogenesis; IMP:HGNC.
DR GO; GO:0043535; P:regulation of blood vessel endothelial cell migration; IMP:HGNC.
DR GO; GO:0045124; P:regulation of bone resorption; ISS:HGNC.
DR GO; GO:0001952; P:regulation of cell-matrix adhesion; ISS:HGNC.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0032228; P:regulation of synaptic transmission, GABAergic; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; ISS:HGNC.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR GO; GO:0048745; P:smooth muscle tissue development; ISS:HGNC.
DR GO; GO:0021510; P:spinal cord development; ISS:HGNC.
DR GO; GO:0048485; P:sympathetic nervous system development; ISS:HGNC.
DR GO; GO:0008542; P:visual learning; ISS:HGNC.
DR GO; GO:0042060; P:wound healing; ISS:HGNC.
DR Gene3D; 1.25.10.10; -; 6.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR001251; CRAL-TRIO_dom.
DR InterPro; IPR028553; Neurofibromin.
DR InterPro; IPR001936; RasGAP.
DR InterPro; IPR023152; RasGAP_CS.
DR InterPro; IPR008936; Rho_GTPase_activation_prot.
DR PANTHER; PTHR10194:SF7; PTHR10194:SF7; 1.
DR Pfam; PF13716; CRAL_TRIO_2; 1.
DR Pfam; PF00616; RasGAP; 1.
DR SMART; SM00323; RasGAP; 1.
DR SMART; SM00516; SEC14; 1.
DR SUPFAM; SSF48350; SSF48350; 1.
DR SUPFAM; SSF48371; SSF48371; 11.
DR PROSITE; PS50191; CRAL_TRIO; 1.
DR PROSITE; PS00509; RAS_GTPASE_ACTIV_1; 1.
DR PROSITE; PS50018; RAS_GTPASE_ACTIV_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; GTPase activation; Lipid-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; RNA editing; Tumor suppressor.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 2839 Neurofibromin.
FT /FTId=PRO_0000010773.
FT CHAIN 2 1305 Neurofibromin truncated.
FT /FTId=PRO_0000010774.
FT DOMAIN 1235 1451 Ras-GAP.
FT DOMAIN 1580 1738 CRAL-TRIO.
FT REGION 1580 1837 Lipid binding.
FT COMPBIAS 1352 1355 Poly-Ser.
FT MOD_RES 2 2 N-acetylalanine (By similarity).
FT MOD_RES 864 864 Phosphoserine.
FT MOD_RES 876 876 Phosphoserine.
FT MOD_RES 2188 2188 Phosphoserine.
FT MOD_RES 2515 2515 Phosphoserine.
FT MOD_RES 2521 2521 Phosphoserine.
FT MOD_RES 2543 2543 Phosphoserine.
FT MOD_RES 2817 2817 Phosphoserine.
FT VAR_SEQ 548 551 ALLV -> VRGK (in isoform 3).
FT /FTId=VSP_001629.
FT VAR_SEQ 552 2839 Missing (in isoform 3).
FT /FTId=VSP_001630.
FT VAR_SEQ 574 593 SSQMLFYICKKLTSHQMLSS -> RYMYFYFLNSTFKFYFV
FT FLS (in isoform 5).
FT /FTId=VSP_043467.
FT VAR_SEQ 594 2839 Missing (in isoform 5).
FT /FTId=VSP_043468.
FT VAR_SEQ 1371 1391 Missing (in isoform 1 and isoform 6).
FT /FTId=VSP_001628.
FT VAR_SEQ 1591 1598 SIFYQAGT -> TPPPEPET (in isoform 4).
FT /FTId=VSP_001631.
FT VAR_SEQ 1599 2839 Missing (in isoform 4).
FT /FTId=VSP_001632.
FT VAR_SEQ 2792 2792 P -> PASLPCSNSAVFMQLFPHQ (in isoform 6).
FT /FTId=VSP_053587.
FT VARIANT 31 31 H -> R (in NF1; dbSNP:rs199474725).
FT /FTId=VAR_032459.
FT VARIANT 74 74 A -> D (in mismatch repair deficient
FT cancer cells; dbSNP:rs199474726).
FT /FTId=VAR_017550.
FT VARIANT 80 80 Y -> C.
FT /FTId=VAR_022254.
FT VARIANT 80 80 Y -> S (in dbSNP:rs4795581).
FT /FTId=VAR_049135.
FT VARIANT 82 82 S -> F (in NF1; dbSNP:rs199474729).
FT /FTId=VAR_021730.
FT VARIANT 93 93 C -> Y (in NF1; dbSNP:rs199474728).
FT /FTId=VAR_017551.
FT VARIANT 117 117 I -> S (in NF1; dbSNP:rs199474731).
FT /FTId=VAR_010989.
FT VARIANT 145 145 L -> P (in NF1; dbSNP:rs199474734).
FT /FTId=VAR_032460.
FT VARIANT 157 157 I -> N (in NF1; dbSNP:rs199474744).
FT /FTId=VAR_021731.
FT VARIANT 160 160 R -> T (in NF1; dbSNP:rs199474752).
FT /FTId=VAR_065888.
FT VARIANT 176 176 D -> E (found in mismatch repair
FT deficient cancer cells; also found in a
FT cutaneous neurofibroma from a patient
FT with neurofibromatosis; somatic mutation;
FT dbSNP:rs112306990).
FT /FTId=VAR_017552.
FT VARIANT 186 186 D -> V (in NF1; reduced splicing
FT enhancement).
FT /FTId=VAR_032461.
FT VARIANT 194 194 L -> R (in NFNS; dbSNP:rs199474753).
FT /FTId=VAR_032462.
FT VARIANT 216 216 L -> P (in NF1; dbSNP:rs199474756).
FT /FTId=VAR_021732.
FT VARIANT 324 324 C -> R (in NF1; dbSNP:rs199474735).
FT /FTId=VAR_032463.
FT VARIANT 330 330 A -> T (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474767).
FT /FTId=VAR_067201.
FT VARIANT 337 337 E -> V (in NF1; dbSNP:rs199474736).
FT /FTId=VAR_032464.
FT VARIANT 338 338 D -> G (in NF1; dbSNP:rs199474773).
FT /FTId=VAR_010990.
FT VARIANT 357 357 L -> P (in NF1; dbSNP:rs137854563).
FT /FTId=VAR_021733.
FT VARIANT 393 393 H -> D (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474768).
FT /FTId=VAR_067202.
FT VARIANT 393 393 H -> L (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474769).
FT /FTId=VAR_067203.
FT VARIANT 489 489 Y -> C (in NF1; dbSNP:rs137854557).
FT /FTId=VAR_032465.
FT VARIANT 491 491 Y -> C (in NF1; dbSNP:rs199474757).
FT /FTId=VAR_021734.
FT VARIANT 508 508 L -> P (in NF1; dbSNP:rs137854558).
FT /FTId=VAR_010991.
FT VARIANT 519 519 Q -> P (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474770).
FT /FTId=VAR_067204.
FT VARIANT 532 532 L -> P (in NF1; dbSNP:rs199474737).
FT /FTId=VAR_032466.
FT VARIANT 549 549 L -> P (in NF1; dbSNP:rs199474758).
FT /FTId=VAR_021735.
FT VARIANT 574 574 S -> R (in NF1).
FT /FTId=VAR_032467.
FT VARIANT 578 578 L -> R (in NF1; dbSNP:rs199474774).
FT /FTId=VAR_021736.
FT VARIANT 581 581 I -> T (in NF1; dbSNP:rs199474759).
FT /FTId=VAR_021737.
FT VARIANT 583 583 K -> R (in NF1; dbSNP:rs199474760).
FT /FTId=VAR_021738.
FT VARIANT 604 604 L -> V (in NF1; dbSNP:rs142712751).
FT /FTId=VAR_017553.
FT VARIANT 629 629 G -> R (in NF1; affects splicing by
FT creating a novel splice acceptor site;
FT dbSNP:rs199474738).
FT /FTId=VAR_002653.
FT VARIANT 665 665 S -> F (in NF1; unknown pathological
FT significance; dbSNP:rs145891889).
FT /FTId=VAR_021739.
FT VARIANT 678 678 P -> L (in dbSNP:rs17881753).
FT /FTId=VAR_022255.
FT VARIANT 695 695 L -> P (in NF1; dbSNP:rs199474761).
FT /FTId=VAR_021740.
FT VARIANT 712 712 H -> R (in mismatch repair deficient
FT cancer cells; dbSNP:rs199474727).
FT /FTId=VAR_017554.
FT VARIANT 763 763 L -> P (in NF1; dbSNP:rs199474762).
FT /FTId=VAR_021741.
FT VARIANT 765 765 R -> H (in dbSNP:rs199474777).
FT /FTId=VAR_021742.
FT VARIANT 776 776 A -> T (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474771).
FT /FTId=VAR_067205.
FT VARIANT 777 777 W -> S (in NF1; dbSNP:rs199474745).
FT /FTId=VAR_021743.
FT VARIANT 780 780 T -> K (in NF1; dbSNP:rs199474746).
FT /FTId=VAR_021744.
FT VARIANT 781 781 H -> P (in NF1; dbSNP:rs199474763).
FT /FTId=VAR_021745.
FT VARIANT 784 784 W -> C (in NF1; dbSNP:rs199474778).
FT /FTId=VAR_021746.
FT VARIANT 784 784 W -> R (in NF1; dbSNP:rs199474730).
FT /FTId=VAR_021747.
FT VARIANT 844 844 L -> F (in NF1; dbSNP:rs199474785).
FT /FTId=VAR_010992.
FT VARIANT 844 844 L -> P (in NF1; dbSNP:rs137854566).
FT /FTId=VAR_032468.
FT VARIANT 844 844 L -> R (in NF1; sporadic;
FT dbSNP:rs137854566).
FT /FTId=VAR_002654.
FT VARIANT 847 847 L -> P (in NF1; dbSNP:rs199474747).
FT /FTId=VAR_021748.
FT VARIANT 848 848 G -> E (in NF1; dbSNP:rs199474748).
FT /FTId=VAR_021749.
FT VARIANT 873 873 R -> C (in dbSNP:rs199474739).
FT /FTId=VAR_032469.
FT VARIANT 898 898 L -> P (in NF1; sporadic;
FT dbSNP:rs199474786).
FT /FTId=VAR_002655.
FT VARIANT 920 920 L -> P (in NF1; patient with cafe-au-lait
FT spots; may be a distinct form of NF1;
FT dbSNP:rs199474775).
FT /FTId=VAR_021750.
FT VARIANT 968 968 M -> R (in NF1; dbSNP:rs199474749).
FT /FTId=VAR_021751.
FT VARIANT 991 991 Missing (in NF1).
FT /FTId=VAR_002656.
FT VARIANT 1035 1035 M -> R (in NF1; dbSNP:rs137854553).
FT /FTId=VAR_002657.
FT VARIANT 1073 1073 M -> V (in NF1; dbSNP:rs199474740).
FT /FTId=VAR_032470.
FT VARIANT 1147 1147 L -> P (in NF1; dbSNP:rs199474779).
FT /FTId=VAR_021752.
FT VARIANT 1156 1156 N -> S (in NF1; dbSNP:rs199474764).
FT /FTId=VAR_021753.
FT VARIANT 1166 1166 G -> D (in NF1; dbSNP:rs199474787).
FT /FTId=VAR_010993.
FT VARIANT 1187 1187 L -> I (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035543.
FT VARIANT 1193 1193 F -> C (in NF1; dbSNP:rs199474780).
FT /FTId=VAR_021754.
FT VARIANT 1196 1196 L -> R (in NF1; dbSNP:rs199474741).
FT /FTId=VAR_032471.
FT VARIANT 1204 1204 R -> G (in NF1; dbSNP:rs199474732).
FT /FTId=VAR_021755.
FT VARIANT 1204 1204 R -> W (in NF1; dbSNP:rs199474732).
FT /FTId=VAR_010994.
FT VARIANT 1243 1243 L -> P (in NF1; with neurofibromatous
FT neuropathy; dbSNP:rs137854564).
FT /FTId=VAR_032472.
FT VARIANT 1250 1250 R -> P (in NF1; dbSNP:rs199474765).
FT /FTId=VAR_021756.
FT VARIANT 1276 1276 R -> G (in NF1; dbSNP:rs199474742).
FT /FTId=VAR_032473.
FT VARIANT 1276 1276 R -> P (in NF1; complete loss of GAP
FT activity; dbSNP:rs137854556).
FT /FTId=VAR_010995.
FT VARIANT 1276 1276 R -> Q (in NF1 and mismatch repair
FT deficient cancer cells;
FT dbSNP:rs137854556).
FT /FTId=VAR_017555.
FT VARIANT 1411 1411 L -> F (in NFNS; dbSNP:rs199474789).
FT /FTId=VAR_065236.
FT VARIANT 1412 1412 R -> S (in NF1; significant reduction of
FT GAP activity; dbSNP:rs137854554).
FT /FTId=VAR_010996.
FT VARIANT 1422 1422 Y -> H (in dbSNP:rs17884349).
FT /FTId=VAR_022256.
FT VARIANT 1430 1430 K -> E (in NF1).
FT /FTId=VAR_032474.
FT VARIANT 1440 1440 K -> Q (in NF1; dbSNP:rs199474790).
FT /FTId=VAR_010997.
FT VARIANT 1440 1440 K -> R (in NF1; dbSNP:rs199474788).
FT /FTId=VAR_002658.
FT VARIANT 1444 1444 K -> E (in NF1 and NFNS; significant
FT reduction of intrinsic GAP activity;
FT dbSNP:rs137854550).
FT /FTId=VAR_002659.
FT VARIANT 1444 1444 K -> N (in NF1; dbSNP:rs199474750).
FT /FTId=VAR_021757.
FT VARIANT 1444 1444 K -> R (in NF1; dbSNP:rs199474781).
FT /FTId=VAR_021758.
FT VARIANT 1446 1446 L -> P (in NF1; dbSNP:rs199474733).
FT /FTId=VAR_008129.
FT VARIANT 1451 1451 N -> T (in NFNS; dbSNP:rs199474754).
FT /FTId=VAR_032475.
FT VARIANT 1453 1453 V -> L (in NFNS; dbSNP:rs199474755).
FT /FTId=VAR_032476.
FT VARIANT 1459 1459 Missing (in NFNS).
FT /FTId=VAR_032477.
FT VARIANT 1484 1484 S -> F (in a cutaneous neurofibroma from
FT a patient with neurofibromatosis; somatic
FT mutation; dbSNP:rs199474772).
FT /FTId=VAR_067206.
FT VARIANT 1489 1489 S -> G (in NF1; dbSNP:rs199474743).
FT /FTId=VAR_010998.
FT VARIANT 1605 1605 I -> V (in NF1; reduces protein
FT stability; dbSNP:rs199474766).
FT /FTId=VAR_021759.
FT VARIANT 1611 1611 R -> W (in NF1).
FT /FTId=VAR_002660.
FT VARIANT 1733 1733 L -> LGHEQQKLPAATLAL (in NF1).
FT /FTId=VAR_002661.
FT VARIANT 1785 1785 A -> S (in NF1; dbSNP:rs199474782).
FT /FTId=VAR_021760.
FT VARIANT 1951 1951 P -> L (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035544.
FT VARIANT 1952 1952 W -> R (in NF1; dbSNP:rs199474791).
FT /FTId=VAR_002662.
FT VARIANT 1953 1953 L -> P (in NF1; dbSNP:rs199474792).
FT /FTId=VAR_002663.
FT VARIANT 1953 1953 Missing (in NF1).
FT /FTId=VAR_021761.
FT VARIANT 2001 2001 G -> R (in NF1; dbSNP:rs199474751).
FT /FTId=VAR_021762.
FT VARIANT 2012 2012 D -> N (in NF1; dbSNP:rs199474783).
FT /FTId=VAR_021763.
FT VARIANT 2088 2088 L -> P (in FSNF; null mutation; 50%
FT reduction of protein level; no cafe-au-
FT lait macules; dbSNP:rs137854561).
FT /FTId=VAR_017669.
FT VARIANT 2164 2164 L -> M (in NF1; dbSNP:rs137854551).
FT /FTId=VAR_002664.
FT VARIANT 2192 2192 Y -> N (in NF1).
FT /FTId=VAR_002665.
FT VARIANT 2221 2221 P -> A (in NF1; dbSNP:rs199474776).
FT /FTId=VAR_021764.
FT VARIANT 2357 2357 E -> K (in NF1; dbSNP:rs199474784).
FT /FTId=VAR_021765.
FT VARIANT 2387 2388 Missing (in NF1).
FT /FTId=VAR_002666.
FT VARIANT 2507 2507 T -> I (in NF1; dbSNP:rs149055633).
FT /FTId=VAR_021766.
FT VARIANT 2511 2511 V -> L (in dbSNP:rs2230850).
FT /FTId=VAR_022257.
FT VARIANT 2631 2631 T -> A (in NF1; dbSNP:rs199474793).
FT /FTId=VAR_002667.
FT VARIANT 2745 2745 G -> R (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035545.
FT MUTAGEN 1691 1691 K->A: Reduces phospholipid binding; when
FT associated with A-1695; A-1769 and A-
FT 1771.
FT MUTAGEN 1695 1695 R->A: Reduces phospholipid binding; when
FT associated with A-1691; A-1769 and A-
FT 1771.
FT MUTAGEN 1769 1769 R->A: Reduces phospholipid binding; when
FT associated with A-1691; A-1695 and A-
FT 1771.
FT MUTAGEN 1771 1771 K->A: Reduces phospholipid binding; when
FT associated with A-1691; A-169 and A-1769.
FT MUTAGEN 1771 1771 Missing: Reduces protein stability.
FT CONFLICT 496 496 M -> I (in Ref. 11; AAA74897/AAB59558).
FT CONFLICT 1094 1095 EL -> ST (in Ref. 14; AAA59923).
FT CONFLICT 1576 1576 H -> HH (in Ref. 11; AAA74897/AAB59558).
FT HELIX 1208 1216
FT HELIX 1224 1228
FT HELIX 1233 1235
FT HELIX 1236 1248
FT TURN 1249 1251
FT HELIX 1253 1263
FT STRAND 1266 1270
FT HELIX 1282 1293
FT HELIX 1296 1299
FT STRAND 1300 1302
FT TURN 1335 1337
FT TURN 1339 1342
FT HELIX 1343 1352
FT TURN 1353 1356
FT HELIX 1361 1370
FT TURN 1394 1396
FT HELIX 1402 1412
FT HELIX 1414 1419
FT HELIX 1434 1440
FT HELIX 1442 1451
FT HELIX 1462 1464
FT HELIX 1465 1470
FT HELIX 1472 1481
FT HELIX 1510 1514
FT HELIX 1517 1520
FT HELIX 1535 1544
FT HELIX 1569 1578
FT TURN 1582 1586
FT HELIX 1587 1590
FT STRAND 1592 1598
FT STRAND 1604 1609
FT HELIX 1610 1612
FT TURN 1615 1617
FT HELIX 1620 1631
FT TURN 1632 1636
FT STRAND 1639 1644
FT HELIX 1650 1652
FT HELIX 1656 1661
FT TURN 1662 1664
FT HELIX 1668 1672
FT STRAND 1674 1681
FT HELIX 1684 1692
FT HELIX 1694 1697
FT TURN 1698 1702
FT STRAND 1706 1711
FT HELIX 1714 1717
FT HELIX 1721 1723
FT HELIX 1728 1732
FT STRAND 1738 1749
FT STRAND 1751 1757
FT STRAND 1759 1767
FT STRAND 1770 1772
FT STRAND 1775 1777
FT STRAND 1780 1784
FT HELIX 1785 1787
FT STRAND 1788 1795
FT STRAND 1798 1803
FT STRAND 1810 1813
FT HELIX 1817 1833
SQ SEQUENCE 2839 AA; 319372 MW; C079475139DBD51E CRC64;
MAAHRPVEWV QAVVSRFDEQ LPIKTGQQNT HTKVSTEHNK ECLINISKYK FSLVISGLTT
ILKNVNNMRI FGEAAEKNLY LSQLIILDTL EKCLAGQPKD TMRLDETMLV KQLLPEICHF
LHTCREGNQH AAELRNSASG VLFSLSCNNF NAVFSRISTR LQELTVCSED NVDVHDIELL
QYINVDCAKL KRLLKETAFK FKALKKVAQL AVINSLEKAF WNWVENYPDE FTKLYQIPQT
DMAECAEKLF DLVDGFAEST KRKAAVWPLQ IILLILCPEI IQDISKDVVD ENNMNKKLFL
DSLRKALAGH GGSRQLTESA AIACVKLCKA STYINWEDNS VIFLLVQSMV VDLKNLLFNP
SKPFSRGSQP ADVDLMIDCL VSCFRISPHN NQHFKICLAQ NSPSTFHYVL VNSLHRIITN
SALDWWPKID AVYCHSVELR NMFGETLHKA VQGCGAHPAI RMAPSLTFKE KVTSLKFKEK
PTDLETRSYK YLLLSMVKLI HADPKLLLCN PRKQGPETQG STAELITGLV QLVPQSHMPE
IAQEAMEALL VLHQLDSIDL WNPDAPVETF WEISSQMLFY ICKKLTSHQM LSSTEILKWL
REILICRNKF LLKNKQADRS SCHFLLFYGV GCDIPSSGNT SQMSMDHEEL LRTPGASLRK
GKGNSSMDSA AGCSGTPPIC RQAQTKLEVA LYMFLWNPDT EAVLVAMSCF RHLCEEADIR
CGVDEVSVHN LLPNYNTFME FASVSNMMST GRAALQKRVM ALLRRIEHPT AGNTEAWEDT
HAKWEQATKL ILNYPKAKME DGQAAESLHK TIVKRRMSHV SGGGSIDLSD TDSLQEWINM
TGFLCALGGV CLQQRSNSGL ATYSPPMGPV SERKGSMISV MSSEGNADTP VSKFMDRLLS
LMVCNHEKVG LQIRTNVKDL VGLELSPALY PMLFNKLKNT ISKFFDSQGQ VLLTDTNTQF
VEQTIAIMKN LLDNHTEGSS EHLGQASIET MMLNLVRYVR VLGNMVHAIQ IKTKLCQLVE
VMMARRDDLS FCQEMKFRNK MVEYLTDWVM GTSNQAADDD VKCLTRDLDQ ASMEAVVSLL
AGLPLQPEEG DGVELMEAKS QLFLKYFTLF MNLLNDCSEV EDESAQTGGR KRGMSRRLAS
LRHCTVLAMS NLLNANVDSG LMHSIGLGYH KDLQTRATFM EVLTKILQQG TEFDTLAETV
LADRFERLVE LVTMMGDQGE LPIAMALANV VPCSQWDELA RVLVTLFDSR HLLYQLLWNM
FSKEVELADS MQTLFRGNSL ASKIMTFCFK VYGATYLQKL LDPLLRIVIT SSDWQHVSFE
VDPTRLEPSE SLEENQRNLL QMTEKFFHAI ISSSSEFPPQ LRSVCHCLYQ ATCHSLLNKA
TVKEKKENKK SVVSQRFPQN SIGAVGSAMF LRFINPAIVS PYEAGILDKK PPPRIERGLK
LMSKILQSIA NHVLFTKEEH MRPFNDFVKS NFDAARRFFL DIASDCPTSD AVNHSLSFIS
DGNVLALHRL LWNNQEKIGQ YLSSNRDHKA VGRRPFDKMA TLLAYLGPPE HKPVADTHWS
SLNLTSSKFE EFMTRHQVHE KEEFKALKTL SIFYQAGTSK AGNPIFYYVA RRFKTGQING
DLLIYHVLLT LKPYYAKPYE IVVDLTHTGP SNRFKTDFLS KWFVVFPGFA YDNVSAVYIY
NCNSWVREYT KYHERLLTGL KGSKRLVFID CPGKLAEHIE HEQQKLPAAT LALEEDLKVF
HNALKLAHKD TKVSIKVGST AVQVTSAERT KVLGQSVFLN DIYYASEIEE ICLVDENQFT
LTIANQGTPL TFMHQECEAI VQSIIHIRTR WELSQPDSIP QHTKIRPKDV PGTLLNIALL
NLGSSDPSLR SAAYNLLCAL TCTFNLKIEG QLLETSGLCI PANNTLFIVS ISKTLAANEP
HLTLEFLEEC ISGFSKSSIE LKHLCLEYMT PWLSNLVRFC KHNDDAKRQR VTAILDKLIT
MTINEKQMYP SIQAKIWGSL GQITDLLDVV LDSFIKTSAT GGLGSIKAEV MADTAVALAS
GNVKLVSSKV IGRMCKIIDK TCLSPTPTLE QHLMWDDIAI LARYMLMLSF NNSLDVAAHL
PYLFHVVTFL VATGPLSLRA STHGLVINII HSLCTCSQLH FSEETKQVLR LSLTEFSLPK
FYLLFGISKV KSAAVIAFRS SYRDRSFSPG SYERETFALT SLETVTEALL EIMEACMRDI
PTCKWLDQWT ELAQRFAFQY NPSLQPRALV VFGCISKRVS HGQIKQIIRI LSKALESCLK
GPDTYNSQVL IEATVIALTK LQPLLNKDSP LHKALFWVAV AVLQLDEVNL YSAGTALLEQ
NLHTLDSLRI FNDKSPEEVF MAIRNPLEWH CKQMDHFVGL NFNSNFNFAL VGHLLKGYRH
PSPAIVARTV RILHTLLTLV NKHRNCDKFE VNTQSVAYLA ALLTVSEEVR SRCSLKHRKS
LLLTDISMEN VPMDTYPIHH GDPSYRTLKE TQPWSSPKGS EGYLAATYPT VGQTSPRARK
SMSLDMGQPS QANTKKLLGT RKSFDHLISD TKAPKRQEME SGITTPPKMR RVAETDYEME
TQRISSSQQH PHLRKVSVSE SNVLLDEEVL TDPKIQALLL TVLATLVKYT TDEFDQRILY
EYLAEASVVF PKVFPVVHNL LDSKINTLLS LCQDPNLLNP IHGIVQSVVY HEESPPQYQT
SYLQSFGFNG LWRFAGPFSK QTQIPDYAEL IVKFLDALID TYLPGIDEET SEESLLTPTS
PYPPALQSQL SITANLNLSN SMTSLATSQH SPGIDKENVE LSPTTGHCNS GRTRHGSASQ
VQKQRSAGSF KRNSIKKIV
//

MIM 114500
*RECORD*
*FIELD* NO
114500
*FIELD* TI
#114500 COLORECTAL CANCER; CRC
;;COLON CANCER
*FIELD* TX
A number sign (#) is used with this entry because mutations in several
read moredifferent genes have been identified in colorectal cancer (CRC).

DESCRIPTION

Colorectal cancer is a heterogeneous disease that is common in both men
and women. In addition to lifestyle and environmental risk factors, gene
defects can contribute to an inherited predisposition to CRC. CRC is
caused by changes in different molecular pathogenic pathways, such as
chromosomal instability, CpG island methylator phenotype, and
microsatellite instability. Chromosome instability is the most common
alteration and is present in almost 85% of all cases (review by
Schweiger et al., 2013).

- Genetic Heterogeneity of Colorectal Cancer

Mutations in a single gene result in a marked predisposition to
colorectal cancer in 2 distinct syndromes: familial adenomatous
polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer
(HNPCC; see 120435). FAP is caused by mutations in the APC gene
(611731), whereas HNPCC is caused by mutations in several genes,
including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259),
MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing
of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other
colorectal cancer syndromes include autosomal recessive adenomatous
polyposis (608456), which is caused by mutations in the MUTYH gene
(604933), and oligodontia-colorectal cancer syndrome (608615), which is
caused by mutations in the AXIN2 gene (604025).

The CHEK2 gene (604373) has been implicated in susceptibility to
colorectal cancer in Finnish patients. A germline mutation in the
PLA2G2A gene (172411) was identified in a patient with colorectal
cancer.

Germline susceptibility loci for colorectal cancer have also been
identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene
(610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24;
CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on
chromosome 18; CRCS4 (601228) is conferred by variation on 15q that
causes increased and ectopic expression of the GREM1 gene (603054);
CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to
chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589)
maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591)
is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13;
CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is
conferred by mutation in the POLE gene (174762) on chromosome 12q24.

Somatic mutations in many different genes, including KRAS (190070),
PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2
(604025), AKT1 (164730), MCC (159350), MYH11 (160745), and PARK2
(602544) have been identified in colorectal cancer.

CLINICAL FEATURES

Colon cancer is a well-known feature of familial polyposis coli. Cancer
of the colon occurred in 7 members of 4 successive generations of the
family reported by Kluge (1964), leading him to suggest a simple genetic
basis for colonic cancer independent of polyposis. The combination of
colonic and endometrial cancer has been observed in many families (e.g.,
Williams, 1978).

Sivak et al. (1981) studied a kindred with the familial cancer syndrome
in which every confirmed affected member had at least 1 primary
carcinoma of the colon. The average age at which cancer appeared was 38
years. Multiple primary neoplasms occurred in 23% of cancer patients.

Budd and Fink (1981) reported a family with a high frequency of mucoid
colonic carcinoma. Since endometrial carcinoma, atypical endometrial
hyperplasia, uterine leiomyosarcoma, bladder transitional carcinoma, and
renal cell carcinoma also occurred in the family, this may be the same
disorder as the Lynch cancer family syndrome type II (120435).

Bamezai et al. (1984) reported an Indian Sikh kindred in which 8 persons
suffered from cancer of the cecum, not associated with polyposis.

Burt et al. (1985) studied a large Utah kindred called to attention
because of occurrence of colorectal cancer in a brother, a sister, and a
nephew. No clear inheritance pattern was discernible until systematic
screening was undertaken for colonic polyps using flexible
proctosigmoidoscopy. One or more adenomatous polyps were found in 41 of
191 family members (21%) and 12 of 132 controls (9%)--p less than 0.005.
Pedigree analysis showed best fit with autosomal dominant inheritance.
Cannon-Albright et al. (1988) extended the studies with investigations
of 33 additional kindreds. The kindreds were selected through either a
single person with an adenomatous polyp or a cluster of relatives with
colonic cancer. The kindreds all had common colorectal cancers, not the
rare inherited condition of familial polyposis coli or nonpolyposis
inherited colorectal cancer. Likelihood analysis strongly supported
dominant inheritance of a susceptibility to colorectal adenomas and
cancers, with a gene frequency of 19%. According to the most likely
genetic model, adenomatous polyps and colorectal cancers occur only in
genetically susceptible persons; however, the 95% confidence interval
for this proportion was 53 to 100%.

Ponz de Leon et al. (1992) analyzed data on 605 families of probands
with colorectal cancer in the province of Modena in Italy. Among the 577
presumed nonpolyposis cases, both parents had colorectal cancer in 11,
one parent in 130, and neither parent in 436. Segregation was compatible
with dominant transmission of susceptibility to cancer.

Mecklin (1987) investigated the frequency of hereditary colorectal
cancer among all colorectal cancer patients diagnosed in 1 Finnish
county during the 1970s. The cancer family syndrome type of hereditary
nonpolyposis colorectal carcinoma emerged as the most common verifiable
risk factor, involving between 3.8 and 5.5% of all colorectal cancer
patients. The frequencies of familial adenomatosis and ulcerative
colitis were 0.2% and 0.6%, respectively. The observed frequency is
probably an underestimate. The patients with cancer family syndrome were
young, accounting for 29 to 39% of the patients under 50 years of age,
and their tumors were located predominantly (65%) in the right
hemicolon.

PATHOGENESIS

The state of DNA methylation appears to play a role in genetic
instability in colorectal cancer cells. Lengauer et al. (1997) noted
that DNA methylation is essential in prokaryotes, dispensable in lower
eukaryotes (such as Saccharomyces cerevisiae) yet present and presumably
important in mammals. Many cancers have been shown to have a global
hypomethylation of DNA compared with normal tissues. Treatment of cells
or animals with 5-azacytidine (5-aza-C), a demethylating agent that
irreversibly inactivates methyltransferase (see 156569), is oncogenic in
vitro and in vivo. Conversely, other studies showed that
hypermethylation of specific sequences found in some tumors can be
associated with the inactivation of tumor suppressor gene expression.
Mice genetically deficient in methyltransferase are resistant to
colorectal tumorigenesis initiated by mutation of the APC (611731) tumor
suppressor gene, and treatment of these mice with 5-aza-C enhances the
resistance (Laird et al., 1995).

Lengauer et al. (1997) reported a striking difference in the expression
of exogenously introduced retroviral genes in various colorectal cancer
cell lines. Extinguished expression was associated with DNA methylation
and could be reversed by treatment with the demethylating agent 5-aza-C.
A striking correlation between genetic instability and methylation
capacity suggested that methylation abnormalities may play a role in the
chromosome segregation processes in cancer cells. It has been speculated
that genetic instability is necessary for a tumor to accumulate the
numerous genetic alterations that accompany carcinogenesis. There
appeared to exist 2 pathways of genetic instability in colorectal
cancer. The first is found in about 15% of tumors and involves point
mutations, microdeletions, and microinsertions associated with
deficiency of mismatch repair (MMR). The second is found in
MMR-proficient cells and involves gains and losses of whole chromosomes.
Lengauer et al. (1997) suggested that methylation abnormalities are
intrinsically and directly involved in the generation of the second type
of instability, thus allowing for the selection of methylation-negative
cells during the clonal evolution of tumors. The hypothesis was
supported by the observation that demethylation is associated with
chromosomal aberrations, including mitotic dysfunction and
translocation, and was consistent with the hypothesis relating
methylation and aneuploidy put forward by Thomas (1995). Jones and
Gonzalgo (1997) commented on altered DNA methylation and genome
instability as a new pathway to cancer.

In a second report, Lengauer et al. (1997) showed that tumors without
microsatellite instability exhibit a striking defect in chromosome
segregation, resulting in gains or losses in excess of 10(-2) per
chromosome per generation. This form of chromosomal instability
reflected a continuing cellular defect that persisted throughout the
lifetime of the tumor cell and was not simply related to chromosome
number. While microsatellite instability is a recessive trait,
chromosomal instability appeared to be dominant. The data indicated that
persistent genetic instability may be critical for the development of
all colorectal cancers, and that this instability can arise through 2
distinct pathways.

Adenocarcinoma of the small intestine is rare in the general population,
but its histologic features are similar to those of the much more common
colorectal adenocarcinoma, and it is seen as part of the HNPCC tumor
predisposition spectrum. Wheeler et al. (2002) examined the possible
role of mismatch repair defects in the pathogenesis of sporadic small
intestinal adenocarcinoma. The replication error status was determined
in a total of 21 nonfamilial, nonampullary small intestinal
adenocarcinomas: only 1 tumor was scored as replication error-positive.
This tumor showed normal immunostaining for MLH1 (see 120436) and MSH2.
The authors commented that this result may reflect an epigenetic change
in the tumor rather than germline mutation in a mismatch repair gene,
and concluded that mismatch repair defects were unlikely to contribute
significantly to the genetic pathway leading to sporadic small
intestinal adenocarcinoma.

Vilar and Gruber (2010) reviewed the role of microsatellite instability
(MSI) in the development of CRC. They stated that approximately 15% of
CRCs display MSI owing either to epigenetic silencing of MLH1 or to a
germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6,
or PMS2. They noted that MSI tumors have a better prognosis than
microsatellite stable CRCs, but that MSI cancers do not necessarily have
the same response to the chemotherapeutic strategies used to treat
microsatellite stable tumors.

Batlle et al. (2005) showed that although Wnt (see 164820) signaling
remains constitutively active, most human colorectal cancers lose
expression of EphB (see 600600) at the adenoma-carcinoma transition.
They found that loss of EphB expression strongly correlated with degree
of malignancy. Furthermore, reduction of EphB activity accelerated
tumorigenesis in the colon and rectum of Apc(Min/+) mice (see 611731),
and resulted in formation of aggressive adenocarcinomas. Batlle et al.
(2005) concluded that loss of EphB expression represents a critical step
in colorectal cancer progression.

By microdissection of bifurcating colonic crypts and sequencing of the
entire mitochondrial genome in all of the cells, Greaves et al. (2006)
demonstrated that stochastic mutations in mtDNA resulting in phenotypic
cytochrome c oxidase (COX) deficiency of were identical in both arms of
a crypt that was bifurcating. Furthermore, they showed that patches of
neighboring crypts deficient in COX also shared identical mitochondrial
mutations, and that these patches increased in size with age, indicating
that crypt fission is a mechanism by which mutations can spread within
the colon.

Xia et al. (2012) showed that prostaglandin E2 (PGE2) silences certain
tumor suppressor and DNA repair genes through DNA methylation to promote
tumor growth. Their findings uncovered a theretofore unrecognized role
for PGE2 in the promotion of tumor progression, and provided a rationale
for considering the development of a combination treatment using PTGS2
(600262) inhibitors and demethylating agents for the prevention or
treatment of colorectal cancer.

Seshagiri et al. (2012) systematically analyzed more than 70 pairs of
primary human colon tumors using next-generation sequencing to
characterize their exomes, transcriptomes, and copy number alterations.
They identified 36,303 protein-altering somatic changes that included
several novel recurrent mutations in the Wnt pathway gene TCF7L2
(602228), chromatin-remodeling genes such as TET2 (612839) and TET3
(613555), and receptor tyrosine kinases including ERBB3 (190151). The
analysis for significantly mutated cancer genes identified 23
candidates, including the cell cycle checkpoint kinase ATM (607585).
Copy number and RNA-seq data analysis identified amplifications and
corresponding overexpression of IGF2 in a subset of colon tumors.
Furthermore, using RNA-seq data, Seshagiri et al. (2012) identified
multiple fusion transcripts including recurrent gene fusions involving
R-spondin family members RSPO2 (610575) and RSPO3 (610574) that together
occur in 10% of colon tumors. The RSPO fusions were mutually exclusive
with APC (611731) mutations, indicating that they probably have a role
in the activation of Wnt signaling and tumorigenesis. Consistent with
this, Seshagiri et al. (2012) showed that RSPO fusion proteins were
capable of potentiating Wnt signaling.

Grivennikov et al. (2012) investigated mechanisms responsible for
tumor-elicited inflammation in a mouse model of colorectal tumorigenesis
which, like human colorectal cancer, exhibits upregulation of IL23
(605580) and IL17 (603149). They showed that IL23 signaling promotes
tumor growth and progression, and development of tumoral IL17 response.
IL23 is mainly produced by tumor-associated myeloid cells that are
likely to be activated by microbial products, which penetrate the tumors
but not adjacent tissue. Both early and late colorectal neoplasms
exhibit defective expression of several barrier proteins. Grivennikov et
al. (2012) proposed that barrier deterioration induced by colorectal
cancer-initiating genetic lesions results in adenoma invasion by
microbial products that trigger tumor-elicited inflammation, which in
turn drives tumor growth.

Huber et al. (2012) described the crucial role of IL22BP (606648) in
controlling tumorigenesis and epithelial cell proliferation in the
colon. IL22BP is highly expressed by dendritic cells in the colon in
steady-state conditions. Sensing of intestinal tissue damage via the
NLRP3 (606416) or NLRP6 (609650) inflammasomes led to an IL18
(600953)-dependent downregulation of IL22BP, thereby increasing the
ratio of IL22 (605330)/IL22BP. IL22, which is induced during intestinal
tissue damage, exerted protective properties during the peak of damage,
but promoted tumor development if uncontrolled during the recovery
phase. Thus, the IL22-IL22BP axis critically regulates intestinal tissue
repair and tumorigenesis in the colon.

Vermeulen et al. (2013) quantified the competitive advantage during
tumor development of Apc (611731) loss, Kras (190070) activation, and
p53 (191170) mutations in the mouse intestine. Their findings indicated
that the fate conferred by these mutations is not deterministic, and
many mutated stem cells are replaced by wildtype stem cells after biased
but still stochastic events. Furthermore, Vermeulen et al. (2013) found
that p53 mutations display a condition-dependent advantage, and
especially in colitis-affected intestines, clones harboring mutations in
this gene were favored. Vermeulen et al. (2013) concluded that their
work confirmed the notion that the tissue architecture of the intestine
suppresses the accumulation of mutated lineages.

CLINICAL MANAGEMENT

Various laboratory, clinical, and epidemiologic evidence suggested that
calcium may help prevent colorectal adenomas. Baron et al. (1999)
conducted a randomized, double-blind trial of the effect of
supplementation with calcium carbonate on the recurrence of colorectal
adenomas. They found a significant, though moderate, reduction in the
risk of recurrent colorectal adenomas in the supplemented group.

In randomized trials of aspirin to determine its efficacy in prevention
of colorectal adenomas, Sandler et al. (2003) and Baron et al. (2003)
studied patients with either previous colorectal cancer or recent
histologically documented adenomas, respectively. Both studies found
that aspirin was associated with a significant reduction in the
incidence of colorectal adenomas.

Inhibition of the BRAF(V600E) (164757.0001) oncoprotein by the
small-molecule drug PLX4032 (vemurafenib) is highly effective in the
treatment of melanoma. However, colon cancer patients harboring the same
BRAF(V600E) oncogenic lesion have poor prognosis and show only a very
limited response to this drug. To investigate the cause of this limited
therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al.
(2012) performed an RNA interference-based genetic screen in human cells
to search for kinases whose knockdown synergizes with BRAF(V600E)
inhibition. They reported that blockade of the epidermal growth factor
receptor (EGFR; 131550) shows strong synergy with BRAF(V600E)
inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant
colon cancers that inhibition of EGFR by the antibody drug cetuximab or
the small-molecule drugs gefitinib or erlotinib is strongly synergistic
with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically,
Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid
feedback activation of EGFR, which supports continued proliferation in
the presence of BRAF(V600E) inhibition. Melanoma cells express low
levels of EGFR and are therefore not subject to this feedback
activation. Consistent with this, Prahallad et al. (2012) found that
ectopic expression of EGFR in melanoma cells is sufficient to cause
resistance to PLX4032. Prahallad et al. (2012) concluded that
BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon
cancers) might benefit from combination therapy consisting of BRAF and
EGFR inhibitors.

- Development of Resistance to Chemotherapeutic Agents

Antibodies against EGFR, cetuximab and panitumumab, are widely used to
treat colorectal cancer. Unfortunately, patients eventually develop
resistance to these agents. Montagut et al. (2012) described an acquired
EGFR ectodomain mutation (S492R) that prevents cetuximab binding and
confers resistance to cetuximab. Cells with this mutation, however,
retain binding to and are growth inhibited by panitumumab. Two of 10
subjects studied with metastatic colon cancer progression after
cetuximab treatment acquired this mutation. One subject with cetuximab
resistance harboring the S492R mutation responded to treatment with
panitumumab.

Misale et al. (2012) showed that molecular alterations (in most
instances point mutations) of KRAS (190070) are causally associated with
the onset of acquired resistance to anti-EGFR treatment in colorectal
cancers. Expression of mutant KRAS under the control of its endogenous
gene promoter was sufficient to confer cetuximab resistance, but
resistant cells remained sensitive to combinatorial inhibition of EGFR
and mitogen-activated protein kinase kinase (MEK; see 176872). Analysis
of metastases from patients who developed resistance to cetuximab or
panitumumab showed the emergence of KRAS amplification in one sample and
acquisition of secondary KRAS mutations in 60% (6 out of 10) of the
cases. KRAS mutant alleles were detectable in the blood of
cetuximab-treated patients as early as 10 months before radiographic
documentation of disease progression. Misale et al. (2012) concluded
that their results identified KRAS mutations as frequent drivers of
acquired resistance to cetuximab in colorectal cancers, indicated that
the emergence of KRAS mutant clones can be detected noninvasively months
before radiographic progression, and suggested early initiation of a MEK
inhibitor as a rational strategy for delaying or reversing drug
resistance.

Diaz et al. (2012) determined whether mutant KRAS DNA could be detected
in the circulation of 28 patients receiving monotherapy with
panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of
24 (38%) patients whose tumors were initially KRAS wildtype developed
detectable mutations in KRAS in their sera, 3 of which developed
multiple different KRAS mutations. The appearance of these mutations was
very consistent, generally occurring between 5 and 6 months following
treatment. Mathematical modeling indicated that the mutations were
present in expanded subclones before the initiation of panitumumab
treatment. Diaz et al. (2012) concluded that the emergence of KRAS
mutations is a mediator of acquired resistance to EGFR blockade and that
these mutations can be detected in a noninvasive manner. The results
also explained why solid tumors develop resistance to targeted therapies
in a highly reproducible fashion.

Among 512 patients who had metastatic colorectal cancer without RAS
(KRAS or NRAS, 164790) mutations, Douillard et al. (2013) found that
progression-free survival was 10.1 months with the combination of
panitumumab-FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) versus
7.9 months with FOLFOX4 alone (hazard ratio for progression or death
with combination therapy, 0.72; 95% CI 0.58 to 0.90; p = 0.004). Overall
survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2
months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI
0.62-0.99; p = 0.04). A total of 108 patients (17%) with nonmutated KRAS
exon 2 had other RAS mutations. These mutations were associated with
inferior progression-free survival and overall survival with
panitumumab-FOLFOX4 treatment, which was consistent with the findings in
patients with KRAS mutations in exon 2. BRAF mutations were a negative
prognostic factor.

DIAGNOSIS

- Prediction of Colorectal Cancer Risk

Loss of imprinting, an epigenetic alteration affecting the insulin-like
growth factor II gene (IGF2; 147470), is found in normal colonic mucosa
of about 30% of colorectal cancer patients, but it is found in only 10%
of healthy individuals. In a pilot study to investigate the utility of
loss of imprinting as a marker of colorectal cancer risk, Cui et al.
(2003) evaluated 172 patients at a colonoscopy clinic. The adjusted odds
ratio for loss of imprinting in lymphocytes was 5.15 for patients with a
positive family history (95% CI, 1.70-16.96; p = 0.002), 3.46 for
patients with adenomas (95% CI, 1.14-11.37; p = 0.026), and 21.7 for
patients with colorectal cancer (95% CI, 3.48-153.6; p = 0.0005). Loss
of imprinting can be assayed with a DNA-based blood test, and Cui et al.
(2003) concluded that it may be a valuable predictive marker of an
individual's risk for colorectal cancer.

MAPPING

To identify susceptibility genes for familial colorectal neoplasia,
Daley et al. (2008) conducted a comprehensive, genomewide linkage scan
of 194 kindreds. Clinical information (histopathology, size and number
of polyps, and other primary cancers) was used in conjunction with age
at onset and family history for classification of the families into 5
phenotypic subgroups (severe histopathology, oligopolyposis, young
colon/breast and multiple cancer) before analysis. By expanding the
traditional affected sib pair design to include unaffected and
discordant sib pairs, analytical power and robustness to type I error
were increased. Linkage peaks of interest were identified at several
sites. At marker D1S1665 (1p31.1), there was strong evidence for linkage
in the multiple cancer subgroup (p = 0.00007). For 15q14-q22, a linkage
peak was identified in the full sample, oligopolyposis, and young
phenotypes. This region includes the locus associated with hereditary
mixed polyposis syndrome (HMPS; 601228) in families of Ashkenazi
descent. Daley et al. (2008) provided compelling evidence linking this
region in families of European descent with oligopolyposis and/or young
age at onset (51 years or younger) phenotypes. They found linkage to
BRCA2 (600185) in the colon/breast phenotypic subgroup and identified a
second locus in the region of D21S1437 segregating with, but distinct
from, BRCA2. Linkage to 17p13.3 at marker D17S1308 in the breast/colon
subgroup identified HIC1 (603825) as a candidate gene. The study
demonstrated that using clinical information, unaffected sibs, and
family history can increase the analytic power of a linkage study.

- Associations Pending Confirmation

In a large kindred with excess colorectal cancer, Neklason et al. (2010)
performed 2 separate genomewide scans and additional fine mapping and
identified a single major locus on chromosome 13q22.1-q31.3 that
segregated with adenomatous polyps and colon cancer, for which they
obtained a nonparametric linkage score of 24 (lod score of 2.99; p =
0.001) at D13S251. Haplotype analysis identified a 21-Mb interval
encompassing a nonrecombinant region bounded by dbSNP rs2077779 and
dbSNP rs2351871 and containing 27 genes. Sequencing of 8 candidate genes
failed to identify a clearly deleterious mutation. Neklason et al.
(2010) noted that chromosome 13q is commonly gained and overexpressed in
colon cancers and correlates with metastasis, suggesting the presence of
an important cancer progression gene, and stated that evaluation of
tumors from the kindred revealed a gain of chromosome 13q as well.

CYTOGENETICS

Bass et al. (2011) reported whole-genome sequencing from 9 individuals
with colorectal cancer, including primary colorectal tumors and matched
adjacent nontumor tissues, at an average of 30.7x and 31.9x coverage,
respectively. They identified an average of 75 somatic rearrangements
per tumor, including complex networks of translocations between pairs of
chromosomes. Eleven rearrangements encode predicted in-frame fusion
proteins, including a fusion of VTI1A (614316) and TCF7L2 (602278) found
in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which
cooperates with beta-catenin (116806) in colorectal carcinogenesis, the
fusion lacks the TCF4 beta-catenin-binding domain. Bass et al. (2011)
found a colorectal carcinoma cell line harboring the fusion gene to be
dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA
interference-mediated knockdown.

MOLECULAR GENETICS

In the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al.
(1981) demonstrated the same or closely related transforming elements.
By DNA-mediated gene transfer, mouse fibroblasts could be
morphologically transformed and rendered tumorigenic in nude mice.

In preliminary observations, Pathak and Goodacre (1986) found deletion
of 12p in colorectal cancer specimens.

Fearon et al. (1987) studied the clonal composition of human colorectal
tumors. Using X-linked RFLPs, they showed that all 50 tumors from
females showed a monoclonal pattern of X-chromosome inactivation; these
tumors included 20 carcinomas and 30 adenomas of either familial or
spontaneous type. In over 75% of carcinomas examined, somatic loss of
chromosome 17p sequences was found; such loss was rare in adenomas.
Fearon et al. (1987) suggested that a gene on the short arm of
chromosome 17 may be associated with progression from the benign to the
malignant state.

By a combination of DNA hybridization analyses and tissue sectioning
techniques, Bos et al. (1987) demonstrated that RAS gene mutations occur
in over a third of colorectal cancers, that most of the mutations are at
codon 12 of the KRAS gene (190070), and that the mutations usually
precede the development of malignancy.

In 38 tumors from 25 patients with familial polyposis coli, and in 20
sporadic colon carcinomas, Okamoto et al. (1988) found frequent
occurrence of allele loss on chromosome 22, with some additional losses
on chromosomes 5, 6, 12q, and 15. The DNA probe C11p11, which has been
found to be linked to familial polyposis coli, also detected frequent
allele loss in both familial and sporadic colon carcinomas but not in
benign adenomas. In a more extensive study, Vogelstein et al. (1988)
studied the interrelationships of the 4 alterations demonstrated in
colorectal cancer (RAS gene mutations and deletions of chromosome 5, 17
and 18 sequences) and determined their occurrence with respect to
different stages of colorectal tumorigenesis. They found RAS gene
mutations frequently in adenomas, this being the first demonstration of
such in benign human tumors. In adenomas greater than 1 cm in size, the
prevalence was similar to that observed in carcinomas (58% and 47%,
respectively). Sequences on chromosome 5 that are linked to familial
adenomatous polyposis were seldom lost in adenomas from such patients.
Therefore, the Knudson model is unlikely to be applicable to the
adenoma/carcinoma sequence in this disorder. Chromosome 18 sequences
were lost frequently in colon carcinomas (73%) and in advanced adenomas
(47%), but only occasionally in earlier stage adenomas (11-13%); see
120470. Chromosome 17 sequences were usually lost only in carcinomas
(75%). The results suggested a model wherein the steps required for
malignancy involve the activation of a dominantly acting oncogene
coupled with the loss of several genes that normally suppress
tumorigenesis.

Wildrick and Boman (1988) found deletion of the glucocorticoid receptor
locus (138040), located on 5q, in colorectal cancers.

Law et al. (1988) examined the question of whether the gene for familial
polyposis coli on chromosome 5 may be the site of changes leading to
colorectal cancer in the general population, analogous to recessive
tumor genes in retinoblastoma and Wilms tumor. To avoid error in
interpretation of allelic loss from a study of nonhomogeneous samples,
tumor cell populations were first microdissected from 24 colorectal
carcinomas, an additional 9 cancers were engrafted in nude mice, and
nuclei were flow-sorted in an additional 2. Of 31 cancers informative
for chromosome 5 markers, only 6 (19%) showed loss of heterozygosity of
chromosome 5 alleles, compared to 19 of 34 (56%) on chromosome 17, and
17 of 33 (52%) on chromosome 18. Law et al. (1988) concluded that FPC is
a true dominant for adenomatosis but not a common recessive gene for
colon cancer, and that simple mendelian models involving loss of alleles
at a single locus may be inappropriate for understanding common human
solid tumors.

Vogelstein et al. (1989) examined the extent and variation of allelic
loss for polymorphic DNA markers in every nonacrocentric autosomal arm
in 56 paired colorectal carcinoma and adjacent normal colonic mucosa
specimens. They referred to the analysis as an allelotype, in analogy
with a karyotype. Three major conclusions were drawn from the study: (1)
Allelic deletions are remarkably common; 1 of the alleles of each
polymorphic marker tested was lost in at least some tumors, and some
tumors lost more than half of their parental alleles. (2) In addition to
allelic deletions, new DNA fragments not present in normal tissue were
identified in 5 carcinomas; these new fragments contained repeated
sequences (of the variable-number-of-tandem-repeat type). (3) Patients
with more than the median percentage of allelic deletions had a
considerably worse prognosis than did the other patients, although the
stage and size of the primary tumors were very similar in the 2 groups.

Delattre et al. (1989) reviewed the 3 general types of genetic
alterations in colorectal cancer: (1) change in DNA content of the
malignant cells as monitored by flow cytometry; (2) specific loss of
genetic material, i.e., a complete loss of chromosome 18 and a
structural rearrangement of chromosome 17 leading most often to the loss
of 1 short arm, and loss of part of 5q as demonstrated by loss of
heterozygosity; and (3) in nearly 40% of tumors, activation by point
mutation of RAS oncogenes (never HRAS, rarely NRAS, and most frequently
KRAS). In KRAS, with 1 exception, the activation has always occurred by
a change in the coding properties of the twelfth or thirteenth codon. In
studies of the multiple genetic alterations in colorectal cancer,
Delattre et al. (1989) found that deletions and mitotic abnormalities
occurred more frequently in distal than in proximal tumors. The
frequency of KRAS mutations did not differ between proximal and distal
cancers.

In studies of 15 colorectal tumors, Konstantinova et al. (1991) found
rearrangements of the short arm of chromosome 17, leading to deletion of
this arm or part of it in 12; in 2 others, one of the homologs of pair
17 was lost. One chromosome 18 was lost in 12 out of 13 cases with fully
identified numerical abnormalities; chromosome 5, in 6 tumors; and other
chromosomes in lesser numbers of cases. See 120470 for a discussion of a
gene on chromosome 18 called DCC ('deleted in colorectal cancer') that
shows mutations, including point mutations, in colorectal tumor tissue;
also see 164790 for a discussion of a mutation in the NRAS oncogene in
colorectal cancer.

On the basis of complex segregation analysis of a published series of
consecutive pedigrees ascertained through patients undergoing treatment
for colorectal cancer, Houlston et al. (1992) concluded that a dominant
gene (or genes) with a frequency of 0.006 with a lifetime penetrance of
0.63 is likely. The gene was thought to account for 81% of colorectal
cancer in patients under 35 years of age; however, by age 65, about 85%
appeared to be phenocopies.

Fearon and Vogelstein (1990) reviewed the evidence supporting their
multistep genetic model for colorectal tumorigenesis. They suggested
that multiple mutations lead to a progression from normal epithelium to
metastatic carcinoma through hyperplastic epithelium--early
adenoma--intermediate adenoma--late adenoma--and carcinoma. The genes in
which mutations occur at steps in this process include APC (611731) on
chromosome 5, KRAS on chromosome 12, TP53 (191170) on 17p, and DCC on
chromosome 18. Other genes that have been demonstrated or suspected of
involvement in colorectal cancer include MSH2 (609309) on chromosome 2
and the DRA candidate colon tumor-suppressor gene (126650) on chromosome
7. Sarraf et al. (1999) presented evidence that colon cancer in humans
is associated with loss-of-function mutations in the PPARG gene
(601487).

Kikuchi-Yanoshita et al. (1992) presented evidence that genetic changes
in both alleles of the TP53 gene through mutation and LOH, which result
in abnormal protein accumulation, are involved in the conversion of
adenoma to early carcinoma in both familial adenomatous polyposis and in
nonfamilial polyposis cases.

Kinzler and Vogelstein (1996) gave a review of hereditary colorectal
cancer and the multistep process of carcinogenesis that typically
develops over decades and appears to require at least 7 genetic events
for completion. They stated that the genetic defect in FAP involves the
rate of tumor initiation by targeting the gatekeeper function of the APC
gene. In contrast, the defect in HNPCC largely affects tumor aggression
by targeting the genome guardian function of DNA repair.

Rajagopalan et al. (2002) systematically evaluated mutation in BRAF
(164757) and KRAS (190070) in 330 colorectal tumors. There were 32
mutations in BRAF, 28 with a V600E mutation (164757.0001) and 1 each
with the R462I (164757.0002), I463S (164757.0003), G464E (164757.0004),
or K601E (164757.0005) mutations. All but 2 mutations seemed to be
heterozygous, and in all 20 cases for which normal tissue was available,
the mutations were shown to be somatic. In the same set of tumors there
were 169 mutations in KRAS. No tumor exhibited mutations in both BRAF
and KRAS. There was also a striking difference in the frequency of BRAF
mutations between cancers with and without mismatch repair deficiency.
All but 1 of the 15 BRAF mutations identified in mismatch repair
deficient cases resulted in a V600E substitution. Rajagopalan et al.
(2002) concluded their results provide strong support for the hypothesis
that BRAF and KRAS mutations are equivalent in their tumorigenic
effects. Both genes seem to be mutated at a similar phase of
tumorigenesis, after initiation but before malignant conversion.
Moreover, no tumor concurrently contained both BRAF and KRAS mutations.

To determine whether carriers of BLM (604610) mutations are at increased
risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of
colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry,
to estimate the relative risk of colorectal cancer among carriers of the
BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were
more than twice as likely to carry the BLM(Ash) (604610.0001) mutation
than Ashkenazi Jewish controls without colorectal cancer (odds ratio =
2.45, 95% confidence interval 1.3 to 4.8; p = 0.0065). Gruber et al.
(2002) verified that the APC I1307K mutation (611731.0029) did not
confound their results.

Lynch and de la Chapelle (2003) provided a general discussion of
hereditary colorectal cancer. They presented a flow diagram of the
breakdown of 1,044 unselected consecutive patients with colorectal
cancer. Tumors from 129 patients (12%) were positive for microsatellite
instability; 28 of these patients were positive for germline mutations
in MLH1 or MSH2, giving HNPCC a 2.7% frequency among the 1,044 patients.
In the 88% of the patients whose tumors had no microsatellite
instability, no mutations were found in MLH1 or MSH2.

Bardelli et al. (2003) used high-throughput sequencing technologies and
bioinformatics to investigate how many or how often members of the
tyrosine kinase family were altered in any particular cancer type. The
protein kinase complement of the human genome (the 'kinome') can be
organized into a dendrogram containing 9 broad groups of genes. Bardelli
et al. (2003) selected 1 major branch of this dendrogram, containing 3
of the 9 groups, including the 90 tyrosine kinase genes (TK group), the
43 tyrosine kinase-like genes (TKL group), and the 5 receptor guanylate
cyclase genes (RGC group), for mutation analysis. The 819 exons
containing the kinase domains from the annotated TK, TKL, and RGC genes
were screened from 35 colorectal cancer cell lines and were directly
sequenced. Fourteen genes had somatic mutations within their kinase
domains. Bardelli et al. (2003) analyzed these 14 genes for mutations in
another 147 colorectal cancers and identified 46 mutations, 2 of which
were synonymous; the remainder were either nonsynonymous or splice site
alterations. All of these mutations were found to be somatic in the
cancers that could be assessed by sequencing DNA from matched normal
tissue. Seven genes were mutated in more than 1 tumor in the cohort:
NTRK3 (191316), FES (190030), KDR (191306), EPHA3 (179611), NTRK2
(600456), MLK4, and GUCY2F (300041).

Samuels et al. (2004) examined the sequences of 117 exons that encode
the predicted kinase domains of 8 phosphatidylinositol-3 kinase genes
and 8 PI3K-like genes in 35 colorectal cancers. PIK3CA (171834) was the
only gene with somatic mutations. Subsequent sequence analysis of all
coding exons of PIK3CA in 199 additional colorectal cancers revealed
mutations in a total of 74 tumors (32%). Samuels et al. (2004) also
evaluated 76 premalignant colorectal tumors; only 2 mutations were
found, both in very advanced tubulovillous adenomas greater than 5 cm in
diameter. Thus, Samuels et al. (2004) concluded that PIK3CA mutations
generally arise late in tumorigenesis, just before or coincident with
invasion. Mutations in PIK3CA were also identified in 4 of 15
glioblastomas (27%), 3 of 12 gastric cancers (25%), 1 of 12 breast
cancers (8%), and 1 of 24 lung cancers (4%). No mutations were observed
in 11 pancreatic cancers or 12 medulloblastomas. In total, 92 mutations
were observed, all of which were determined to be somatic in the cancers
that could be assessed. Samuels et al. (2004) concluded that the sheer
number of mutations observed in this gene strongly suggests that they
are functionally important. Furthermore, most of the mutations were
nonsynonymous and occurred in the PI3K helical and kinase domains,
suggesting functional significance.

Clear-cut inherited mendelian traits, such as FAP or HNPCC, account for
less than 4% of colorectal cancers. Another 20% of all colorectal
cancers are thought to occur in individuals with a significant inherited
multifactorial susceptibility to colorectal cancer that is not obviously
familial. Incompletely penetrant, comparatively rare missense variants
in the APC gene (611731) have been described in patients with multiple
colorectal adenomas. For example, the I1307K mutation in the APC gene,
which is found in Ashkenazi Jewish populations with an incidence of
approximately 6%, confers a significantly increased risk of developing
multiple adenomas and colorectal cancer. The glu1317-to-gln mutation in
the APC gene (E1317Q; 611731.0036), which is found in non-Jewish
Caucasian populations at a low frequency, similarly appears to confer a
significantly increased risk of multiple adenomatous polyps. These
variants represent a category of variation that has been suggested,
generally, to account for a substantial fraction of such multifactorial
inherited susceptibility to colorectal cancer. Fearnhead et al. (2004)
explored this rare variant hypothesis for multifactorial inheritance
using multiple colorectal adenomas as the model. Patients with multiple
adenomas were screened for germline variants in a panel of candidate
genes. Germline DNA was obtained from 124 patients with 3 to 100
histologically proven synchronous or metachronous adenomatous polyps.
All patients were tested for the APC gene variants I1307K and E1317Q and
for variants in the AXIN1 (603816), CTNNB1, MLH1, and MSH2 genes. The
control group consisted of 483 randomly selected individuals.
Potentially pathogenic germline variants were found in 30 of 124
patients (24.9%), compared with 55 of 483 controls (approximately 12%).
This overall difference was highly significant, suggesting that many
rare variants collectively contribute to inherited susceptibility to
colorectal adenomas.

Parsons et al. (2005) selected 340 genes encoding serine/threonine
kinases from the human genome and analyzed them for mutations in the
kinase domain in tumors from colorectal cancer patients. A total of 23
changes, including 20 nonsynonymous point mutations, 1 insertion, and 1
splice site alteration, were identified. The gene mutations affected 8
different proteins: 6 were in mitogen-activated protein kinase kinase-4
(MKK4/JNKK1; 601335), 6 in myosin light-chain kinase-2 (MYLK2; 606566),
3 in phosphoinositide-dependent protein kinase-1 (PDK1; 605213, of which
2 mutations affected the same residue in the kinase domain), 2 in
p21-activated kinase-4 (PAK4; 605451), 2 in v-akt murine thymoma viral
oncogene homolog-2 kinase (AKT2; 164731), and 2 in MAP/microtubule
affinity-regulating kinase-3 (MARK3; 602678); there was 1 alteration in
cell-division cycle-7 kinase (CDC7; 603311) and another in a
hypothetical casein kinase (PDIK1L). Eighteen of the 23 somatic
mutations occurred at evolutionarily conserved residues. MKK4/JNKK1 is
altered in a variety of tumor types, but no mutations in any of the
other genes had theretofore been found in colorectal cancers. Three of
the altered genes, PDK1, AKT2, and PAK4, encode proteins involved in the
phosphatidylinositol-3-hydroxykinase pathway, and 2 of these (AKT2 and
PAK4) are overexpressed in human cancers. Overall, nearly 40% of
colorectal tumors had alterations in 1 of 8 PI(3)K-pathway genes.

Boraska Jelavic et al. (2006) studied genotype and allele frequencies of
the GT microsatellite repeat polymorphism in intron 2 of the TLR2 gene
(603028.0002) in 89 Croatian patients with sporadic colorectal cancer
and 88 Croatian sex- and age-matched controls. The frequency of TLR2
alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p =
0.001, respectively) and the frequency of the allele with 31 GT repeats
was increased (p = 0.0147) in patients versus controls. The authors also
found that the gly299 allele of the TLR4 gene (603030.0001) was more
frequent in colorectal cancer patients than controls (p = 0.0269).

Sjoblom et al. (2006) determined the sequence of well-annotated human
protein-coding genes in 2 common tumor types. Analysis of 13,023 genes
in 11 breast and 11 colorectal cancers revealed that individual tumors
accumulate an average of about 90 mutant genes, but that only a subset
of these contribute to the neoplastic process. Using stringent criteria
to delineate this subset, Sjoblom et al. (2006) identified 189 genes
(average of 11 per tumor) that were mutated at significant frequency.
The vast majority of these were not known to be genetically altered in
tumors and were predicted to affect a wide range of cellular functions,
including transcription, adhesion, and invasion. Sjoblom et al. (2006)
concluded that their data defined the genetic landscape of 2 human
cancer types, provided new targets for diagnostic and therapeutic
intervention, and opened fertile avenues for basic research in tumor
biology.

Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007)
commented on the article by Sjoblom et al. (2006), citing statistical
problems that, if addressed, would result in the identification of far
fewer genes with significantly elevated mutation rates. Parmigiani et
al. (2007) responded that the conclusions of the above authors were
inaccurate because they were based on analyses that did not fully take
into account the experimental design and other critical features of the
Sjoblom et al. (2006) study.

To catalog the genetic changes that occur during tumorigenesis, Wood et
al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and
determined the sequences of the genes in the Reference Sequence database
in these samples. Based on analysis of exons representing 20,857
transcripts from 18,191 genes, Wood et al. (2007) concluded that the
genomic landscapes of breast and colorectal cancers are composed of a
handful of commonly mutated gene 'mountains' and a much larger number of
gene 'hills' that are mutated at low frequency. Wood et al. (2007)
described statistical and bioinformatic tools that may help identify
mutations with a role in tumorigenesis. The gene mountains are comprised
of well-known cancer genes such as APC (611731), KRAS (190070), and TP53
(191170). Furthermore, Wood et al. (2007) observed that most tumors
accumulated approximately 80 mutations, and that the majority of these
were harmless. Fewer than 15 mutations are likely to be responsible for
driving the initiation, progression, or maintenance of the tumor.

Alhopuro et al. (2008) identified somatic mutations in the MYH11 gene in
56 (56%) of 101 samples of colorectal cancer tissue showing
microsatellite instability. All 56 mutations were within a
mononucleotide repeat of 8 cytosines (C8) in the last exon of the MYH11
SM2 isoform, which is susceptible to mutations under microsatellite
instability, and were predicted to lead to a frameshift and elongation
of the protein. All mutations were found within epithelial cells.
Analysis of microsatellite stable tumors identified 2 somatic mutations
in the same tumor that were not in the C8 repeat. Functional expression
studies of the mutant proteins showed unregulated actin-activated motor
activity.

McMurray et al. (2008) showed that a large proportion of genes
controlled synergistically by loss-of-function p53 and Ras activation
are critical to the malignant state of murine and human colon cells.
Notably, 14 of 24 'cooperation response genes' were found to contribute
to tumor formation in gene perturbation experiments. In contrast, only 1
of 14 perturbations of the genes responding in a nonsynergistic manner
had a similar effect. McMurray et al. (2008) concluded that synergistic
control of gene expression by oncogenic mutations thus emerges as an
underlying key to malignancy, and provides an attractive rationale for
identifying intervention targets in gene networks downstream of
oncogenic gain- and loss-of-function mutations.

To help distinguish between driver and passenger mutations in colorectal
cancer, Starr et al. (2009) used a transposon-based genetic screen in
mice to identify candidate genes. Mice harboring mutagenic 'Sleeping
Beauty' (SB) transposons were crossed with mice expressing SB
transposase in gastrointestinal tract epithelium. Most of the offspring
developed intestinal lesions including intraepithelial neoplasia,
adenomas, and adenocarcinomas. Analysis of over 16,000 transposon
insertions identified 77 candidate CRC genes, 60 of which are mutated
and/or dysregulated in human CRC and thus are most likely to drive
tumorigenesis. The genes included APC, PTEN (601728), and SMAD4
(600993). The screen also identified 17 candidate genes that had not
been implicated in CRC, including POLI (605252), PTPRK (602545), and
RSPO2 (610575).

In colonocytes from COX-deficient crypts from 2 patients with colon
cancer, Greaves et al. (2006) identified 2 missense mutations in the
MTCO1 gene (see 516030.0010 and 516030.0011, respectively).

Using high-throughput screening of 14,662 human protein coding
transcripts, Sjoblom et al. (2006) found that the PKHD1 gene (606702)
was the seventh most common somatically mutated gene in colorectal
cancer. Germline mutations in the PKHD1 gene cause autosomal recessive
polycystic kidney disease (263200). Ward et al. (2011) observed an
association between the common T36M PKHD1 allele (606702.0001) and
protection against colorectal cancer. Germline heterozygosity for the
mutant allele was found in 0.42% of 3,603 healthy European controls and
in 0.027% of 3,767 patients with colorectal cancer (p = 0.0002; odds
ratio of 0.072). The authors postulated that reduced PKHD1 activity may
enhance mitotic instability, which may inhibit carcinogenesis.

Dorard et al. (2011) identified a mutant of HSP110 (see 610703), which
they called HSP110-delta-E9, in colorectal cancer showing microsatellite
instability (MSI CRC), generated from an aberrantly spliced mRNA and
lacking the HSP110 substrate-binding domain. This mutant was expressed
at variable levels in almost all MSI CRC cell lines and primary tumors
tested. HSP110-delta-E9 impaired both the normal cellular localization
of HSP110 and its interaction with other HSPs, thus abrogating the
chaperone activity and antiapoptotic function of HSP110 in a
dominant-negative manner. HSP110-delta-E9 overexpression caused the
sensitization of cells to anticancer agents such as oxaliplatin and
5-fluorouracil, which are routinely prescribed in the adjuvant treatment
of people with colorectal cancer. The survival and response to
chemotherapy of subjects with colorectal cancer showing microsatellite
instability was associated with the tumor expression level of
HSP110-delta-E9. Dorard et al. (2011) concluded that HSP110 may thus
constitute a major determinant for both prognosis and treatment response
in colorectal cancer.

The Cancer Genome Atlas Network (2012) conducted a genome-scale analysis
of 276 colorectal carcinoma samples analyzing exome sequence, DNA copy
number, promoter methylation, and mRNA and microRNA expression. A subset
of these samples (97) underwent low-depth-of-coverage whole-genome
sequencing. In total, 16% of colorectal carcinomas were found to be
hypermutated: three-quarters of these had the expected high
microsatellite instability, usually with hypermethylation and MLH1
silencing, and one-quarter had somatic mismatch-repair gene and
polymerase epsilon mutations. Excluding the hypermutated cancers, colon
and rectal cancers were found to have considerably similar patterns of
genomic alteration. Twenty-four genes were significantly mutated. In
addition to the expected APC, TP53, SMAD4, PIK3CA, and KRAS mutations,
the authors found frequent mutations in ARID1A (603024), SOX9 (608160),
and FAM123B (300647). Recurrent copy number alterations included
potentially drug-targetable amplification of ERBB2 (164870) and
amplification of IGF2 (147470). Recurrent chromosomal translocations
included the fusion of NAV2 (607026) and WNT pathway member TCF7L1
(604652). Integrative analyses suggested new markers for aggressive
colorectal carcinoma and an important role for MYC-directed
transcriptional activation and repression.

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224-226, 2012.

*FIELD* CS

Oncology:
Hereditary nonpolyposis colorectal carcinoma;
Associated endometrial carcinoma, atypical endometrial hyperplasia,
uterine leiomyosarcoma, bladder transitional carcinoma, gastric, biliary
and renal cell carcinoma;
APC, RAS, DCC or KRAS gene mutations;
Allele loss on chromosomes 5, 6, 12q, 15, 17, 18, or 22

Inheritance:
Autosomal dominantly acting oncogene plus loss of suppressor gene(s)

*FIELD* CN
Ada Hamosh - updated: 12/06/2013
Ada Hamosh - updated: 10/23/2013
Cassandra L. Kniffin - updated: 2/18/2013
Ada Hamosh - updated: 12/4/2012
Ada Hamosh - updated: 9/18/2012
Ada Hamosh - updated: 9/5/2012
Ada Hamosh - updated: 8/10/2012
Ada Hamosh - updated: 7/17/2012
Ada Hamosh - updated: 6/26/2012
Ada Hamosh - updated: 3/15/2012
Ada Hamosh - updated: 3/14/2012
Ada Hamosh - updated: 12/12/2011
Cassandra L. Kniffin - updated: 4/20/2011
Marla J. F. O'Neill - updated: 12/1/2010
Carol A. Bocchini - updated: 11/4/2010
Marla J. F. O'Neill - updated: 10/5/2009
Ada Hamosh - updated: 9/14/2009
Ada Hamosh - updated: 6/18/2009
Ada Hamosh - updated: 7/29/2008
Ada Hamosh - updated: 7/18/2008
Cassandra L. Kniffin - updated: 4/28/2008
Ada Hamosh - updated: 2/14/2008
Ada Hamosh - updated: 1/9/2008
Victor A. McKusick - updated: 11/20/2007
Ada Hamosh - updated: 10/31/2006
Marla J. F. O'Neill - updated: 9/22/2006
Ada Hamosh - updated: 9/8/2005
Ada Hamosh - updated: 7/27/2005
Victor A. McKusick - updated: 4/15/2005
Ada Hamosh - updated: 4/30/2004
Ada Hamosh - updated: 5/29/2003
Ada Hamosh - updated: 4/3/2003
Victor A. McKusick - updated: 3/14/2003
Ada Hamosh - updated: 9/30/2002
George E. Tiller - updated: 9/26/2002
Ada Hamosh - updated: 9/17/2002
Paul Brennan - updated: 3/19/2002
Paul Brennan - updated: 3/13/2002
Paul Brennan - updated: 3/6/2002
George E. Tiller - updated: 6/19/2001
Stylianos E. Antonarakis - updated: 7/20/1999
Victor A. McKusick - updated: 2/9/1999
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 12/06/2013
alopez: 10/23/2013
tpirozzi: 10/1/2013
carol: 3/11/2013
carol: 2/19/2013
ckniffin: 2/18/2013
alopez: 12/6/2012
terry: 12/4/2012
alopez: 9/19/2012
terry: 9/18/2012
alopez: 9/5/2012
carol: 8/10/2012
terry: 8/10/2012
terry: 7/27/2012
alopez: 7/19/2012
terry: 7/17/2012
alopez: 6/26/2012
terry: 6/26/2012
alopez: 3/15/2012
alopez: 3/14/2012
alopez: 12/19/2011
terry: 12/12/2011
carol: 9/7/2011
wwang: 5/2/2011
ckniffin: 4/20/2011
carol: 4/20/2011
wwang: 12/3/2010
carol: 12/2/2010
terry: 12/1/2010
carol: 11/4/2010
carol: 3/19/2010
alopez: 2/4/2010
ckniffin: 1/15/2010
wwang: 10/14/2009
terry: 10/5/2009
wwang: 9/29/2009
alopez: 9/14/2009
wwang: 7/29/2009
alopez: 6/24/2009
terry: 6/18/2009
wwang: 2/13/2009
ckniffin: 2/9/2009
terry: 1/12/2009
terry: 1/9/2009
carol: 9/19/2008
alopez: 8/18/2008
terry: 7/29/2008
wwang: 7/18/2008
wwang: 6/9/2008
ckniffin: 4/28/2008
carol: 2/15/2008
alopez: 2/15/2008
terry: 2/14/2008
ckniffin: 2/5/2008
carol: 1/31/2008
ckniffin: 1/28/2008
alopez: 1/28/2008
terry: 1/9/2008
alopez: 12/7/2007
terry: 11/20/2007
alopez: 9/27/2007
alopez: 8/31/2007
alopez: 11/3/2006
terry: 10/31/2006
alopez: 10/9/2006
wwang: 9/22/2006
wwang: 5/17/2006
carol: 4/14/2006
alopez: 12/5/2005
alopez: 9/9/2005
terry: 9/8/2005
alopez: 7/28/2005
terry: 7/27/2005
carol: 6/3/2005
mgross: 4/15/2005
mgross: 4/14/2005
mgross: 4/13/2005
tkritzer: 2/11/2005
alopez: 4/30/2004
terry: 4/30/2004
carol: 7/10/2003
mgross: 5/29/2003
joanna: 5/29/2003
terry: 5/29/2003
terry: 4/3/2003
carol: 3/21/2003
tkritzer: 3/18/2003
terry: 3/14/2003
alopez: 9/30/2002
tkritzer: 9/30/2002
cwells: 9/26/2002
alopez: 9/17/2002
alopez: 3/19/2002
alopez: 3/13/2002
alopez: 3/6/2002
cwells: 6/20/2001
cwells: 6/19/2001
carol: 10/20/2000
carol: 8/12/1999
mgross: 7/20/1999
mgross: 2/16/1999
mgross: 2/15/1999
terry: 2/9/1999
alopez: 6/27/1997
jenny: 4/21/1997
terry: 4/14/1997
terry: 12/10/1996
terry: 12/9/1996
carol: 5/31/1994
terry: 5/13/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 2/24/1993
carol: 10/12/1992

MIM 162200
*RECORD*
*FIELD* NO
162200
*FIELD* TI
#162200 NEUROFIBROMATOSIS, TYPE I; NF1
;;NEUROFIBROMATOSIS, PERIPHERAL TYPE;;
VON RECKLINGHAUSEN DISEASE
read more*FIELD* TX
A number sign (#) is used with this entry because neurofibromatosis type
I (NF1) is caused by mutation in the neurofibromin gene (NF1; 613113) on
chromosome 17q11.2.

DESCRIPTION

Neurofibromatosis type I is an autosomal dominant disorder characterized
by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors
of the skin. Individuals with the disorder have increased susceptibility
to the development of benign and malignant tumors. NF1 is sometimes
referred to as 'peripheral neurofibromatosis.' The worldwide incidence
of NF1 is 1 in 2,500 to 1 in 3,000 individuals (reviews by Shen et al.,
1996 and Williams et al., 2009).

Type II neurofibromatosis (NF2; 101000) is a genetically distinct
disorder caused by mutation in the gene encoding merlin (NF2; 607379) on
chromosome 22q12. NF2, sometimes known as 'central neurofibromatosis,'
is characterized by bilateral acoustic neuroma and meningioma, but few
skin lesions or neurofibromas (Rouleau et al., 1993).

Some patients with homozygous or compound heterozygous mutations in
mismatch repair genes (see, e.g., MLH1; 120436 and MSH2; 609309) have a
phenotype characterized by early onset malignancies and mild features of
NF1, especially cafe-au-lait spots; this is known as the mismatch repair
cancer syndrome (276300), sometimes referred to as brain tumor-polyposis
syndrome-1 or Turcot syndrome. These patients typically do not have
germline mutations in the NF1 gene, although a study by Wang et al.
(2003) suggested that biallelic mutations in mismatch repair genes may
cause somatic mutations in the NF1 gene, perhaps resulting in isolated
features resembling NF1.

See also Legius syndrome (611431), a genetically distinct disorder with
a similar phenotype to NF1.

CLINICAL FEATURES

Sorensen et al. (1986) conducted a valuable follow-up study of the
natural history of NF1 in a nationwide cohort of 212 patients with the
disorder identified in Denmark by Borberg (1951). Malignant neoplasms or
benign CNS tumors occurred in 45% of the probands, giving a relative
risk of 4.0 compared with expected numbers. All 76 probands had been
ascertained through hospitals and were more severely affected than their
incidentally identified relatives, although relatives had poorer
survival rates than persons in the general population. The worst
prognosis was shown by female probands.

Friedman et al. (1993) described a central database designed to collect
information on NF1 from 16 centers around the world. The aspects of the
disorder for which information was being collected included renal artery
stenosis and cerebral artery stenosis.

Dugoff and Sujansky (1996) reported outcome data of 247 pregnancies in
105 women with NF1. The 247 pregnancies resulted in 44 first trimester
spontaneous abortions. The cesarean section rate (36%) was greater than
in the general population (9.1 to 23.5%). In 7 of the patients, cesarean
section was required because of maternal complications of NF1 including
pelvic neurofibromas, pelvic bony abnormality with or without
kyphoscoliosis, pheochromocytoma, and spinal cord neurofibroma. Dugoff
and Sujansky (1996) reported that 80% of the women in their study
experienced either the appearance of new neurofibromas, growth of
existing neurofibromas, or both. Thirty-three percent of these women
noted a decrease in the size of their neurofibromas in the postpartum
period. Eighteen percent of the women reported no changes in
neurofibromas and no appearance of new neurofibromas during pregnancy.

Friedman and Birch (1997) summarized clinical information about NF1
patients based on the International Database maintained by the National
NF Foundation (NNFF), which contained information on 1,479 probands and
249 of their affected relatives with NF1 at the time of analysis. The
age at diagnosis of NF1 was 8 years younger in the probands than in the
affected relatives, and many of the manifestations of NF1 were more
frequent in the probands than in their affected relatives. The
age-specific prevalence of most manifestations of NF1 increased with
age. Despite biases inherent in a convenience sample from specialist
clinics, the frequency of manifestations of NF1 in many of the series
was similar to those in 2 smaller population-based studies. Lisch
nodules were said to be present in 57% of probands and 69.9% of affected
relatives.

McGaughran et al. (1999) reported a study of 523 individuals from 304
families with NF1. More than 6 cafe-au-lait patches were seen in 383 of
442 (86.7%); 310 of 370 (83.8%) had axillary freckling; 151 of 357
(42.3%) had inguinal freckling; and 157 of 249 (63%) had Lisch nodules.
Cutaneous neurofibromas were seen in 217 of 365 (59.4%), and
subcutaneous tumors were present in 150 of 330 (45.5%). A positive
family history of NF1 was found in 327 of 459 (71.2%). Learning
disabilities of varying severity were seen in 186 of 300 (62%), and 49
(9.4%) of patients had CNS tumors, 25 of which were optic gliomas.
Scoliosis was seen in 11.7%; 1.9% had pseudoarthrosis; 4.3% had
epilepsy; and 2.1% had spinal neurofibromas.

Macrocephaly and short stature have been reported in several clinical
studies of NF1. Clementi et al. (1999) studied growth in 528 NF1
patients obtained from a population-based registry in northeast Italy.
Although macrocephaly was a consistent and common finding in NF1, short
stature was less prominent and less frequent than previously reported.
No differences in height were apparent between NF1 and normal subjects
up to 7 years of age in girls and 12 years of age in boys. Clementi et
al. (1999) presented growth charts for use by physicians following NF1
patients to assist in the identification of the effects of secondary
growth disorders, for growth prognosis, and for evaluation of the
effects of therapy.

Szudek et al. (2000) presented growth charts derived from study of 569
white North American children with NF1. They found that stature and
occipitofrontal circumference (OFC) measurements were shifted and
unimodal, with 13% of children being at or more than 2 SD below mean and
24% having OFC at or more than 2 SD above mean.

Rasmussen et al. (2001) used Multiple-Cause Mortality Files, compiled
from U.S. death certificates by the National Center for Health
Statistics for 1983-1997, to obtain information on mortality in NF1.
They identified 3,770 cases among 32,722,122 deaths in the United
States, a frequency of 1 in 8,700, which is one-third to one-half the
estimated prevalence. Mean and median ages at death for persons with NF1
were 54.4 and 59 years, respectively, compared with 70.1 and 74 years in
the general population. Results of proportionate mortality ratio (PMR)
analyses showed that persons with NF1 were 34 times more likely to have
a malignant connective or other soft-tissue neoplasm listed on their
death certificates than were persons without NF1. Overall, persons with
NF1 were 1.2 times more likely than expected to have a malignant
neoplasm listed on their death certificates, but the PMR was 6.07 for
persons who died at 10 to 19 years of age and was 4.93 for those who
died at 20 to 29 years of age. Similarly, vascular disease was recorded
more often than expected on death certificates of persons with NF1 who
died before 30 years of age, but not in older persons.

Szudek et al. (2003) studied statistical associations among 13 of the
most common or significant clinical features of NF1 in data from 4 large
sets of NF1 patients comprising about 3,000 patients. The results
suggested grouping 9 of the clinical features into 3 sets: (1)
cafe-au-lait spots, intertriginous freckling, and Lisch nodules; (2)
cutaneous, subcutaneous, and plexiform neurofibromas; (3) macrocephaly,
optic glioma, other neoplasms. In addition, 3-way interactions among
cafe-au-lait spots, intertriginous freckling, and subcutaneous
neurofibromas indicated that the first 2 groups are not independent.
Cafe-au-lait spots, intertriginous freckles, and Lisch nodules are all
derived from cells of melanocytic origin, which derive from the
embryonic neural crest. Thus, NF1 can be considered a neurocristopathy.
The common thread between optic gliomas, other neoplasms, and
macrocephaly may be glial hyperplasia. There was an observed association
between pseudarthrosis and other neoplasms, which was more difficult to
understand. Szudek et al. (2003) noted that these results cannot be used
to predict which NF1 patients will get which particular features, but
suggest that some affected individuals may be more likely than others to
develop certain features of the disease.

Khosrotehrani et al. (2003) performed a cohort study among 378 NF1
patients receiving more than 1 year of follow-up care at an NF1 referral
center in France. Clinical features, especially dermatologic, were
evaluated as potential factors associated with mortality. Factors
associated independently with mortality were the presence of
subcutaneous neurofibromas (odds ratio, 10.8; 95% CI, 2.1-56.7; p less
than 0.001), the absence of cutaneous neurofibromas (odds ratio, 5.3;
95% CI, 1.2-25.0; p = 0.03), and facial asymmetry (odds ratio, 11.4; 95%
CI, 2.6-50.2; p less than 0.01). The absence of cutaneous neurofibromas
in adulthood associated with high mortality may correspond to a subtype
of NF1, familial spinal neurofibromatosis (162210). Khosrotehrani et al.
(2003) concluded that features that can be found by a routine clinical
examination are associated with mortality in patients with NF1, and that
clinical follow-up should be focused on patients with subcutaneous
neurofibromas, absence of cutaneous neurofibromas, and/or facial
asymmetry. In a parallel study of a cohort of 703 NF1 patients in North
America, Khosrotehrani et al. (2005) validated the observation that
subcutaneous neurofibromas were associated with mortality.

- Skin Manifestations

Variable numbers of hyperpigmented cafe-au-lait spots usually develop in
the first years of life, but may be present at birth, and are often the
first apparent feature of NF1. The quantity and size of these macules
has not been linked to disease severity, and they show no tendency to
malignant degeneration. The presence of 6 or more cafe-au-lait macules
with diameter 0.5 cm before puberty or 1.5 cm after puberty is a
diagnostic feature (see DIAGNOSIS below). Axillary and inguinal
freckling ('Crowe sign') are usually noted between 3 and 5 years of age.
Freckling can also occur above the eyelids, around the neck, and under
the breasts. (reviews by Ferner et al., 2007 and Williams et al., 2009).

Neurofibromas are benign Schwann cell tumors that are classified
according to their appearance and location: focal or diffuse cutaneous,
subcutaneous, nodular or diffuse plexiform, and spinal. Focal cutaneous
or dermal neurofibromas typically appear in late childhood or early
adolescence, rarely cause pain or neurologic deficits, and do not
transform into malignant tumors. Subcutaneous lesions can be noted on
palpation of the skin and may present with tenderness or tingling
distributed along the affected nerve. Plexiform neurofibromas arise from
nerve fascicles, tend to grow along the length of the nerve, may involve
multiple nerve branches and plexuses, and can cause significant
morbidity. The growth rate is unpredictable, and soft tissue hypertrophy
is often noted. Only the plexiform type of neurofibromas have a
potential for transformation into malignant peripheral nerve sheath
tumors (MPNST, see below) (reviews by Rosser and Packer, 2002; Ferner et
al., 2007, and Williams et al., 2009).

Waggoner et al. (2000) conducted a retrospective review of neurofibromas
among NF1 patients seen in a tertiary care referral center. Sixty-eight
(16.8%) of 405 patients with NF1 had plexiform neurofibromas, which were
located on the trunk (43%), the head and neck region (42%), and the
extremities (15%). About 44% of these tumors were detected by 5 years of
age. Presenting symptoms were most often related to the increasing size
of the tumor, a loss of function (usually weakness), or pain. Only 2
patients (3%) developed malignant peripheral nerve sheath tumors in
their preexisting plexiform neurofibromas. No specific NF1 features were
associated with plexiform tumors.

To analyze growth rate and prognostic factors for progression of
postoperative plexiform neurofibromas in patients with NF1, Nguyen et
al. (2013) studied 52 patients (mean age 25 years, range 3-64 years)
with 56 plexiform neurofibromas and looked at postoperative tumor volume
change per year on MRI. Initial median tumor volume was 40.3 mL.
Surgical indications included disfigurement in 21 patients, pain in 20
patients, and functional deficits in 16 patients. Sixteen percent of all
cases experienced acute surgical complication, and 13% showed late
complication. Eight patients (19%; 6 children, 2 adults) with residual
tumor had repeat surgery for tumor progression. Median tumor progression
was 0.6% change per year and 2.9% from baseline. Patients aged 21 years
and younger had the highest progression rate (p less than 0.01). For
every year of age the mean growth rate decreased by -0.463 mean percent
(p = 0.03). With age as a continuous variable, age, the site of the
tumor, and depth were the only factors associated with tumor
progression. Fourteen plexiform neurofibromas (10 nodular and 4 diffuse)
in 13 patients (5 children and 8 adults) were completely resected by
visualization and did not relapse during observation (mean: 2.9 years;
range: 1.1-5.8 years). Nguyen et al. (2013) concluded that age, tumor
type, location, and depth are helpful to estimate the progression of
plexiform neurofibromas after surgery and that patients benefit from
elective surgery of small and completely removable plexiform
neurofibromas.

- Ophthalmologic Manifestations

Williams et al. (2009) noted that Lisch nodules, melanocytic iris
hamartomas that do not affect vision, are pathognomonic of NF1.

Perry and Font (1982) used electron microscopic studies to demonstrate
that the spindle-shaped cells within Lisch nodules are of melanocytic
origin and represent melanocytic hamartomas. Thus, Lisch nodules are
true tumors, not merely hyperpigmented patches.

Zehavi et al. (1986) found Lisch nodules in 73% of 30 NF1 cases, and
found that their presence correlated directly with the severity of skin
manifestations. Lisch nodules appeared as smooth, well-defined,
gelatinous masses protruding from the surface of the iris on slit-lamp
examination.

Ragge et al. (1993) provided a comprehensive discussion of Lisch nodules
accompanied by colored photographs in irides of different colors. They
pointed out that iris nodules were reported by several workers in the
decade before the paper by Lisch (1937). In particular, Sakurai (1935)
published a beautifully illustrated paper linking characteristic iris
nodules with von Recklinghausen neurofibromatosis. Ragge et al. (1993)
suggested that the lesions be renamed Sakurai-Lisch nodules in her
honor.

On rare occasions, fibromas may occur in the iris, and glaucoma may
occur (Grant and Walton, 1968). Westerhof et al. (1983) found
hypertelorism in 24% of patients with neurofibromatosis.

Yasunari et al. (2000) studied 33 eyes of 17 consecutive NF1 patients
diagnosed with NF1 by conventional ophthalmoscopy and by noninvasive
infrared monochromatic light with confocal scanning laser ophthalmoscopy
(SLO). Twenty-one digital fluorescein and indocyanine-green
angiographies were obtained from 11 adult patients, and 77 angiograms
were obtained from age-matched controls. Infrared monochromatic light
examination by confocal SLO showed multiple bright patchy regions at and
around the entire posterior pole of all 33 NF1 eyes. All bright patchy
regions seen in adult patients corresponded to hypofluorescent areas on
their indocyanine-green angiograms; however, no abnormalities were noted
in any patient at corresponding areas under conventional ophthalmoscopic
examination or fluorescein angiography. Control patients and their
angiograms showed no choroidal abnormalities. Iris nodules were noted in
25 eyes (76%) of 14 patients (82%) and eyelid neurofibroma in 5 patients
(29%). Since choroidal abnormalities were detected in 100% of NF1
patients examined, Yasunari et al. (2000) suggested that this
abnormality be included in the diagnostic criteria for NF1.

Otsuka et al. (2001) performed serial ophthalmologic exams on 70
patients of various ages with NF1. Lisch nodules were found in 80% of
patients of all ages and in two-thirds of patients younger than 10
years. Only 2 of 45 individuals older than age 10 years did not have
Lisch nodules. Lisch nodules were more frequent in familial cases than
in sporadic cases. Cutaneous neurofibromas developed at the average +/-
SD age of 15.1 +/- 3.6 years in patients who had more than 10 Lisch
nodules and at 21.8 +/- 3.9 years in those who had fewer than 10 Lisch
nodules. The former group was significantly younger than the latter.

Lee et al. (2004) classified the periorbital deformities of adult
orbitotemporal NF, reported previously undescribed clinical findings,
and recommended guidelines for surgical treatment as well as management
of surgical complications. They proposed a new classification for
periorbital deformities: (1) brow ptosis; (2) upper eyelid infiltration
with ptosis; (3) lower eyelid infiltration; (4) lateral canthal
disinsertion; and (5) conjunctival and lacrimal gland infiltration. Of
33 patients over age 16 years with orbitotemporal NF, 2 (6%) had
bilateral involvement whereas 31 (94%) had unilateral orbitotemporal NF.
Previously undescribed findings included severe brow infiltration,
lacrimal gland involvement, and functional nasolacrimal duct
obstruction.

- Optic Pathway Gliomas

Optic pathway gliomas (OPGs) are typically low-grade pilocytic
astrocytomas that involve some combination of the optic nerves, chiasm,
or optic tracts that occur in about 15% of children with NF1. OPGs are
the most common intracranial malignancy in NF1. While most have a benign
course, some may manifest as precocious puberty (reviews by Ferner et
al., 2007 and Williams et al., 2009).

A longitudinal study of 219 patients with NF1 reported that clinical
precocious puberty developed in 7 children, all of whom had optic
chiasmal tumors (Listernick et al., 1994, 1995).

Parazzini et al. (1995) documented spontaneous regression of optic
pathway lesions in 4 NF1 patients and cautioned against diagnosis of
optic nerve glioma without evidence of progression.

Parsa et al. (2001) observed spontaneous regression of large, clinically
symptomatic optic gliomas in 13 patients, 5 with and 8 without NF1.
Regression manifested as an overall shrinkage in tumor size or as a
signal change on serial MRI. A variable degree of improvement in visual
function accompanied regression. The authors concluded that the
possibility of spontaneous regression of an optic glioma should be
considered in planning the treatment of patients with these tumors.

Balcer et al. (2001) examined the neuroophthalmologic records and
brain/orbital MRI scans from 43 consecutive pediatric NF1 patients with
optic pathway gliomas. Involvement of the optic tracts and other
postchiasmal structures was associated with a significantly higher
probability of visual acuity loss. Visual loss was noted in 47% of
patients at a median age of 4 years. However, 7% of patients developed
initial visual loss during adolescence. The authors recommended close
follow-up beyond the early childhood years, particularly for those
children with postchiasmal tumor.

Singhal et al. (2002) compared the natural history of sporadic and
NF1-associated optic gliomas in a series of 52 patients from northwest
Britain. Ages at presentation were similar, but those associated with
NF1 were less likely to present with impaired vision. Although NF1 optic
gliomas were less aggressive, there was little difference in 5- and
10-year mortality rates between the 2 tumor groups. NF1 optic glioma
cases were also at risk of a second primary central nervous system
tumor; in 2 of 5 cases this occurred following radiotherapy, suggesting
an etiologic link.

Thiagalingam et al. (2004) reviewed the natural history of optic pathway
gliomas in 54 patients with NF1. The mean age at the time of diagnosis
was 5.2 years, with 32 patients having signs or symptoms at the time of
diagnosis. Seventeen patients were diagnosed after the age of 6 years.
Twenty-two patients had tumor progression within 1 year of diagnosis and
6 patients showed progression after 1 year. Most conditions were managed
conservatively (68.5%). At follow-up, 17 patients (31.5%) had severe
visual impairment in their worse eye and 16.7% had bilateral moderate to
severe visual impairment. Contrary to previous reports (e.g., Balcer et
al., 2001), these results showed that optic pathway gliomas in patients
with NF1 often presented in older children and might progress some time
after diagnosis. Given the potential for serious visual consequences,
the authors stressed the need for regular ophthalmologic monitoring of
patients with NF1 for a long duration.

Liu et al. (2004) described the clinical and radiologic features of 7
children with NF1 with optic pathway gliomas involving the pregeniculate
optic pathway in addition to the optic radiations. Two of the patients
had expanding mass lesions within the white matter of the temporal or
parietal lobes, which were histopathologically demonstrated to be
pilocytic astrocytomas; the other 5 had radiographic involvement of the
optic radiations but did not undergo biopsy. In 3 of the cases, the
visual acuity was 20/200 or worse in each eye. Liu et al. (2004)
concluded that optic pathway gliomas in NF1 rarely involve the optic
radiations, but that optic radiation involvement might signal a more
aggressive optic pathway glioma in patients with NF1.

- Malignant Peripheral Nerve Sheath Tumors

One of the most clinically aggressive cancers associated with NF1 is the
malignant peripheral nerve sheath tumor (MPNST), estimated to occur in 3
to 15% of patients over a lifetime (Knight et al., 1973).

King et al. (2000) reviewed 1,475 individuals with NF1 from a cohort of
patients examined by a single investigator, Vincent M. Riccardi, between
1977 and 1996. MPNST was identified in 34 individuals (2%), yielding a
relative risk value of 113. Lesions occurred in the limbs in 18 patients
(53%), and those with limb lesions survived longer than those with
nonlimb MPNSTs. Pain associated with a mass was the strongest suggestion
of MPNST development.

Leroy et al. (2001) performed a retrospective study of MPNST in a cohort
of 395 patients with NF1 followed for 11 years in a teaching hospital
setting. Seventeen patients (4.3%) developed tumors, with a mean age at
diagnosis of 32 years (SD = 14 years). Twelve patients had high-grade
tumors; all tumors except 1 developed on preexisting nodular or
plexiform neurofibromas. Pain and enlarging mass were the first and
predominant signs. None of the benign tumors displayed significant p53
(TP53; 191170) staining or p53 mutations. Six of 12 malignant tumors
significantly overexpressed p53, and 4 of 6 harbored p53 missense
mutations. Median survival was 18 months overall, 53 months in
peripheral locations, and 21 months in axial locations. Leroy et al.
(2001) concluded that investigations and deep biopsy of painful and
enlarging nodular or plexiform neurofibromas should be considered in
patients with NF1, and that late appearance of p53 mutations and
overexpression precludes their use as predictive markers for malignant
transformation.

Evans et al. (2002) ascertained NF1 patients with MPNST in an attempt to
assess lifetime risk. They found 21 NF1 patients who developed MPNST,
equivalent to an annual incidence of 1.6 per 1,000 and a lifetime risk
of 8 to 13%. There were 37 patients with sporadic MPNST. The median age
at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years
in patients with sporadic MPNST. In Kaplan-Meier analyses, the 5-year
survival after diagnosis was 21% for NF1 patients with MPNST, compared
to 42% for sporadic cases. One NF1 patient developed 2 separate MPNSTs
in the radiation field of a previous optic glioma.

McCaughan et al. (2007) surveyed Scottish medical records across a
10-year period and identified 14 NF1 patients with a coexistent
diagnosis of MPNST. The lifetime risk of developing MPNST was calculated
to be 5.9 to 10.3%, and the mean age at diagnosis of the tumors was 42.1
years. Five-year survival after diagnosis of MPNST was significantly
lower in NF1 patients compared to patients without NF1 (0% vs 54%, p
less than 0.01).

- Susceptibility to Other Malignancies

Crowe et al. (1956) found 6 secondary malignant lesions in 168 patients
with neurofibromatosis. D'Agostino et al. (1963) discovered 21 cases of
secondary neoplasms in his study of 678 cases of neurofibromatosis.

Knight et al. (1973) reviewed 69 patients with single and 45 patients
with multiple neurofibromas. Five patients in the group were found to
have a total of 11 secondary malignant lesions including 3
fibrosarcomas, 3 squamous cell carcinomas, and 1 neurofibrosarcoma,
among other forms. Some earlier studies have reported mainly sarcomas
associated with neurofibromatosis.

Clark and Hutter (1982) reported an apparent association between the
rare entity juvenile chronic myelogenous leukemia and neurofibromatosis.
They suggested that other types of nonlymphocytic leukemia have an
increased frequency, but Riccardi (1982) raised the question as to
whether these are families with only cafe-au-lait spots.

Kalff et al. (1982) found pheochromocytoma in 10 of 18 NF1 patients with
hypertension. Age at diagnosis ranged from 15 to 62 years. The clinical
characteristics of the neurofibromatosis did not predict the presence of
pheochromocytoma. One patient without pheochromocytoma had coarctation
of the aorta and 1 had renal artery stenosis; this patient was described
as having the Turner phenotype. At least 2 of the pheochromocytoma
patients had renal artery stenosis, and 3 had small bowel and/or stomach
neurofibromata. One patient with pheochromocytoma also had hypernephroma
with metastases and another had disseminated metastases from an
undifferentiated leiomyosarcoma thought to originate from her upper
gastrointestinal tract.

Voutsinas and Wynne-Davies (1983) suggested that the risk of malignancy
in NF1 had been exaggerated and that the true value was 2.0% (or 4.2% of
those over 21 years).

Crawford (1986) reported on a study of 116 NF1 patients under 12 years
of age and reviewed the literature. Among the unusual presentations was
rhabdomyosarcoma projecting from the urethra in a girl who also had
congenital pseudarthrosis of the tibia. Crawford (1986) stated that
'most of the rhabdomyosarcomas associated with neurofibromatosis involve
the genitourinary tract.'

Sayed et al. (1987) described malignant schwannoma in 3 brothers who had
inherited neurofibromatosis from their mother. Two of the brothers had
been reported by Herrmann (1950).

Griffiths et al. (1987) reported 9 cases of NF1 with a carcinoid tumor
in the duodenum that had widespread somatostatin (SST; 182450)
immunoreactivity. The duodenum was also the primary site in 18 of 20
published NF1 cases with carcinoid tumor. Pheochromocytoma was also
present in 6 of the 27 cases with NF1 and duodenal carcinoid tumor. In
cases of von Hippel-Lindau syndrome (193300), with which
pheochromocytoma also occurs, Griffiths et al. (1987) found no carcinoid
tumors, but did find islet cell tumor in association with
pheochromocytoma. Swinburn et al. (1988) reported 2 patients with
neurofibromatosis and duodenal carcinoid tumor, bringing the total
number of cases of this association to 18. Their 2 cases as well as 5
others were positively identified as somatostatinomas. The histologic
finding of psammoma bodies is important in the diagnosis of duodenal
somatostatinomas. One patient also had a parathyroid adenoma, which was
found postmortem.

Although NF1 has been called 'peripheral neurofibromatosis,' it has been
associated with tumors of the central nervous system, which include
astrocytomas of the visual pathways, ependymomas, meningiomas, and some
primitive neuroectodermal tumors. The most common neuroimaging
abnormality in NF1 is a high signal intensity lesion in the basal
ganglia, thalamus, brainstem, cerebellum, or subcortical white matter
referred to as an 'unidentified bright object' (UBO). These UBOs are
thought to represent sites of vacuolar change. Molloy et al. (1995)
studied 17 NF1 patients with brainstem tumors, which also presented
increased T2 signal abnormality on MRI scanning. Fifteen of these 17
patients had neurologic signs and symptoms indicative of brainstem
dysfunction and 35% of them had evidence of radiographic tumor
progression. In the 2 patients that had partial surgical resection,
pathology demonstrated either a fibrillary or anaplastic astrocytoma. As
15 of these 17 patients remained alive after a 52-month follow-up, this
suggested that these are much less aggressive than typical pontine
tumors which should be distinguished from the UBOs seen elsewhere in the
brains of neurofibromatosis patients.

Hunerbein et al. (1996) described a 56-year-old man with NF1 who had had
a 6-month history of recurrent epigastric pain and was found to have a
multifocal malignant schwannoma of the duodenum causing biliary
obstruction.

Sakaguchi et al. (1996) described a 48-year-old man with NF1 and
paroxysmal hypertension in progressive respiratory insufficiency.
Clinical investigation displayed calcified tumors in the anterior
mediastinum and perirenal region. Histologic examination at autopsy
revealed composite tumors consisting of pheochromocytoma and malignant
peripheral nerve sheath tumor at 2 sites: the left adrenal gland and the
region surrounding the inferior vena cava, probably corresponding to the
right adrenal gland. In addition, the gastrointestinal tract was
involved with mesenchymal tumors showing neurogenic differentiation.

Coffin et al. (2004) reviewed information indicating that children and
young adults with NF1 have a higher risk for non-neurogenic sarcomas
than the general population, in addition to an increased risk for
malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas
occur in early childhood, a subsequent malignant peripheral nerve sheath
tumor can occur as a second malignant neoplasm, especially after
alkylating agent chemotherapy and irradiation. Coffin et al. (2004)
presented 4 patients. In 1, embryonal rhabdomyosarcoma was diagnosed at
the age of 2 years, and was treated by surgery, radiation, and
chemotherapy. A malignant peripheral nerve sheath tumor was detected at
the age of 13 years. A second patient likewise had the diagnosis of
embryonal rhabdomyosarcoma at the age of 2 years and had the same
therapy followed by T-cell lymphoblastic lymphoma at the age of 7 years.

Oguzkan et al. (2006) described 2 cases of NF1 with rhabdomyosarcoma.
The first was that of an infant with overlapping phenotypic features of
neurofibromatosis and Noonan syndrome (NS1; 163950) (see NFNS, 601321)
who presented with rhabdomyosarcoma of the bladder. The second infant
likewise exhibited NF1 features and was also associated with bladder
rhabdomyosarcoma. Loss of heterozygosity (LOH) analysis of the NF1 gene
using 7 intragenic markers and 1 extragenic polymorphic marker detected
a deletion in the NF1 gene in the NFNS case associated with bladder
rhabdomyosarcoma.

Bausch et al. (2006) reported that 15 (3%) of 565 pheochromocytoma cases
in a pheochromocytoma registry had an NF1 mutation. In 10 additional
cases contributed specifically for a study of pheochromocytoma in NF1,
they found 92% had germline NF1 mutations. The 25 patients with NF1 were
compared with patients with other syndromes associated with
pheochromocytoma: 31 patients with multiple endocrine neoplasia type 2
(MEN2; 171400) due to mutation in the RET gene (164761); 21 patients
with paragangliomas-1 (168000) due to mutation in the SDHD gene
(602690); 33 patients with paragangliomas-4 (115310) due to mutation in
the SDHB gene (185470); 75 patients with von Hippel-Lindau disease
(193300) due to mutation in the VHL gene (608537); and 380 patients with
pheochromocytoma as a sporadic disease. The characteristics of patients
with pheochromocytoma related to NF1 were similar to those of patients
with sporadic pheochromocytoma. There were significant differences
between the NF1 group and the other respective groups in the age at
diagnosis (von Hippel-Lindau disease and paragangliomas-1); in the
extent of multifocal tumors (MEN2, von Hippel-Lindau disease, and
paragangliomas-1); and in the extent of extraadrenal tumors (MEN2, von
Hippel-Lindau disease, paragangliomas-1, and paragangliomas-4). Patients
with NF1 had a relatively high (but not significant) prevalence of
malignant disease (12%), second only to that among patients with
paragangliomas-4 who had a germline mutation in the SDHB gene (24%).
Taken together, 33% of all symptomatic patients with pheochromocytoma in
the multicenter, multinational registry carried germline mutations in 1
of the 5 genes, including the NF1 gene.

- Vascular Manifestations

Renal artery stenosis due to 'vascular neurofibromatosis' is a
relatively common cause of hypertension in patients with NF1. Reubi
(1945) first described vascular NF1. Involvement of the heart in
neurofibromatosis was described and reviewed by Rosenquist et al.
(1970), who also reviewed involvement of the abdominal aorta and renal,
carotid, and other arteries.

Salyer and Salyer (1974) found peculiar arterial lesions in 7 of 18
autopsy cases of NF1 at the Johns Hopkins Hospital. They proposed that
the pathogenesis of the arterial lesions was proliferation of Schwann
cells within arteries with secondary degenerative changes, e.g.,
fibrosis, resulting in lesions with various appearances.

Among 40 pediatric patients (16 girls and 24 boys), aged 22 months to 17
years, undergoing operation for renovascular hypertension, Stanley and
Fry (1981) found that 10 had neurofibromatosis, including 3 with
abdominal aortic anomalies. Abdominal aortic coarctation affected 5
other children. Cure of the hypertension was achieved in 34 patients
(85%); the condition was improved in 5; and one case was classified as a
therapeutic failure. Single cases of renovascular hypertension in
neurofibromatosis were reported by Allan and Davies (1970), Finley and
Dabbs (1988), and others.

Brunner et al. (1974) described an unusual case of chronic mesenteric
arterial insufficiency caused by vascular neurofibromatosis in a
50-year-old man with a 30-year history of chronic malabsorption and
chronic small intestinal paralysis. He was said to have no signs of
systemic disease or cafe-au-lait spots. Pigmentation of the perioral
area and lips of the patient were attributed to longstanding
malabsorption syndrome.

Zochodne (1984) reported a 16-year-old NF1 girl with aneurysm of the
superior mesenteric artery complicating renovascular hypertension
associated with coarctation of the abdominal aorta from above the celiac
trunk to above the origin of the inferior mesenteric artery. The
coarctation was associated with stenosis of the renal, celiac, and
superior mesenteric arteries. The patient had typical skin signs of
neurofibromatosis and had had a right below-knee amputation at age 5 for
nonunion of a tibial fracture. The mother and 2 sibs were affected. A
very similar patient with neurofibromatosis vasculopathy, or vascular
neurofibromatosis, was reported by Lehrnbecher et al. (1994). The
4-year-old boy presented with congenital pseudarthrosis of the right
tibia, suggesting the vascular origin of this well-known complication,
multiple cafe-au-lait spots, short stature, and mild systemic arterial
hypertension. The mother and grandmother had NF1. Subsequent
complications of the vasculopathy were hypertension, septic infection of
an aneurysm in the deltoid muscle, infarction of a segment of colon,
sudden appearance of multiple arterial aneurysms, and venous thrombosis.
Histologic examination of the bowel specimen confirmed the clinical
diagnosis of vascular NF1: the proliferating cells seemed to have
originated from myoblasts or myofibroblasts, and not from Schwann cells.

Craddock et al. (1988) reported a 24-year-old white woman with NF1 who
had renovascular hypertension resulting from a proximal renal artery
stenosis and poststenotic aneurysmal degeneration. Her sister, aged 38
years, presented similarly but without clinical evidence of
neurofibromatosis.

Uren et al. (1988) found a congenital left atrial wall aneurysm in a
patient with neurofibromatosis; however, the association may have been
coincidental. Fitzpatrick and Emanuel (1988) observed the association of
typical NF1 with hypertrophic cardiomyopathy in a brother and sister.

Kousseff and Gilbert-Barness (1989) reported what they referred to as
'vascular neurofibromatosis' in 2 patients who as infants developed
idiopathic gangrene with vascular changes resembling those of NF1. An
additional review of 105 patients uncovered a 27-month-old boy with NF1
and extensive vascular changes with renal hypertension. They discussed
the possible relationship to arterial fibromuscular dysplasia. Stanley
(1975) found that 5 of 25 children with arterial fibromuscular dysplasia
had NF1 as well.

Nopajaroonsri and Lurie (1996) described venous aneurysm, arterial
dysplasia, and near-fatal hemorrhages in a 62-year-old who was said to
have familial neurofibromatosis (no family history was given). The
patient presented with an aneurysm of the internal jugular vein which
was associated with dysplasia of cervical arteries. Neurofibromatous
tissue was found in the wall of the aneurysm as well as in small veins.
During and after surgical excision of the aneurysm, the patient
developed massive hemorrhages that required reexploration and evacuation
of cervical hematomas. During surgery, bleeding was difficult to control
because of excessive friability of blood vessels. Despite the vascular
invasion by a tumor, there was no evidence of malignancy or malignant
transformation in the patient after a 10-year follow-up.

Because neurofibromin is expressed in blood vessel endothelial and
smooth muscle cells, Hamilton and Friedman (2000) suggested that NF1
vasculopathy may result from an alteration of neurofibromin function in
these cells.

Riccardi (2000) supported the view that endothelial injury and its
repair, which appear to be important in the pathogenesis of
atherosclerosis, may also play a role in NF1 vasculopathy. He
recommended a regimen of aggressive antihypertensive treatment of
children with NF1 in whom either episodic or persistent systemic
hypertension is documented. The goal would be to decrease intravascular
trauma, based on the supposition that such trauma is directly related to
the evolution of the vascular disease in patients with NF1.

Lin et al. (2000) reviewed cases of NF1 and cardiovascular malformations
among 2,322 patient records in the National Neurofibromatosis Foundation
International Database, collected between 1991 and 1998. Cardiovascular
malformations were reported in 54 (2.3%) of the NF1 patients, 4 of whom
had Watson syndrome (193520) or neurofibromatosis-Noonan syndrome (NFNS;
601321). Of the 54 patients, 25 had pulmonic stenosis, and 5 had
coarctation of the aorta, representing a higher proportion of all
cardiovascular malformations than expected. The authors recommended that
all individuals with NF1 have careful cardiac auscultation and blood
pressure monitoring as part of every NF-related examination.

Hamilton et al. (2001) reported a previously healthy 33-year-old man
with NF1 who died suddenly. Autopsy revealed multiple cardiac
abnormalities, including evidence of an intramyocardial vasculopathy
characteristic of the vascular pathology found in NF1. Other cardiac
findings included nonspecific cardiomyopathic changes, myocardial
fibrosis, and a floppy mitral valve. The authors emphasized the
importance of recognition of vascular lesions in patients with NF1 so
that appropriate management can be provided.

Friedman et al. (2002) reviewed cardiovascular disease in NF1. The NF1
Cardiovascular Task Force suggested that all patients with NF1,
especially those with Watson or NF1-Noonan phenotypes, have a careful
cardiac examination with auscultation and blood pressure measurement.

Tomsick et al. (1976) reported intracranial arterial occlusive disease
in NF1. Erickson et al. (1980) described 2 sisters with
neurofibromatosis and intracranial arterial occlusive disease leading to
the moyamoya pattern of collateral circulation (MYMY1; 252350). Four
other members of their sibship of 8, and members of 2 previous
generations, including the mother, had neurofibromatosis. Yamauchi et
al. (2000) stated that more than 50 cases of the association of NF1 and
moyamoya disease had been described, including the cases reported by
Woody et al. (1992) and Barrall and Summers (1996). See MYMY2 (607151)
for a form of moyamoya disease showing linkage to chromosome 17q25.

Benatar (1994) described a 27-year-old man with neurofibromatosis who
presented with 3 intracranial fusiform aneurysms. He referred to 3
previous descriptions of large intracranial fusiform aneurysms in
patients with NF1, which he considered to be considerably less common
than renal and gastrointestinal vascular lesions in this disorder.

Schievink et al. (2005) detected incidental intracranial aneurysms in 2
(5%) of 39 patients with NF1 who were hospitalized for other reasons.
Limiting the patient population to the 22 patients who had a brain MRI
resulted in a significantly higher detection rate of 9% compared to 0%
in 526 control patients with primary or metastatic brain tumors who
underwent brain MRI. The findings suggested that patients with NF1 are
at an increased risk of developing intracranial aneurysms as a vascular
manifestation of NF1.

- Central Nervous System Abnormalities

Adornato and Berg (1977) observed the diencephalic syndrome in 2 infants
who had neurofibromatosis and hypothalamic tumors.

Horwich et al. (1983) presented evidence that aqueductal stenosis occurs
in neurofibromatosis.

Senveli et al. (1989) reported 6 patients with NF1 who had aqueductal
stenosis and hydrocephalus requiring surgical intervention. Ages varied
from 14 to 24 years. Twenty-two similar cases were found in the
literature.

Winter (1991) described dural ectasia in neurofibromatosis causing bony
erosion that was sufficiently severe to destroy spinal stability.
Eichhorn et al. (1995) described dural ectasia in a 20-year-old woman
with NF1 who presented with back and leg pain. Increasingly severe back
pain led to investigations which showed multiple fractures of the
pedicles of L1 to L4 with dural ectasia penetrating the body of L2. The
transverse diameter of the dura was twice that of the vertebral body at
that level, reaching and lifting the psoas.

Mukonoweshuro et al. (1999) reviewed the central nervous system
manifestations and neuroradiologic findings in NF1.

- Skeletal Manifestations

Skeletal abnormalities in NF1 include short stature, scoliosis, sphenoid
wing dysplasia, and tibial pseudarthrosis, a bowing of the long bone
that looks like a false joint (reviews by Ferner et al., 2007 and
Williams et al., 2009).

Konishi et al. (1991) described a 40-year-old woman with NF1 and typical
hypophosphatemic osteomalacia. Bone pain, multiple pseudofractures,
marked increase in osteoid by bone biopsy, and hypophosphatemia with
renal phosphate wasting were features. Treatment with oral phosphate and
vitamin D was effective. They found reports of 34 similar cases and
pointed out that of the 67 patients collected by Dent (1952), 2 had
neurofibromatosis.

In a father and 3 children by 2 different women, Schotland et al. (1992)
described cosegregation of NF1 and osseous fibrous dysplasia. In the 4
individuals with NF1, cafe-au-lait spots and neurofibromata were present
in all 4, Lisch nodules and macrocrania in 3, and scoliosis and
curvature of the long bones in 2. Schotland et al. (1992) found at least
8 reports of NF1 and osseous fibrous dysplasia associated in individuals
but no previous description of a familial association. The osseous
dysplasia consisted of multiple lesions at the distal ends of the shafts
of the femurs and in the tibias and fibulas, with bowing of the fibulas.

Stevenson et al. (1999) reported a descriptive analysis of tibial
pseudarthrosis in a large series of NF1 patients. A male predominance
was observed among patients with pseudarthrosis, leading the authors to
suggest that male gender may be a susceptibility factor. Examination of
the natural history of pseudarthrosis showed that half of the patients
who had a fracture sustained it before age 2 years, and that
approximately 16% of the pseudarthrosis patients had an amputation.

Long bone dysplasia, seen in 2% (Ferner et al., 2007) to 5% (Stevenson
et al., 2006) of patients with NF1, typically involves the tibia and
frequently presents with anterolateral bowing that may progress to
fracture and nonunion. Tibial dysplasia is most often unilateral,
evident in the first year of life, and usually not associated with a
neurofibroma at the site, suggesting a random molecular event. Stevenson
et al. (2006) documented double inactivation of the NF1 gene in
pseudarthrosis tissue, and suggested involvement of the
neurofibromin-Ras signal transduction pathway. Prospectively acquired
tissue from the pseudarthrosis site of 2 individuals with NF1 did not
show typical immunohistochemical features of neurofibroma, but genetic
markers spanning the NF1 locus demonstrated loss of heterozygosity.
Patient 1 of Stevenson et al. (2006) was a 42-year-old man with a father
with NF1 and a brother with NF1 associated with lower limb
pseudarthrosis requiring amputation. Patient 2 was a 2-year-old boy
whose tibial and fibular bowing presented at birth, with subsequent
fibular fracture at age 2 weeks. Clinical findings consistent with NF1
included more than 5 cafe-au-lait macules and tibial pseudarthrosis. The
mother had NF1.

Lammert et al. (2006) found significantly lower mean serum levels of
25-hydroxyvitamin D in 55 NF1 patients compared to controls (14.0 ng/ml
in patients, 31.4 ng/ml in controls). Among the NF1 patients, there was
a highly significant inverse correlation between serum vitamin D
concentration and the number of dermal neurofibromas. Lammert et al.
(2006) noted that focal osseous abnormalities and decreased bone mineral
density are observed in patients with NF1, which may be related to
inadequate circulating vitamin D. The relationship of serum vitamin D to
neurofibromas was unclear.

- Cognitive and Neuropsychologic Manifestations

Twelve NF1 families with 1 affected child, an unaffected sib, and both
natural parents were studied by Hofman et al. (1994) to assess the
presence of cognitive deficits or learning disability. NF1 children with
known intracranial problems were excluded, but family members with known
learning disabilities or hyperactivity disorders were not, making some
of the results difficult to interpret. Full scale IQs ranged from 70 to
130 among children with NF1 and from 99 to 139 among unaffected sibs.
Scores of parents with NF1 ranged from 85 to 114 compared to 80 to 134
in unaffected parents. Children with NF1 showed significant deficits in
language and reading abilities compared to sibs, but not in mathematics.
They also had impaired visuospatial and neuromotor skills. In 11 of 12
NF1 children but in none of the unaffected sibs, foci of high signal
intensity on T2-weighted MRI scan images were observed. A statistically
significant correlation was found between lowering of IQ and
visuospatial deficits and the number of foci seen on scan.

Legius et al. (1994) studied the neuropsychologic profiles of 46
children with NF1. They found a reduction in total IQ, but a
significantly better verbal rating than performance rating in all age
groups. Concentration problems were especially significant in children
with a higher IQ. Legius et al. (1994) suggested that these children may
benefit from the use of Ritalin.

T2 'unidentified bright objects' are seen in 50 to 75% of children with
NF1, most frequently in the basal ganglia, corpus cerebellum, and
brainstem. Legius et al. (1995) found no difference in the mean
intelligence of 18 children with such lesions and 10 neurofibromatosis
children who did not show such lesions.

Silva et al. (1997) stated that learning disabilities are said to occur
in 30 to 45% of patients with NF1, even in the absence of any apparent
neuropathology. The learning disabilities may include a depression in
mean IQ scores, visuoperceptual problems, and impairment in spatial
cognitive abilities.

Schrimsher et al. (2003) found an association between visuospatial
performance deficits and attention deficit-hyperactivity disorder (ADHD;
143465) in patients with NF1.

- Unusual Features

Neurofibromata of the intestine are a recognized, though rare, feature
of von Recklinghausen neurofibromatosis. Hashemian (1952, 1953) reported
patients with mild skin changes of NF1 who had intestinal fibromatosis.
Neurofibromata of the bowel leading to gastrointestinal bleeding were
described by Manley and Skyring (1961) in a patient with striking skin
changes. Chu et al. (1999) described a 10-year-old girl with NF1 who had
a a 9-month history of anemia and low gastrointestinal bleeding
associated with a jejunal leiomyoma.

Massaro and Katz (1966) established the association of interstitial
pulmonary fibrosis (fibrosing alveolitis) with NF1 on the basis of
studies of 76 patients. Porterfield et al. (1986) described pulmonary
hypertension secondary to interstitial pulmonary fibrosis.

Hayes et al. (1961) reported hypoglycemia associated with massive
intraperitoneal tumor of mesodermal origin in a patient with typical
cutaneous lesions. Unusual clinical manifestations were described by
Diekmann et al. (1967): hypertension due to renal artery stenosis, and
hypertrophy of the clitoris. Sutphen et al. (1995) described
clitoromegaly in 4 patients with NF1 and reviewed the literature
documenting 26 NF1 patients with clitoral involvement.

Kurotaki et al. (1993) described the case of a 13-year-old Japanese boy
who was found to have small nodules in the lung on chest radiography. He
was asymptomatic. Although there was no family history of NF1, he had
multiple cafe-au-lait spots over the whole body since birth, and soft
subcutaneous tumors of the forehead and back were noticed from the age
of 7 years. On biopsy the lung lesions were found to be papillary
adenomas of type II pneumocytes. The patient had remained asymptomatic
for 6 years thereafter.

Zacharin (1997) reported the unusual occurrence of precocious puberty in
a 5-year-old girl and 8-year-old boy with NF1 in whom imaging studies
failed to demonstrate any abnormality of the optic tracts or optic
chiasm. Previous studies have indicated that optic tract lesions develop
at a mean age of 3.6 years, and longitudinal studies have failed to
demonstrate symptomatic optic tract tumors occurring after age 6 years.
The 2 patients of Zacharin (1997) were aged 11 and 14.7 years at the
time of the report.

Bahuau et al. (2001) reported a family with neurofibromatosis type I, in
which 2 female children had congenital megacolon due to intestinal
neuronal dysplasia type B (601223). The affected infants were found be
doubly heterozygous for a mutation in the NF1 gene and in the GDNF gene
(600837).

- Neurofibromatous Neuropathy

Neurofibromatous neuropathy, a common feature of NF2 but an unusual
complication of NF1, is characterized by a distal sensorimotor
neuropathy associated with diffuse neurofibromatous change in thickened
peripheral nerves (Thomas et al., 1990). NF2-associated neurofibromatous
neuropathy is entirely different clinically and histologically from
NF1-associated neurofibromatous neuropathy (Sperfeld et al., 2002).

Ferner et al. (2004) described 8 patients with NF1 and neurofibromatous
neuropathy among 600 NF1 patients from 1 clinic, thus demonstrating a
frequency of 1.3%. The patients had an indolent symmetric predominantly
sensory axonal neuropathy and unusual early development of large numbers
of neurofibromas. The biopsied nerves showed diffuse neurofibromatous
change and disruption of the perineurium. Two patients developed a high
grade malignant peripheral nerve sheath tumor. Ferner et al. (2004)
pictured the side of the neck of a patient with a thickened greater
auricular nerve. They also pictured studies of the lumbar spine showing
neurofibromas involving all the nerve roots but not causing cord
compression. Disease-causing mutations were identified in 2 individuals
(613113.0040-613113.0041) and molecular studies did not reveal any whole
gene deletions. Ferner et al. (2004) suggested that the cause of
neurofibromatous neuropathy may be a diffuse neuropathic process arising
from inappropriate signaling between Schwann cells, fibroblasts, and
perineurial cells.

- Segmental Neurofibromatosis

Nicolls (1969) described 2 cases of sectorial (or segmental)
neurofibromatosis, which he plausibly interpreted as representing
somatic mutation. One had a mediastinal neurofibroma and, in the skin
area corresponding segmentally to the site of the internal lesion, 5
small neurofibromas. Miller and Sparkes (1977) also reported on this
phenomenon.

Zonana and Weleber (1984) illustrated a patient who had multiple
cafe-au-lait spots of von Recklinghausen type only on the right side of
the body. Iris hamartomata (Lisch nodules) were present in the right eye
only. The findings were consistent with a segmental form of NF1.

Riccardi and Eichner (1986) referred to the segmental form as
neurofibromatosis type V. Combemale et al. (1994) presented 2 new cases
of segmental NF1 and reviewed reports concerning 88 cases. One of their
patients was a 71-year-old woman with multiple cutaneous tumors limited
to the left side of the trunk, which were present since the age of 41
years.

In a survey of 56,183 young men, aged 17 and 18 years, Ingordo et al.
(1995) found 11 cases of NF1 and 1 case of segmental NF. In this group,
the relative frequency was 0.02% for NF and 0.0018% for segmental NF.
From November 1988 through August 1995, Wolkenstein et al. (1995) saw
308 patients with NF1 according to the criteria of the National
Institutes of Health Consensus Development Conference (1988) and 9
patients with segmental NF according to the classification of Riccardi
(1982). These findings and those of Ingordo et al. (1995) suggested that
segmental NF is about 30 times less frequent than NF type I.

Tinschert et al. (2000) provided molecular confirmation that segmental
neurofibromatosis represents a postzygotic NF1 gene mutation. Using
FISH, they identified an NF1 microdeletion in a patient with segmental
NF in whom cafe-au-lait spots and freckles were limited to a single body
region. The mutant allele was present in a mosaic pattern in cultured
fibroblasts from a cafe-au-lait spot lesion, but was absent in
fibroblasts from normal skin as well as in peripheral blood leukocytes.

INHERITANCE

Crowe et al. (1956) estimated that about 50% of NF1 patients have new
mutations. Crowe et al. (1956) estimated the relative fertility of
affected males and females to be 0.41 and 0.75, respectively. Samuelsson
and Akesson (1988) estimated that the relative fertility of
neurofibromatosis cases is 78% and the mutation rate somewhere between
2.4 and 4.3 x 10(-5).

Miller and Hall (1978, 1978) reported a possible maternal effect on the
severity of NF1. They found that patients born of affected mothers had
more severe disease than those born of affected fathers. In their series
of 62 patients from 54 families, only 16 were new mutations.

Ritter and Riccardi (1985) studied 111 3-generation families with NF1
and found no instance of skipped generation. They suggested that
penetrance of autosomal dominant NF1 is complete and that previous
impressions to the contrary failed to recognize heterogeneity, minimal
clinical expression, and nonpaternity.

Clementi et al. (1990) used the methods of classic segregation analysis
to test whether there was a deviation from the expected mendelian
segregation rate for NF1 in a sample of 129 Italian sibships. With this
approach, they obtained a maximum likelihood estimate of the proportion
of sporadic cases, and estimated the mutation rate for NF1 to be 6.5 x
10(-5) gametes per generation.

Jadayel et al. (1990) used molecular methods to identify the parental
origin of new mutations in NF1. They found that the new mutation was of
paternal origin in 12 of 14 families with NF1. The estimated mutation
rate, 1 in 10,000 gametes, was one of the highest for a human disorder
(Huson et al., 1989) and suggested that the NF1 gene is large or has
some other structural peculiarity. The same bias toward paternal origin
of new mutations had been demonstrated for retinoblastoma (180200).
Neither disorder shows a paternal age effect in the incidence of
mutations. (Riccardi et al. (1984), however, reported an increased
paternal age effect.)

In 10 families with an NF1 mutation, Stephens et al. (1992) found that
the mutation had occurred in the paternally derived chromosome 17. The
probability of observing this result by chance was estimated as less
than 0.001, assuming an equal frequency of mutation of paternal and
maternal NF1 genes. They suggested a role for genomic imprinting that
may either enhance mutation of the paternal NF1 gene or confer
protection from mutation to the maternal NF1 gene.

Easton et al. (1993) studied variation in expression of 3 quantitative
traits (number of cafe-au-lait patches, number of cutaneous
neurofibromas, and head circumference) and 5 binary traits (presence or
absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy,
and referral for remedial education). For cafe-au-lait patches and
neurofibromas, correlation was highest between MZ twins, less high
between first-degree relatives, and lower still between more distant
relatives. The higher correlation between MZ twins suggested a strong
genetic component in variation of expression, but the low correlation
between distant relatives suggested that the type of mutation at the NF1
locus itself plays only a minor role. All 5 binary traits, with the
exception of plexiform neurofibromas, also showed significant familial
clustering. The familial effects for these traits were consistent with
polygenic effects, but there were insufficient data to rule out other
models, including a significant effect of NF1 mutations. There was no
evidence of any association between different traits in affected
individuals. Easton et al. (1993) concluded that the phenotypic
expression of NF1 is to a large extent determined by the genotype at
other 'modifying' loci and that these modifying genes are trait
specific.

Lazaro et al. (1994) observed a family in which completely normal
parents had a son and daughter with a clinically severe form of NF1. The
sibs showed no inheritance of paternal alleles for a marker in intron 38
of the NF1 gene, whereas they received alleles from both parents for
other NF1 markers. Analysis with probes from this region of the NF1 gene
showed a 12-kb deletion involving exons 32 to 39, in the affected
offspring. In the father's spermatozoa, 10% were found to carry the same
NF1 deletion, but the abnormality was not detected in DNA from his
lymphocytes. Thus, this appeared to be an example of gonadal mosaicism.

DIAGNOSIS

Based on the 1988 National Institutes of Health Consensus Development
Conference on Neurofibromatosis, the diagnosis of NF1 is made in an
individual with any 2 of the following clinical features: (1) 6 or more
cafe-au-lait spots, (2) axillary or groin freckling, (3) 2 or more Lisch
nodules, (4) 2 or more neurofibromas, (5) optic pathway gliomas (OPGs),
(6) bone dysplasia, and (7) a first-degree family relative with NF1
(reviews by Ferner et al., 2007 and Williams et al., 2009).

Crowe et al. (1956) suggested that the presence of 6 spots, each more
than 1.5 cm in diameter, is necessary for the diagnosis of
neurofibromatosis. Crowe (1964) considered axillary freckling to be an
especially useful diagnostic clue. Occasional features included
scoliosis, pseudarthrosis of the tibia, pheochromocytoma, meningioma,
glioma, acoustic neuroma, optic neuroma, mental retardation,
hypertension, and hypoglycemia.

Johnson and Charneco (1970) suggested that the cafe-au-lait spot of
neurofibromatosis can be distinguished from the innocent spot that
occurs in normal persons and from the pigmented areas of McCune-Albright
syndrome (MAS; 174800) by the presence of a large number of
DOPA-positive melanocytes that have giant pigment granules in the
cytoplasm. The plexiform neuroma is specific to von Recklinghausen
disease: only on this feature can the histopathologist make a definitive
diagnosis.

Ward et al. (1990) estimated that tightly linked, flanking DNA markers
available permitted prediction of NF1 in a child with greater than 98%
accuracy. They predicted that even after the NF1 gene is cloned, linkage
testing would probably remain important. Linked markers may remain more
cost-effective than screening for 1 genetic event among a large number
of possible mutations that could be responsible for NF1 in a particular
family.

Gutmann et al. (1997) provided guidelines for the diagnostic evaluation
and multidisciplinary management of both NF1 and NF2.

Cnossen et al. (1998) reported a 10-year prospective follow-up study of
209 children suspected of having NF1, 150 of whom were ultimately given
this diagnosis. Minor disease features of macrocephaly, short stature,
hypertelorism, and thorax abnormalities were highly prevalent in
children with NF1 and significantly associated with the diagnosis of NF1
at 6 years of age. In addition, children with 3 or more minor disease
features were all diagnosed with NF1 under the age of 6 years. Cnossen
et al. (1998) concluded that in children aged less than 6 years with
insufficient diagnostic criteria, documentation of minor disease
features may be helpful in predicting the diagnosis of NF1.

Park and Pivnick (1998) used a protein truncation assay to screen for
mutations in 15 NF1 patients and obtained positive results in 11 (73%)
of them. Sequencing of cDNA and genomic DNA yielded identification of 10
different mutations. No correlations between genotype and phenotype were
apparent.

Ablon (2000) interviewed 18 unaffected parents of an affected child to
document their experiences in receiving their child's diagnosis of NF1.
The author found that methods of disclosure were often at variance with
suggestions made in recent years for conveying 'bad news.' She also
found that certain factors assist parents in receiving and more
positively adapting to their child's diagnosis. These factors include
physicians' attention to the setting and style of disclosure, imparting
appropriate and positive information, allowing additional time for
careful explanation, and scheduling a follow-up appointment.

DeBella et al. (2000) studied 1,893 NF1 patients under 21 years of age
from the National Neurofibromatosis Foundation International Database to
determine the age at which the features included in the NIH Diagnostic
Criteria appear. Approximately 46% of sporadic NF1 cases failed to meet
the NIH Diagnostic Criteria by 1 year of age. Nearly all (97%; 95% CI,
94-98) NF1 patients met the criteria for diagnosis by 8 years of age,
and all did so by 20 years of age. The usual order of appearance of the
clinical features listed as NIH criteria was cafe-au-lait macules,
axillary freckling, Lisch nodules, and neurofibromas. Symptomatic optic
glioma was usually diagnosed by 3 years of age, and characteristic
osseous lesions were usually apparent within the first year of life.

Ferner et al. (2007) provided guidelines for the diagnosis and
management of NF1 according to organ system, as well as suggestions for
genetic counseling.

MAPPING

By linkage analysis of 15 Utah kindreds with NF1, Barker et al. (1987,
1987) found a locus on chromosome 17, about 4 cM from the centromere
(lod score of 4.21 at theta = 0.04). There was no evidence for genetic
heterogeneity. Seizinger et al. (1987, 1987) presented evidence that the
NF1 gene is linked to the nerve growth factor receptor gene (NGFR;
162010) on 17q12-q22 (peak lod score of 4.41 at theta of 0.14). However,
crossovers between the 2 loci suggested that a mutation in NGFR was not
the fundamental defect.

On the basis of the occurrence of neurofibromatosis and galactokinase
deficiency (230200) in a family reported by Fanconi (1933), Stambolian
and Zackai (1988) suggested that the NF1 locus may be closely linked to
the GALK1 gene (604313) on 17q24. One of the affected sibs in this
family was the first enzymatically identified case of galactokinase
deficiency (Gitzelmann, 1965). The parents of this sibship were first
cousins and the mother had NF1.

Ledbetter et al. (1989) described a patient with NF1 who had a balanced
translocation between chromosome 17q11.2 and chromosome 22. Human-mouse
somatic cell hybridization studies allowed localization of ERBA1 (THRA;
190120), ERBB2 (164870), and (CSF3; 138970) distal to the 17q11.2
breakpoint, and HHH202 (D17S33) and beta-crystallin (CRYB1; 123610)
proximal to the 17q11.2 breakpoint. Schmidt et al. (1987) reported a
family in which a mother and 2 children with NF1 had a balanced
translocation t(1;17)(p34.3;q11.2). Menon et al. (1989) studied further
the translocation t(1;17) described by Schmidt et al. (1987). In a
somatic cell hybrid line containing only the derivative chromosome 1,
they showed that the breakpoint occurred between SRC2 (164940) and
D1S57, which are separated by 14 cM. The translocation breakpoint was
located on chromosome 17 between D17S33 and D17S58, markers that also
flank NF1 within a region of 4 cM.

Vance et al. (1989) reported linkage studies in 6 multigenerational
families with NF1 using 9 markers known to map in the pericentromeric
region of chromosome 17. The closest marker was HHH202 (lod score of
3.86). Two-point lod scores for NF1 versus all the markers studied were
presented, and the most likely gene order determined. Similar studies
were reported by Seizinger et al. (1989), who performed a multipoint
linkage analysis using 6 closely linked markers on chromosome 17 (lod
score of 3.83 at HHH202). The authors concluded, on the basis of the
linkage data, that the NF1 gene maps to the long arm rather than the
short arm of chromosome 17.

Further linkage studies involving the NF1 locus and pericentromeric
markers on chromosome 17 were reported by Diehl et al. (1989), Mathew et
al. (1989), Upadhyaya et al. (1989), Kittur et al. (1989), Goldgar et
al. (1989), and Stephens et al. (1989). Goldgar et al. (1989) summarized
the results of the international consortium for NF1 linkage. The 8 teams
of researchers studied 142 NF1 families with more than 700 affected
persons, using 31 markers in the pericentric region of chromosome 17.
The best gene order derived from these studies was
pter--pA10-41--EW301--cen--pHHH202--NF1--EW206--EW207--EW203--
CRI-L581--CRI-L946--HOX2--NGFR--qter.

Physical mapping data concerning the NF1 region on chromosome 17 were
reported by O'Connell et al. (1989), Fountain et al. (1989), Fain et al.
(1989), and Upadhyaya et al. (1989).

Wallace et al. (1989) described a NotI fragment from human chromosome
17q11.2 which detected breakpoints in the 2 NF1 patients with
translocations involving 17q (Ledbetter et al., 1989; Schmidt et al.,
1987). Fountain et al. (1989) mapped a series of chromosome 17
NotI-linking clones to proximal 17q and studied them by pulsed field gel
electrophoresis in order to define the region of the breakpoint involved
in a 17q11.2 balanced translocation present in 2 NF1 patients. One
clone, D17S133, identified the breakpoint in 1 of the 2 patients. A
pulsed field map indicated that the breakpoint was within 10 to 240 kb
of the cloned segment. Similarly, O'Connell et al. (1989) isolated human
cosmids and mapped them to the immediate vicinity of NF1. One cosmid
probe demonstrated that the breakpoint in both patients, and presumably
the NF1 gene, was contained within a 600-kb NruI fragment.

Yagle et al. (1990) isolated 5 cosmids that mapped directly proximal to
2 NF1 translocations and 11 cosmids that mapped directly distal to them.
Of these, 2 cosmids in each region were found to be linked to the
disease locus and 3 of these 4 cosmids showed no recombination. One
distal cosmid detected the 2 NF1 translocations by pulsed field gel
analysis and was used by Yagle et al. (1990) to produce a long-range
restriction map that covered the translocations.

MOLECULAR GENETICS

- Germline Mutations in the NF1 Gene

Wallace et al. (1990) identified a large transcript from the candidate
NF1 region on chromosome 17q11.2 that was disrupted in 3 patients with
NF1. Two of the patients had previously been reported by Ledbetter et
al. (1989) and Schmidt et al. (1987) as having translocations involving
t(17;22) and t(1;17), respectively. The third patient was found to have
a 0.5-kb insertion. The changes disrupted expression of the NF1
transcript in all 3 patients, consistent with the hypothesis that it
acts as a tumor suppressor.

Using pulsed field gel electrophoresis, Upadhyaya et al. (1990)
identified a 90-kb deletion in the proximal portion of 17q in 1 of 90
unrelated patients with NF1. Viskochil et al. (1990) detected deletions
of 190, 40, and 11 kb in the gene located at the 17q translocation
breakpoint in 3 patients with NF1.

In an NF1 patient, Wallace et al. (1991) identified an insertion of an
Alu sequence in an intron of the NF1 gene, resulting in deletion of the
downstream exon during splicing and a frameshift (613113.0001). Cawthon
et al. (1990) identified 2 different point mutations in the NF1 gene
(L348P, 613113.0003 and R365X, 613113.0004) in patients with NF1.
Upadhyaya et al. (1992) identified multiple germline NF1 mutations (see,
e.g., 613113.0006-613113.0009) in patients with NF1.

Heim et al. (1994) stated that although mutations had been sought in
several hundred NF1 patients, by August 1994, only 70 germline mutations
had been reported in a total of 78 individuals; only the R1947X
(613113.0012) mutation had been seen in as many as 6 unrelated patients.
NF1 mutations that had been identified included 14 large (more than 25
bp) deletions, 3 large insertions, 18 small (less than 25 bp) deletions,
8 small insertions, 6 nonsense mutations, 14 missense mutations, and 7
intronic mutations. At least 56 (80%) of the 70 mutations potentially
encode a truncated protein because of premature translation termination.

Heim et al. (1995) used a protein truncation assay to identify abnormal
polypeptides synthesized in vitro from 5 RT-PCR products that
represented the entire NF1 coding region. Truncated polypeptides were
observed in 14 of 20 patients with familial or sporadic NF1 diagnosed
clinically and in 1 patient with only cafe-au-lait spots and no other
diagnostic criterion. Mutations responsible for the generation of
abnormal polypeptides were characterized by DNA sequencing; 13
previously unpublished mutations were characterized in the 14
individuals. Because the entire NF1 coding region was spanned in each
individual, the distribution of NF1 truncating mutations was discerned
for the first time: the mutations were relatively evenly distributed
throughout the coding region. Upadhyaya et al. (1995) stated that fewer
than 90 mutations had been reported to the NF1 mutation analysis
consortium and details of only 76 of these mutations had been published.
They described 5 new mutations identified by SSCP analysis and
heteroduplex analysis, as well as 3 intragenic deletions identified by
analyzing families with intron-specific microsatellite markers.

Upadhyaya et al. (1997) screened 320 unrelated NF1 patients for
mutations in the GAP (RASA1; 139150)-related region of the NF1 gene,
which is encoded by exons 20-27a and has a known biologic function.
Sixteen different lesions in the NF1-GRD region were identified in a
total of 20 patients. Of these lesions, 14 were novel and together
comprised 3 missense, 2 nonsense, and 3 splice site mutations plus 6
deletions of between 1 and 4 bp.

Klose et al. (1998) identified a missense mutation in the NF1 gene
(R1276P; 613113.0022) in a patient with a classic multisymptomatic NF1
phenotype, including a malignant schwannoma. The mutation specifically
abolished the Ras-GTPase-activating function of neurofibromin, providing
direct evidence that failure of neurofibromin GAP activity is a critical
element in NF1 pathogenesis. The findings also suggested that
therapeutic approaches aimed at the reduction of the Ras-GTP levels in
neural crest-derived cells would be effective.

Upadhyaya et al. (2003) described a Portuguese family in which 3 members
had clinical features of NF1, but each had a different underlying defect
in the NF1 gene; see 613113.0030-613113.0032. The authors speculated
about the mechanism of this unusual situation.

Kluwe et al. (2003) examined 20 patients with spinal tumors from 17
families for clinical symptoms associated with NF1 and for NF1
mutations. Typical NF1 features were found in 12 patients from 11
families, and NF1 mutations were identified in 10 of the 11 index
patients in this group, including 8 truncating mutations, 1 missense
mutation, and 1 deletion of the entire NF1 gene. Eight patients from 6
families had no or only a few additional NF1-associated symptoms besides
multiple spinal tumors, which were distributed symmetrically in all
cases and affected all 38 nerve roots in 6 patients. Only mild NF1
mutations were found in 4 of the 6 index patients in the latter group,
including 1 splicing mutation, 2 missense mutations, and 1 nonsense
mutation in exon 47 at the 3-prime end of the gene. The data indicated
that patients with spinal tumors can have various NF1 symptoms and NF1
mutations; however, patients with no or only a few additional NF1
symptoms may be a subgroup or may have a distinct form of NF1, probably
associated with milder NF1 mutations or other genetic alterations.

In a girl with aniridia (106210), microphthalmia, microcephaly, and
cafe-au-lait macules, Henderson et al. (2007) identified heterozygous
mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and
OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and
PAX6 mutations, had NF1 with typical eye defects; in addition, although
her eyes were of normal size, she had small corneas, and also had
cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal
hypoplasia with normal-sized pupils. The proband's father, who had
multiple ocular defects (MCOPS5; 610125), had previously been studied by
Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation.
Henderson et al. (2007) noted that the proband's phenotype was
surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause
a variety of severe developmental defects.

- Somatic Mosaicism

Colman et al. (1996) reported an NF1 patient who was somatically mosaic
for a large maternally derived deletion in the NF1 gene region. The
deletion extended at least from exon 4 near the 5-prime end of the gene
to intron 39 near the 3-prime end, and included at least 100 kb. Colman
et al. (1996) suggested that the deletion occurred at a relatively early
developmental time point, since signs of NF1 in this patient were not
segmental and both mesodermally and ectodermally derived cells were
affected.

Vandenbroucke et al. (2004) described a patient with NF1 manifestations
throughout the body, but leaving a few sharply delineated segments of
the skin unaffected, suggestive of revertant mosaicism. A large
intragenic deletion was found by mutation analysis using long-range
RT-PCR. The intra-exonic breakpoints were identified in exon 13 and exon
28, resulting in a deletion of 99,571 bp at the genome level. Analysis
of several tissues demonstrated the presence of 2 genetically distinct
cell populations, confirming somatic mosaicism for this NF1 mutation.
Revertant mosaicism was excluded by demonstrating heterozygosity for
markers residing in the deletion region. The findings were significant
because the patient was severely and generally affected and could not be
distinguished clinically from classic NF1 patients, but showed genetic
mosaicism at the cellular level.

- Somatic Mutations in the NF1 Gene: Loss of Heterozygosity

Skuse et al. (1989) observed loss of DNA markers from the NF1 region of
17q in DNA from malignant tumors from patients with NF1, compared with
DNA from nontumor tissue from the same patients. In hereditary cases,
the NF1 allele remaining in the tumor was derived from the affected
parent. The findings suggested that malignant tumors in NF1 arise as a
result of homozygous deficiency of a tumor-suppressor gene, i.e., loss
of heterozygosity. However, LOH was not detected in benign
neurofibromas. This finding suggested that neurofibromas are either
polyclonal or monoclonal in origin, but arise by a mechanism different
from that of NF1 malignancies.

Menon et al. (1990) found no deletions in the proximal region of 17q in
NF1-derived benign tumor specimens. However, neurofibrosarcomas from NF1
patients displayed loss of alleles for polymorphic DNA markers on 17p
outside the area of mapping of NF1. Since the common region of deletion
included the site of the p53 gene (191170), they searched for p53
alterations in neurofibrosarcomas by direct sequencing of PCR-amplified
DNA. In 2 of 7 neurofibrosarcomas they found point mutations in exon 4
of the p53 gene.

Shannon et al. (1992) reviewed the occurrence of leukemia in NF1. In 16
of 21 cases of juvenile chronic myelogenous leukemia in children with
familial NF1, the genetic disorder was inherited from the mother. Of the
21 children, 17 were boys. Myeloid leukemia developed in 12 boys and 4
girls who inherited NF1 from their mothers, and in 5 boys who inherited
the disease from their fathers. Father-to-daughter transmission was not
observed. Shannon et al. (1992) found that among 5 children with bone
marrow monosomy 7 (Mo7), 3 had NF1 and 2 others had suggestive evidence
of NF1. Taken together, the presence of chromosome 7 deletions in the
leukemias of children with NF1, a pattern of inheritance favoring
maternal transmission of NF1, and the marked predilection for boys to
develop leukemia monosomy 7 suggested a multistep mechanism of
oncogenesis in which epigenetic factors might play a role.

In a neural fibrosarcoma from a patient with NF1, Legius et al. (1993)
found a somatic deletion of the NF1 gene on one chromosome and LOH for
all chromosome 17 polymorphisms. Thus, homozygous inactivation of NF1
was demonstrated at the molecular level, providing strong support for
the view that NF1 is a tumor suppressor gene.

Shannon et al. (1994) found LOH for NF1 in the bone marrow from 5 of 11
NF1 children with malignant myeloid disorders. In each case, the NF1
allele was inherited from a parent with NF1 and the normal allele was
deleted. Loss of constitutional heterozygosity had not been reported in
the benign tumors associated with NF1 and had been detected only in a
few malignant neural crest tumors and in some tumor-derived cell lines.
The data provided evidence that NF1 may function as a tumor-suppressor
allele in malignant myeloid diseases and that neurofibromin is a
regulator of RAS in early myelopoiesis.

Colman et al. (1995) examined the '2-hit' hypothesis in relation to
benign neurofibromas in NF1. Using both NF1 intragenic polymorphisms as
well as markers from flanking and more distal regions of chromosome 17,
they investigated loss of heterozygosity in 22 neurofibromas from 5
unrelated NF1 patients. Eight of these tumors revealed somatic deletions
involving NF1, indicating that inactivation of NF1 is associated with at
least some neurofibromas. On the other hand, Stark et al. (1995) found
single-cell PCR on neurofibroma Schwann cells and found that both
alleles of the NF1 gene were present; i.e., there was no evidence of
loss of heterozygosity by a nondisjunction, large deletions, or somatic
recombination. They granted that small mutations inactivating the
wildtype allele could not be excluded.

Shen et al. (1996) speculated that it may be that a second mutation in
another gene is required for genesis of neurofibromas, or that they may
arise because of the loss of 1 allele. Another possibility was that a
second mutation in the NF1 gene was required.

Although several observations support the contention that the NF1 gene
product is a tumor suppressor involved in the RAS signal transduction
pathway, mutations had not been identified in both NF1 alleles in dermal
neurofibromas until the report by Sawada et al. (1996). Their patient
was previously shown to have large submicroscopic deletions of the NF1
locus by both somatic cell hybrid analysis (Kayes et al., 1994) and FISH
of lymphoblastoid cells (Leppig et al., 1996). The deletion extended at
least 125 kb centromeric and 135 kb telomeric to NF1. As part of her
medical care, the patient electively had a scalp neurofibroma removed
surgically. Sawada et al. (1996) showed that the tumor DNA harbored a
4-bp deletion in NF1 exon 4b in the other allele. The authors stated
that this was the first reported definitive identification of a somatic
mutation limited to the NF1 locus in a benign neurofibroma from an NF1
individual in whom the constitutional NF1 mutation was known.

The risk of malignant myeloid disorders in young children with NF1 is
200 to 500 times the normal risk. Side et al. (1997) found that NF1
alleles were inactivated in bone marrow cells from children with NF1
complicated by malignant myeloid disorders. Using an in vitro
transcription and translation system, they screened bone marrow samples
from 18 such children for NF1 mutations that cause a truncated protein.
Mutations were confirmed by direct sequencing of genomic DNA from the
patients, and from the affected parents in cases of familial NF1. The
normal NF1 allele was absent in bone marrow samples from 5 of 8 children
who had truncating mutations of the NF1 gene.

Submalignant tumors occurring in NF1 patients have been found to show
loss of heterozygosity consistent with the 2-hit hypothesis of Knudson,
with 1 allele constitutionally inactivated and the other somatically
mutated. Somatic NF1 deletions in benign neurofibromas were described by
Colman et al. (1995) and mutations in both copies of the NF1 gene in a
dermal neurofibroma were reported by Sawada et al. (1996). Serra et al.
(1997) performed LOH analysis on 60 neurofibromas derived from 17
patients, of whom 9 had a family history of the disease and 8
represented sporadic cases. LOH was found in 25% of the neurofibromas
(corresponding to 53% of the patients). In addition, they found that in
the neurofibromas of patients from familial cases, the deletions
occurred in the allele that was not transmitted with the disease,
indicating that both copies of the NF1 gene were inactivated in these
tumors. The authors concluded that there appears to be double
inactivation of the NF1 gene in benign neurofibromas.

Skuse and Cappione (1997) reviewed the possible molecular basis of the
wide clinical variability in NF1 observed even among affected members of
the same family (Huson et al., 1989). The complexities of alternative
splicing and RNA editing may be involved. Skuse and Cappione (1997)
suggested that the classical 2-hit model for tumor suppressor
inactivation used to explain NF1 tumorigenesis could be expanded to
include post-transcriptional mechanisms that regulate NF1 gene
expression. Aberrations in these mechanisms may play a role in the
observed clinical variability.

Kluwe et al. (1999) stated that plexiform neurofibroma can be found in
about 30% of NF1 patients, often causing severe clinical symptoms. Using
4 intragenic polymorphic markers, they identified LOH in 8 of 14
plexiform neurofibromas from NF1 patients. The findings suggested that
loss of the second allele, and thus inactivation of both alleles of the
NF1 gene, is associated with the development of plexiform neurofibromas.
The 14 plexiform neurofibromas were also examined for mutation in the
TP53 gene; no mutations were found.

Eisenbarth et al. (2000) described a systematic approach of searching
for somatic inactivation of the NF1 gene in neurofibromas. In the course
of these studies, they identified 2 novel intragenic polymorphisms: a
tetranucleotide repeat and a 21-bp duplication. Among 7 neurofibromas
from 4 different NF1 patients, they detected 3 tumor-specific point
mutations and 2 LOH events. The results suggested that small subtle
mutations occur with similar frequency to that of LOH in benign
neurofibromas and that somatic inactivation of the NF1 gene is a general
event in these tumors. Eisenbarth et al. (2000) concluded that the
spectrum of somatic mutations occurring in various tumors from
individual NF1 patients may contribute to the understanding of variable
expressivity of the NF1 phenotype.

Neurofibromas presumably arise from NF1 inactivation in S100+ Schwann
cells. Rutkowski et al. (2000) demonstrated that fibroblasts isolated
from neurofibromas carried at least 1 normal NF1 allele and expressed
both NF1 mRNA and protein, whereas the S100+ cells from 4 of 7 of these
same tumors lacked the NF1 transcript completely. The authors were
unable to document second NF1 mutations in the S100+ cell lines from
tumors, and speculated that additional molecular events aside from NF1
inactivation in Schwann cells and/or other neural crest derivatives
contribute to neurofibroma formation.

To identify somatic mutations responsible for tumorigenesis in NF1, John
et al. (2000) studied DNA from 82 tumors and blood from 45 patients with
NF1. Loss of heterozygosity (LOH) was found in 10 (12%) of 82 tumors
studied, and SSCP/heteroduplex analysis identified 2 somatic mutations
and 5 novel germline mutations. John et al. (2000) suggested that the
low detection rate of somatic mutations might indicate that an
alternative mechanism such as methylation is involved in tumor formation
in NF1. However, they also acknowledged that mutations might be present
but not identified by reason of size, location, or sensitivity of
screening method.

Serra et al. (2000) cultured pure populations of Schwann cells (SCs) and
fibroblasts derived from 10 neurofibromas with characterized NF1
mutations and found that SCs, but not fibroblasts, harbored a somatic
mutation at the NF1 locus in all studied tumors. By culturing
neurofibroma-derived SCs under different in vitro conditions, 2
genetically distinct SC subpopulations were obtained: NF1 -/- and NF1
+/-. The authors hypothesized that NF1 mutations in SCs, but not in
fibroblasts, correlate with neurofibroma formation and that only a
portion of SCs in neurofibromas have mutations in both NF1 alleles.

Serra et al. (2001) pointed out that the large size of the NF1 gene,
together with the multicellular composition of neurofibromas, greatly
hampers the characterization of the second hit, a somatic NF1 mutation,
in these tumors. They presented the somatic NF1 mutation analysis of the
whole set of neurofibromas studied by their group and consisting of 126
tumors derived from 32 NF1 patients. They identified 45 independent
somatic NF1 mutations, 20 of which were reported for the first time.
Among point mutations, those affecting the correct splicing of the NF1
gene were common, coinciding with results reported on germline NF1
mutations. In most cases, they were able to confirm that both copies of
the NF1 gene were inactivated. The study of more than 1 tumor derived
from the same patient was useful for the identification of the germline
mutation, and the culture of neurofibromas with clearing of fibroblasts
facilitated LOH detection in cases in which it had otherwise been
difficult to determine.

Wiest et al. (2003) performed a mutation screen of numerous
neurofibromas from 2 NF1 patients and found a predominance of point
mutations, small deletions, and insertions as second hit mutations in
both patients. Seven novel mutations were reported. Together with the
results of studies that showed LOH as the predominant second hit in
neurofibromas of other patients, these results suggested that different
factors may influence the somatic mutation rate and thereby the severity
of the disease in different patients.

Maertens et al. (2007) reported 3 unrelated patients with NF1: 1 was
mildly affected with both neurofibromas and pigmentary skin changes, and
2 had isolated neurofibromas and pigmentary skin changes, respectively,
consistent with segmental disease. Detailed molecular analysis of
various tissues and cell types showed biallelic NF1 inactivation in
Schwann cells from neurofibromas and biallelic NF1 inactivation in
melanocytes from cafe-au-lait nodules. The data provided molecular
evidence that the distinct clinical picture of the patients was due to
somatic mosaicism for the NF1 mutations and that the mosaic phenotype
reflected embryonic timing.

Bausch et al. (2007) performed mutation scanning of the NF1 gene and
loss-of-heterozygosity analysis using markers in and around the NF1 gene
in 37 patients, aged 14 to 70 years, with pheochromocytoma and NF1. Of
21 patients with corresponding tumor available, 67% showed somatic loss
of the nonmutated allele at the NF1 locus versus 0 of 12 sporadic tumors
(p = 0.0002). Overall, 86% of the 37 patients had exonic or splice site
mutations, and 14% had large deletions or duplications; 79% of the
mutations were novel. The cysteine-serine rich domain (CSR) was affected
in 35%, but the RAS GTPase activating protein domain (RGD) in only 13%.
There did not appear to be an association between any clinical features,
particularly pheochromocytoma presentation and severity, and NF1
mutation genotype.

PATHOGENESIS

Benedict et al. (1968) studied the pigmentary anomaly of
neurofibromatosis in relation to that of Albright polyostotic fibrous
dysplasia. Gross appearance of the pigmented areas was not always
reliable. However, special microscopic studies showed giant pigment
granules in malpighian cells or melanocytes of normal skin and of
neurofibromatosis spots, but rarely in Albright syndrome.

Fialkow et al. (1971) concluded from analysis of neurofibromas from G6PD
A-B heterozygotes with von Recklinghausen disease that each tumor must
originate in many cells, perhaps at least 150. Although the benign
tumors of neurofibromatosis are multiclonal in nature, the malignant
lesion (neurofibrosarcoma) is monoclonal (Friedman et al., 1982).

Schenkein et al. (1974) reported increased nerve growth stimulating
activity in the serum of patients with von Recklinghausen disease.
Kanter et al. (1980) showed an increase only in antigenic activity of
nerve growth factor in central neurofibromatosis and only in functional
activity in peripheral neurofibromatosis.

In 8 of 30 unrelated females with NF1, Skuse et al. (1989) found
heterozygosity for a PGK (311800) RFLP, which could be used to test for
clonality. In all 8 cases the neurofibromas appeared to be monoclonal in
origin. These results supported the suggestion that benign neurofibromas
in NF1 arise by a mechanism that is different from that of the malignant
tumors.

All the lesions of NF1, the benign and malignant tumors, the
cafe-au-lait spots, the Lisch iris nodules, etc., are presumably the
result of 2 mutations, the inherited mutation and a second mutation on
the normal homolog. Collins (1993) suggested that the wide variability
of clinical manifestations in members of the same family is related to
the element of chance in determining what cells are involved by the
second mutation and at what stage of development. The progressive nature
of the disorder is also indicated.

Using polyclonal antibodies to the NF1 protein, Koivunen et al. (2000)
found increased expression of NF1 protein in cultured human
keratinocytes when induced to differentiate in high calcium media. The
NF1 protein appeared to be associated with the intermediate filament
cytoskeleton and was expressed at highest levels during the period of
desmosome formation. Cultured keratinocytes from patients with NF1
showed increased variability in cell size and morphology in comparison
to control keratinocytes, suggesting that NF1 mutations may alter the
organization of the cytoskeleton. The authors proposed that the NF1
tumor suppressor gene exerts its effects in part by controlling
organization of the cytoskeleton during the formation of cellular
contacts.

Cook et al. (1998) presented the hypothesis that some haploinsufficiency
diseases result from an increased susceptibility to stochastic delays of
gene initiation or interruptions of gene expression, events that are
normally buffered by increased gene copy number and relatively
insensitive to dosage compensation. Kemkemer et al. (2002) applied this
line of thought to the tumor suppressor gene NF1 and demonstrated that
haploinsufficiency of the gene results in an increased variation of
dendrite formation in cultured NF1 melanocytes. These morphologic
differences between NF1 and control melanocytes were described by a
mathematical model in which the cell is considered to be a
self-organized automaton. The model described the adjustment of the
cells to a set point and included a noise term that allowed for
stochastic processes. It described the experimental data of control and
NF1 melanocytes. In the cells haploinsufficient for NF1, Kemkemer et al.
(2002) found an altered signal-to-noise ratio detectable as increased
variation in dendrite formation in 2 of 3 investigated morphologic
parameters. They suggested that in vivo NF1 haploinsufficiency results
in an increased noise in cellular regulation and that this effect of
haploinsufficiency may also be found in other tumor suppressors.

POPULATION GENETICS

Littler and Morton (1990) reviewed data from 4 studies on NF1, with the
following results: the carrier incidence at birth was 0.0004; the gene
frequency was 0.0002; and the proportion of cases due to fresh mutation
was 0.56. Lazaro et al. (1994) gave the incidence of NF1 as
approximately 1 in 3,500 and stated that about half of cases are the
result of new mutations.

Garty et al. (1994) found an unusually high frequency of NF1 in young
Israeli adults. They surveyed 374,440 17-year-old Jewish recruits for
military service and concluded that 390 of them had NF1. The prevalence
was 1.04/1,000 (0.94/1,000 for males and 1.19/1,000 for females), which
was 2 to 5 times greater than the previously reported prevalence. NF1
was more common in young adults whose parents were of North African and
Asian origin (1.81/1,000 and 0.95/1,000, respectively) and less common
in those of European and North American origin (0.64/1,000). All these
differences were statistically significant; Garty et al. (1994)
suggested that they may be partially explained by the more advanced
parental age of the NF group (as suggested by the larger number of
children in the North African and Asian families) or by founder effect
or both.

Poyhonen et al. (2000) studied the epidemiology of NF1 in northern
Finland. The observed overall prevalence of NF1 was 1 in 4,436 and the
incidence 1 in 3,647. There was no evidence of geographic clustering of
NF1, nor was there any sign of linkage disequilibrium in DNA studies.

ANIMAL MODEL

Hinrichs et al. (1987) showed that the TAT gene of human T-lymphotropic
virus type 1 (HTLV-1) under control of its own long terminal repeat was
capable of inducing tumors in transgenic mice. The morphologic and
biologic properties of these tumors indicated a close resemblance to
NF1. Multiple tumors developed simultaneously in the transgenic tat mice
at approximately 3 months of age, and the phenotype was successfully
passed through 3 generations. The tumors arose from the nerve sheaths of
peripheral nerves and were composed of perineural cells and fibroblasts.
However, evidence of HTLV-1 infection in patients with neural and other
soft tissue tumors would be needed in order to establish a link between
infection by this human retrovirus and von Recklinghausen disease.

Silva et al. (1997) found that heterozygous Nf1-knockout mouse (Nf1+/-)
showed a deficit of learning and memory similar to humans with NF1. The
deficits were restricted to specific types of learning, were fully
penetrant, could be compensated for with extended training, and did not
involve deficits in simple associative learning.

Vogel et al. (1999) found that 100% of mice harboring null Nf1 and p53
(191170) alleles in cis developed soft tissue sarcomas between 3 and 7
months of age. The sarcomas exhibited loss of heterozygosity (LOH) at
both gene loci, and expressed phenotypic traits characteristic of neural
crest derivatives and human NF1 malignancies. Vogel et al. (1999)
concluded that their data and those of Cichowski et al. (1999) indicated
that an additional mutation in the p53 tumor suppressor gene is required
to predispose Nf1+/- mouse neural crest-derived cells to malignant
transformation. Vogel et al. (1999) stated that their analyses provided
evidence that NF1-associated rhabdomyosarcomas and leiomyosarcomas may
be of neural crest origin and provided a possible explanation for the
development of malignant Triton tumors, or MTTs. Cell lines isolated
from MTTs express both Schwann cell and smooth muscle markers, often in
the same tumor cell. The phenotype of these tumors is consistent with
immortalization of a pluripotent neural crest stem cell, which under
normal circumstances adopts a glial, smooth muscle, or neuronal fate.
Unlike humans, mice that are heterozygous for a mutation in Nf1 do not
develop neurofibromas.

Cichowski et al. (1999) demonstrated that chimeric mice composed in part
of Nf1-/- cells do develop neurofibromas, which demonstrated that loss
of the wildtype NF1 allele is rate-limiting in tumor formation. In
addition, Cichowski et al. (1999) showed that mice that carry linked
germline mutations in Nf1 and p53 develop malignant peripheral nerve
sheath tumors, which supported a cooperative and causal role for p53
mutations in malignant peripheral nerve sheath tumor development.
Cichowski et al. (1999) concluded that the 2 mouse models, either
chimeric for complete loss of Nf1 or carrying Nf1 and p53 LOH, provide
the means to address fundamental aspects of disease development and to
test therapeutic strategies.

Humans with NF1 have an increased risk of optic gliomas, astrocytomas,
and glioblastomas. The TP53 tumor suppressor is often mutated in a
subset of astrocytomas that develop at a young age and progress slowly
to glioblastoma (termed secondary glioblastomas, in contrast to primary
glioblastomas that develop rapidly de novo). Reilly et al. (2000)
presented a mouse model of astrocytoma involving mutation of 2
tumor-suppressor genes, NF1 and Trp53 (TP53). that showed a range of
astrocytoma stages, from low-grade astrocytoma to glioblastoma
multiforme, and thus may accurately model human secondary glioblastomas
involving TP53 loss. This was the first reported mouse model of
astrocytoma initiated by loss of tumor suppressors, rather than
overexpression of transgenic oncogenes.

Costa et al. (2001) generated mice lacking the alternatively spliced
exon 23a, which modifies the GTPase-activating protein (GAP) domain of
NF1, by targeted disruption. Nf1(23a) -/- mice were viable and
physically normal and did not have increased tumor disposition, but
showed specific learning impairments. These mice specifically lacked the
neurofibromin type II isoform. Costa et al. (2001) found that spatial
learning was impaired in Nf1(23a) -/- mice but that additional training
alleviated learning deficits. Nf1(23a) -/- mice were impaired in
contextual discrimination and had delayed acquisition of motor skills.
The Nf1(23a) -/- mutation did not affect all forms of learning. Costa et
al. (2001) demonstrated that the type II isoform of neurofibromin is
important for brain function, but not for embryologic development or
tumor suppression. Their data indicated that the learning deficits
caused by mutations that inactivate NF1 in mice and humans are not the
result of developmental deficits or undetected tumors. Instead, they
suggested that learning deficits in individuals with NF1 are caused by
the disruption of neurofibromin function in the adult brain, a finding
with important implications for treatment of the learning disabilities
associated with NF1. Exon 23a modifies the GAP domain of NF1, indicating
that modulation of the RAS pathway is important to learning and memory.

Although approximately 10% of Nf1 +/- mice are prone to the development
of juvenile myelomonocytic leukemia, they do not manifest pigmentary
abnormalities or develop neurofibromas. Neurofibromin negatively
regulates Ras activity in mouse hemopoietic cells through the Kit
(164920) receptor tyrosine kinase, which is encoded by the dominant
white spotting (W) locus. Ingram et al. (2000) generated mice with
mutations at both the W locus (val831 to met, termed W41, which results
in an abnormal mottled, white coat color) and the Nf1 gene. Mice
homozygous for the W41 mutation and heterozygous at Nf1 had 60 to 70%
restoration of coat color. However, Nf1 haploinsufficiency increased
peritoneal and cutaneous mast cell numbers in wildtype and W41 mice, and
it increased wildtype and W41/W41 bone marrow mast cells in in vitro
cultures containing Steel factor (184745), the mouse Kit ligand and a
mast cell mitogen. Ingram et al. (2000) proposed that increasing the
neurofibromin-specific GAP for Ras activity could be a strategy for
preventing or treating the complications of NF1.

Gutmann et al. (1999) reported that astrocytes from mice heterozygous
for a targeted mutation in the Nf1 gene (Nf1 +/- astrocytes) showed a
cell autonomous growth advantage associated with increased RAS pathway
activation. In addition, Gutmann et al. (2001) demonstrated that Nf1
astrocytes exhibit decreased cell attachment, actin cytoskeletal
abnormalities during the initial phases of cell spreading, and increased
cell motility. Whereas these cytoskeletal abnormalities were also
observed in Nf1 -/- astrocytes, astrocytes expressing a constitutively
active RAS molecule showed increased cell motility and abnormal actin
cytoskeleton organization during cell spreading, but exhibited normal
cell attachment. Increased expression of 2 proteins implicated in cell
attachment, spreading, and motility were seen in Nf1 +/- and Nf1 -/-
astrocytes: GAP43 (162060) and T-cadherin (CDH13; 601364). The authors
hypothesized that tumor suppressor gene heterozygosity may result in
abnormalities in cell function that may contribute to the pathogenesis
of nontumor phenotypes in NF1.

Costa et al. (2002) crossed Nf1 heterozygote mice with mice heterozygous
for a null mutation in the Kras gene (190070) and tested the Nf1
descendants. They found that the double heterozygotes with decreased Ras
function had improved learning relative to Nf1 heterozygote mice. Costa
et al. (2002) also showed that the Nf1 +/- mice have increased
GABA-mediated inhibition and specific deficits in long-term
potentiation, both of which can be reversed by decreasing Ras function.
Costa et al. (2002) concluded that learning deficits associated with Nf1
may be caused by excessive Ras activity, which leads to impairments in
long-term potentiation caused by increased GABA-mediated inhibition.

Through use of a conditional (cre/lox) allele, Zhu et al. (2002)
demonstrated that loss of NF1 in the Schwann cell lineage is necessary,
but not sufficient, to generate tumors. In addition, complete
NF1-mediated tumorigenicity requires both a loss of NF1 in cells
destined to become neoplastic as well as heterozygosity in nonneoplastic
cells, particularly mast cells. Zhu et al. (2002) concluded that the
requirement for a permissive haploinsufficient environment to allow
tumorigenesis may have therapeutic implications for NF1 and other
familial cancers. Zhu et al. (2002) identified a non-cell-autonomous
role for the development of tumors in NF1. The onset, growth potential,
and multicellular nature of the NF1 -/- neurofibromas was suppressed
when the cellular environment retained both functional NF1 alleles. Zhu
et al. (2002) ruled out trivial explanations for the observed difference
in tumor incidence that relate to the potential relative inefficiency of
the Cre transgene. The fact that NF1 +/- mast cells invade preneoplastic
nerves and remain present throughout the development of the tumor is in
stark contrast to the absence of NF1 +/+ mast cells in the NF1
flox/flox;Krox20-cre hyperplasias that fail to form frank neurofibromas.
Zhu et al. (2002) suggested that sensitized heterozygous mast cells
homing to nullizygous NF1 Schwann cells in peripheral nerves would
create a cytokine-rich microenvironment that is apparently permissive
for tumor growth.

Although NF1 is characterized by proliferation and malignant
transformation of neural-crest derivatives, affected individuals often
have disorders that seem unrelated to the neural crest, including
hypertension, renal artery stenosis, increased incidence of congenital
heart disease (Friedman et al., 2002), especially valvular pulmonic
stenosis, and vascular abnormalities in the CNS known as moyamoya
(252350). Attempts to produce animal models of NF1 have been hampered by
the fact that inactivation of Nf1 in mice leads to midgestation
lethality from cardiovascular abnormalities. These defects include
structural malformations of the outflow tract of the heart and enlarged
endocardial cushions, which are the anlage of cardiac valves. Using
tissue-specific gene inactivation, Gitler et al. (2003) showed that
endothelial-specific inactivation of Nf1 recapitulates key aspects of
the complete null phenotype, including multiple cardiovascular
abnormalities involving the endocardial cushions and myocardium. This
phenotype is associated with an elevated level of Ras signaling in Nf1
-/- endothelial cells and greater nuclear localization of the
transcription factor NFATC1 (600489). Inactivation of NF1 in the neural
crest does not cause cardiac defects but results in tumors of
neural-crest origin resembling those seen in humans with NF1. These
results established a new and essential role for NF1 in endothelial
cells and confirmed the requirement for neurofibromin in the neural
crest.

Somatic inactivation of murine Nf1 in Schwann cells is necessary, but
not sufficient, to initiate neurofibroma formation (Zhu et al., 2002).
Neurofibromas occur with high penetrance in mice in which Nf1 is ablated
in Schwann cells in the context of a heterozygous mutant (Nf1 +/-)
microenvironment. Mast cells infiltrate neurofibromas, where they
secrete proteins that remodel the extracellular matrix and initiate
angiogenesis. Yang et al. (2003) showed that homozygous Nf1 mutant (Nf1
-/-) Schwann cells secrete Kit ligand (KITLG; 184745), also known as
mast cell growth factor (MGF), which stimulates mast cell migration.
They also showed that Nf1 +/- mast cells are hypermotile in response to
Kit ligand. Thus, these studies identified a novel interaction between
Schwann cells carrying a homozygous Nf1-null mutation and mast cells
heterozygous for the Nf1 mutation.

Viskochil (2003) pointed out that Riccardi (1981) had presented an 'NF
cellular interaction hypothesis,' implicating that the mast cell is a
major player in neurofibroma formation. He posited that 'the mast cell
now is seen not as a secondary arrival in a developing neurofibroma but
as an inciting factor contributing in a primary, direct fashion to tumor
development.'

Tong et al. (2007) investigated the pathophysiology of NF1 in Drosophila
melanogaster by inactivation or overexpression of the NF1 gene. NF1 gene
mutants had shortened life spans and increased vulnerability to heat and
oxidative stress in association with reduced mitochondrial respiration
and elevated production of reactive oxygen species (ROS). Flies
overexpressing NF1 had increased life spans, improved reproductive
fitness, increased resistance to oxidative and heat stress in
association with increased mitochondrial respiration, and a 60%
reduction in ROS production. These phenotypic effects proved to be
modulated by the adenylyl cyclase/cyclic AMP (cAMP) protein kinase A
(see 176911) pathway, not the Ras/Raf pathway. Treatment of wildtype D.
melanogaster with cAMP analogs increased their life span, and treatment
of NF1 mutants with metalloporphyrin catalytic antioxidant compounds
restored their life span. Thus, Tong et al. (2007) concluded that
neurofibromin regulates longevity and stress resistance through cAMP
regulation of mitochondrial respiration and ROS production. They
suggested that NF1 may be treatable using catalytic antioxidants.

Yan et al. (2008) stated that osteoclasts from NF1 patients and Nf1 +/-
mice show abnormal Ras (see 190020)-dependent bone resorption. They
found that Nf1 +/- osteoclast progenitors had elevated Rac1 (602048)
GTPase activation. Knockdown of Rac1 in Nf1 +/- mice corrected the
osteoclast defects and normalized Erk (see MAPK3; 601795) activation in
Nf1 +/- osteoclasts.

Skeletal anomalies, such as short stature or bowing/pseudoarthrosis of
the tibia, are relatively common in neurofibromatosis type I. Kolanczyk
et al. (2007) created mice with Nf1 knockout directed to
undifferentiated mesenchymal cells of developing limbs. Inactivation of
Nf1 in limbs resulted in bowing of the tibia, diminished growth, and
abnormal vascularization of skeletal tissues, consistent with findings
in patients with neurofibromatosis type I. However, fusion of the hip
joints and other joint abnormalities were also observed in mutant mice,
a finding that had not been reported in patients with neurofibromatosis
type I. Tibial bowing was caused by decreased stability of the cortical
bone due to a high degree of porosity, decreased stiffness, and
reduction in the mineral content, as well as hyperosteoidosis.
Accordingly, cultured osteoblasts showed increased proliferation and
decreased ability to differentiate and mineralize. The reduced growth in
Nf1-knockout mice was due to reduced proliferation and differentiation
of chondrocytes.

HISTORY

Although the Elephant Man (Howell and Ford, 1980) has often been thought
to have had von Recklinghausen disease, it has been suggested (Pyeritz,
1987) that Proteus syndrome (176920) is a more likely diagnosis. After
considering several diagnostic possibilities, Cohen (1988) also
concluded that the skeletal findings in Joseph Merrick are most
consistent with Proteus syndrome. He pointed out that the 'moccasin'
lesions of the feet are particularly characteristic of that disorder.
See the study of the case of Joseph Merrick by Graham and Oehlschlaeger
(1992).

Ruggieri and Polizzi (2003) found several historical examples of what
they interpreted as mosaicism in neurofibromatosis. They suggested that
the segmental lesions can be limited either to the affected area showing
the same degree of severity as that found in the corresponding nonmosaic
trait (type 1 segmental involvement) or may be markedly more pronounced
and superimposed on a milder, nonsegmental, heterozygous manifestation
of the same trait (type 2 segmental involvement).

- Exclusion Mapping Studies

Using RFLPs, Darby et al. (1985) excluded the gene for nerve growth
factor-beta (NGFB; 162030) on chromosome 1p13 as the site of the
mutation in 4 families with neurofibromatosis type 1.

Family studies by Dunn et al. (1985) excluded close linkage of NF1 (lod
score less than -2.0) with 8 markers (ABO, Rh, MNSs, GC, PGP, ACP, GPT,
and HP). Negative lod scores at all values of theta were obtained with
both GC (on 4) and Se (on 19), which others had proposed were linked to
NF. Dietz et al. (1985) excluded linkage of NF with GC. Findings of
DiLiberti et al. (1982) brought the total lod score over 3.0 for linkage
of NF with myotonic dystrophy (DM1; 160900). However, Huson et al.
(1986) excluded linkage with chromosome 19 markers linked to myotonic
dystrophy. Thus, the reports of coinheritance of DM and NF could be not
be explained by close linkage of the 2 loci.

Korenberg et al. (1989) and Pulst et al. (1990, 1991) studied markers
flanking the NF1 locus in multiplex families with achondroplasia (ACH;
100800). By linkage analysis, they excluded the achondroplasia locus
from the region between the 2 groups of markers flanking NF1. Thus, the
concurrence of achondroplasia and NF1 is a single patient was a matter
of chance.

*FIELD* SA
Abeliovich et al. (1995); Allanson et al. (1985); Bidot-Lopez and
Frankel (1983); Boudin et al. (1970); Buntin and Fitzgerald (1970);
Charron and Gariepy (1970); Clark et al. (1977); Cotlier (1977);
Fabricant and Todaro (1981); Fain et al. (1989); Ferner (1998); Fienman
and Yakovac (1970); Gervasini et al. (2002); Gutzmer et al. (2000);
Hochberg et al. (1974); Holt (1978); Izumi et al. (1971); Kaneko
et al. (1989); Kaplan et al. (1982); Kohn (1979); Lund and Skovby
(1991); Miles et al. (1969); Muller-Wiefel (1978); Nager (1964);
Newman and So (1971); O'Connell et al. (1989); Obringer et al. (1989);
Pellock et al. (1980); Philippart (1961); Riccardi (1981); Riccardi
and Mulvihill (1981); Rockower et al. (1982); Sands et al. (1975);
Satran et al. (1980); Siggers et al. (1975); Skuse et al. (1991);
Smith et al. (1970); Taylor (1962); Upadhyaya et al. (1989); von
Recklinghausen (1882); Wallace et al. (1990); Wallis et al. (1970);
Xu et al. (1989); Yagle et al. (1989)
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P. F.: Neurofibromatosis and hypertelorism. Brit. J. Derm. 109:
475-477, 1983.

282. Wiest, V.; Eisenbarth, I.; Schmegner, C.; Krone, W.; Assum, G.
: Somatic NF1 mutation spectra in a family with neurofibromatosis
type 1: toward a theory of genetic modifiers. Hum. Mutat. 22: 423-427,
2003.

283. Williams, V. C.; Lucas, J.; Babcock, M. A.; Gutmann, D. H.; Korf,
B.; Maria, B. L.: Neurofibromatosis type 1 revisited. Pediatrics 123:
124-133, 2009.

284. Winter, R. B.: Spontaneous dislocation of a vertebra in a patient
who had neurofibromatosis: report of a case with dural ectasia. J.
Bone Joint Surg. Am. 73: 1402-1404, 1991.

285. Wolkenstein, P.; Mahmoudi, A.; Zeller, J.; Revuz, J.: More on
the frequency of segmental neurofibromatosis. (Letter) Arch. Derm. 131:
1465, 1995.

286. Woody, R. C.; Perrot, L. J.; Beck, S. A.: Neurofibromatosis
cerebral vasculopathy in an infant: clinical, neuroradiographic, and
neuropathologic studies. Pediat. Path. 12: 613-619, 1992.

287. Xu, W.; Lizhi, L.; Yuengde, B.; Yagle, M.; Solomon, E.: Enrichment
of regional cosmid clones from a human chromosome 17 transfectant
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Cell Genet. 51: 1112, 1989.

288. Yagle, M.; Rider, S. H.; Parruti, G.; Nicolai, H.; Borrow, J.;
Mathew, C.; Ponder, B.; Sheer, D.; Ledbetter, D.; Solomon, E.: Isolation
of cosmids flanking the translocations for acute promyelocytic leukaemia
(APL) and von Recklinghausen neurofibromatosis (NF1). (Abstract) Cytogenet.
Cell Genet. 51: 1112, 1989.

289. Yagle, M. K.; Parruti, G.; Xu, W.; Ponder, B. A. J.; Solomon,
E.: Genetic and physical map of the von Recklinghausen neurofibromatosis
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1990.

290. Yamauchi, T.; Tada, M.; Houkin, K.; Tanaka, T.; Nakamura, Y.;
Kuroda, S.; Abe, H.; Inoue, T.; Ikezaki, K.; Matsushima, T.; Fukui,
M.: Linkage of familial moyamoya disease (spontaneous occlusion of
the circle of Willis) to chromosome 17q25. Stroke 31: 930-935, 2000.

291. Yan, J.; Chen, S.; Zhang, Y.; Li, X.; Li, Y.; Wu, X.; Yuan, J.;
Robling, A. G.; Kapur, R.; Chan, R. J.; Yang, F.-C.: Rac1 mediates
the osteoclast gains-in-function induced by haploinsufficiency of
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292. Yang, F.-C.; Ingram, D. A.; Chen, S.; Hingtgen, C. M.; Ratner,
N.; Monk, K. R.; Clegg, T.; White, H.; Mead, L.; Wenning, M. J.; Williams,
D. A.; Kapur, R.; Atkinson, S. J.; Clapp, D. W.: Neurofibromin-deficient
Schwann cells secrete a potent migratory stimulus for Nf1 +/- mast
cells. J. Clin. Invest. 112: 1851-1861, 2003.

293. Yasunari, T.; Shiraki, K.; Hattori, H.; Miki, T.: Frequency
of choroidal abnormalities in neurofibromatosis type 1. Lancet 356:
988-992, 2000.

294. Zacharin, M.: Precocious puberty in two children with neurofibromatosis
type I in the absence of optic chiasmal glioma. J. Pediat. 130:
155-157, 1997.

295. Zehavi, C.; Romano, A.; Goodman, R. M.: Iris (Lisch) nodules
in neurofibromatosis. Clin. Genet. 29: 51-55, 1986.

296. Zhu, Y.; Ghosh, P.; Charnay, P.; Burns, D. K.; Parada, L. F.
: Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:
920-922, 2002.

297. Zochodne, D.: Von Recklinghausen's vasculopathy. Am. J. Med.
Sci. 287: 64-65, 1984.

298. Zonana, J.; Weleber, R. G.: Segmental neurofibromatosis and
iris hamartomata (Lisch nodules). (Abstract) Proc. Greenwood Genet.
Center 3: 140-141, 1984.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Head];
Macrocephaly;
Sphenoid dysplasia;
[Eyes];
Lisch nodules (iris hamartomas);
Glaucoma;
Hypertelorism

CARDIOVASCULAR:
[Vascular];
Renal artery stenosis;
Hypertension

SKELETAL:
[Spine];
Scoliosis;
Spina bifida;
[Limbs];
Pseudoarthrosis;
Thinning of long bone cortex;
Local bony overgrowth

SKIN, NAILS, HAIR:
[Skin];
Neurofibromas;
Plexiform neurofibroma;
Cafe-au-lait spots;
Axillary freckling;
Inguinal freckling

NEUROLOGIC:
[Central nervous system];
Mental retardation, 30% learning disabilities, 10% mild mental retardation;
Aqueductal stenosis;
Hydrocephalus

NEOPLASIA:
Optic glioma;
Meningioma;
Hypothalamic tumor;
Neurofibrosarcoma;
Rhabdomyosarcoma;
Duodenal carcinoid;
Somatostatinoma;
Parathyroid adenoma;
Pheochromocytoma;
Pilocytic astrocytoma;
Malignant peripheral nerve sheath tumors;
Tumors at multiple other sites including CNS

MISCELLANEOUS:
50% of cases are caused by new mutations

MOLECULAR BASIS:
Caused by mutations in the neurofibromin gene (NF1, 162200.0001)

*FIELD* CN
Michael J. Wright - revised: 6/22/1999
Ada Hamosh - revised: 6/22/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 05/30/2008
ckniffin: 2/14/2007
joanna: 5/16/2006
joanna: 5/1/2002
kayiaros: 6/24/1999
kayiaros: 6/22/1999

*FIELD* CN
Ada Hamosh - updated: 11/13/2013
Marla J. F. O'Neill - updated: 2/22/2013
Patricia A. Hartz - updated: 3/18/2010
Patricia A. Hartz - updated: 1/11/2010
Cassandra L. Kniffin - reorganized: 11/23/2009
Cassandra L. Kniffin - updated: 11/17/2009
Ada Hamosh - updated: 11/26/2008
Cassandra L. Kniffin - updated: 5/30/2008
John A. Phillips, III - updated: 5/28/2008
Victor A. McKusick - updated: 12/14/2007
Cassandra L. Kniffin - updated: 11/28/2007
Cassandra L. Kniffin - updated: 9/27/2007
Cassandra L. Kniffin - updated: 8/20/2007
Cassandra L. Kniffin - updated: 7/18/2007
Victor A. McKusick - updated: 6/8/2007
Cassandra L. Kniffin - updated: 2/27/2007
Cassandra L. Kniffin - updated: 11/9/2006
Cassandra L. Kniffin - updated: 9/29/2006
Cassandra L. Kniffin - updated: 8/24/2006
Victor A. McKusick - updated: 6/26/2006
Victor A. McKusick - updated: 6/13/2006
Victor A. McKusick - updated: 6/9/2006
Ada Hamosh - updated: 6/5/2006
Victor A. McKusick - updated: 12/20/2005
Cassandra L. Kniffin - updated: 8/24/2005
Victor A. McKusick - updated: 8/17/2005
Victor A. McKusick - updated: 12/16/2004
Cassandra L. Kniffin - updated: 10/21/2004
Victor A. McKusick - updated: 9/21/2004
Victor A. McKusick - updated: 9/8/2004
Jane Kelly - updated: 7/30/2004
Victor A. McKusick - updated: 5/26/2004
Victor A. McKusick - updated: 5/3/2004
Victor A. McKusick - updated: 3/1/2004
Victor A. McKusick - updated: 2/10/2004
Victor A. McKusick - updated: 2/9/2004
Victor A. McKusick - updated: 1/12/2004
Victor A. McKusick - updated: 12/29/2003
Victor A. McKusick - updated: 11/24/2003
Victor A. McKusick - updated: 11/6/2003
Victor A. McKusick - updated: 8/5/2003
Victor A. McKusick - updated: 7/9/2003
Gary A. Bellus - updated: 6/12/2003
Victor A. McKusick - updated: 6/4/2003
Victor A. McKusick - updated: 5/15/2003
Victor A. McKusick - updated: 3/25/2003
Ada Hamosh - updated: 3/17/2003
Dawn Watkins-Chow - updated: 2/10/2003
Gary A. Bellus - updated: 2/3/2003
Victor A. McKusick - updated: 1/23/2003
Victor A. McKusick - updated: 1/9/2003
Victor A. McKusick - updated: 12/30/2002
Victor A. McKusick - updated: 12/13/2002
Victor A. McKusick - updated: 12/10/2002
Victor A. McKusick - updated: 11/27/2002
George E. Tiller - updated: 8/19/2002
Victor A. McKusick - updated: 8/15/2002
Paul Brennan - updated: 8/7/2002
Michael J. Wright - updated: 7/31/2002
Victor A. McKusick - updated: 6/4/2002
Ada Hamosh - updated: 5/8/2002
Victor A. McKusick - updated: 1/22/2002
Ada Hamosh - updated: 1/17/2002
Victor A. McKusick - updated: 1/10/2002
Paul J. Converse - updated: 12/21/2001
Paul J. Converse - updated: 12/11/2001
George E. Tiller - updated: 11/14/2001
Deborah L. Stone - updated: 9/13/2001
Victor A. McKusick - updated: 8/30/2001
Michael J. Wright - updated: 8/8/2001
Jane Kelly - updated: 7/17/2001
Jane Kelly - updated: 7/5/2001
George E. Tiller - updated: 6/20/2001
Victor A. McKusick - updated: 6/13/2001
Sonja A. Rasmussen - updated: 6/8/2001
Victor A. McKusick - updated: 5/30/2001
Ada Hamosh - updated: 3/28/2001
Gary A. Bellus - updated: 3/13/2001
George E. Tiller - updated: 3/5/2001
Michael J. Wright - updated: 2/6/2001
Michael J. Wright - updated: 1/9/2001
Victor A. McKusick - updated: 12/18/2000
Victor A. McKusick - updated: 12/4/2000
Sonja A. Rasmussen - updated: 11/27/2000
Ada Hamosh - updated: 10/30/2000
Sonja A. Rasmussen - updated: 10/12/2000
Sonja A. Rasmussen - updated: 9/15/2000
Victor A. McKusick - updated: 8/30/2000
Victor A. McKusick - updated: 8/21/2000
Victor A. McKusick - updated: 7/26/2000
Victor A. McKusick - updated: 6/30/2000
Ada Hamosh - updated: 6/9/2000
Stylianos E. Antonarakis - updated: 5/31/2000
Victor A. McKusick - updated: 5/9/2000
George E. Tiller - updated: 5/8/2000
Michael J. Wright - updated: 5/5/2000
Victor A. McKusick - updated: 4/10/2000
Victor A. McKusick - updated: 3/24/2000
Victor A. McKusick - updated: 2/16/2000
Victor A. McKusick - updated: 2/8/2000
Wilson H. Y. Lo - updated: 2/1/2000
Victor A. McKusick - updated: 1/12/2000
Sonja A. Rasmussen - updated: 1/5/2000
Ada Hamosh - updated: 12/9/1999
Victor A. McKusick - updated: 11/24/1999
Victor A. McKusick - updated: 11/18/1999
Michael J. Wright - updated: 11/3/1999
Victor A. McKusick - updated: 9/8/1999
Sonja A. Rasmussen - updated: 6/30/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 2/20/1999
Michael J. Wright - updated: 11/16/1998
Victor A. McKusick - updated: 11/4/1998
Victor A. McKusick - updated: 8/17/1998
Michael J. Wright - updated: 6/30/1998
Victor A. McKusick - updated: 6/12/1998
Victor A. McKusick - updated: 5/13/1998
Victor A. McKusick - updated: 3/24/1998
Victor A. McKusick - updated: 2/16/1998
Victor A. McKusick - updated: 2/11/1998
Jennifer P. Macke - updated: 6/9/1997
Victor A. McKusick - updated: 10/6/1997
Ada Hamosh - updated: 7/10/1997
Victor A. McKusick - updated: 6/17/1997
Victor A. McKusick - updated: 5/28/1997
Victor A. McKusick - updated: 5/16/1997
Victor A. McKusick - updated: 5/1/1997
Victor A. McKusick - updated: 4/21/1997
Victor A. McKusick - updated: 4/8/1997
Victor A. McKusick - updated: 3/2/1997
Moyra Smith - updated: 1/2/1997
Iosif W. Lurie - updated: 7/17/1996
Orest Hurko - updated: 5/8/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 2/22/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 11/13/2013
carol: 2/22/2013
terry: 11/13/2012
terry: 6/4/2012
carol: 7/6/2011
carol: 6/17/2011
terry: 5/31/2011
wwang: 5/12/2011
terry: 3/11/2011
terry: 3/10/2011
ckniffin: 1/11/2011
ckniffin: 1/4/2011
wwang: 1/4/2011
ckniffin: 12/22/2010
terry: 10/12/2010
terry: 4/30/2010
mgross: 3/18/2010
ckniffin: 3/8/2010
carol: 2/2/2010
mgross: 1/11/2010
terry: 11/24/2009
carol: 11/23/2009
ckniffin: 11/17/2009
terry: 11/9/2009
carol: 11/6/2009
carol: 6/3/2009
carol: 1/30/2009
alopez: 12/5/2008
terry: 11/26/2008
wwang: 10/30/2008
wwang: 6/5/2008
ckniffin: 5/30/2008
carol: 5/28/2008
carol: 4/4/2008
ckniffin: 4/2/2008
wwang: 3/13/2008
ckniffin: 2/5/2008
ckniffin: 1/7/2008
alopez: 12/14/2007
ckniffin: 11/28/2007
wwang: 10/23/2007
ckniffin: 9/27/2007
alopez: 9/26/2007
ckniffin: 8/20/2007
carol: 7/19/2007
ckniffin: 7/18/2007
alopez: 6/13/2007
terry: 6/8/2007
ckniffin: 3/7/2007
wwang: 3/1/2007
ckniffin: 2/27/2007
carol: 1/17/2007
ckniffin: 11/9/2006
wwang: 10/6/2006
ckniffin: 9/29/2006
wwang: 8/31/2006
ckniffin: 8/24/2006
wwang: 6/28/2006
wwang: 6/27/2006
terry: 6/26/2006
alopez: 6/16/2006
terry: 6/13/2006
terry: 6/9/2006
carol: 6/5/2006
alopez: 6/5/2006
ckniffin: 5/30/2006
carol: 4/25/2006
carol: 1/6/2006
terry: 12/21/2005
alopez: 12/20/2005
joanna: 12/16/2005
wwang: 8/29/2005
wwang: 8/26/2005
ckniffin: 8/24/2005
wwang: 8/24/2005
terry: 8/17/2005
terry: 8/3/2005
terry: 7/12/2005
mgross: 4/14/2005
terry: 2/22/2005
alopez: 2/10/2005
wwang: 1/25/2005
tkritzer: 1/14/2005
terry: 12/16/2004
terry: 11/2/2004
ckniffin: 10/28/2004
tkritzer: 10/25/2004
ckniffin: 10/21/2004
tkritzer: 10/19/2004
tkritzer: 9/21/2004
alopez: 9/8/2004
terry: 9/8/2004
carol: 8/20/2004
ckniffin: 8/20/2004
tkritzer: 8/3/2004
terry: 7/30/2004
carol: 7/28/2004
tkritzer: 6/4/2004
terry: 5/26/2004
tkritzer: 5/11/2004
terry: 5/3/2004
carol: 3/19/2004
tkritzer: 3/3/2004
terry: 3/1/2004
cwells: 2/18/2004
terry: 2/10/2004
terry: 2/9/2004
cwells: 1/14/2004
terry: 1/12/2004
cwells: 12/30/2003
terry: 12/29/2003
carol: 12/24/2003
terry: 12/16/2003
alopez: 11/26/2003
terry: 11/24/2003
tkritzer: 11/10/2003
terry: 11/6/2003
tkritzer: 8/6/2003
tkritzer: 8/5/2003
carol: 7/18/2003
terry: 7/9/2003
tkritzer: 7/9/2003
alopez: 6/12/2003
cwells: 6/9/2003
terry: 6/4/2003
cwells: 6/2/2003
tkritzer: 5/19/2003
terry: 5/15/2003
alopez: 5/14/2003
terry: 3/25/2003
cwells: 3/17/2003
carol: 2/19/2003
tkritzer: 2/10/2003
alopez: 2/3/2003
carol: 1/30/2003
tkritzer: 1/27/2003
terry: 1/23/2003
alopez: 1/9/2003
alopez: 1/8/2003
carol: 1/7/2003
tkritzer: 1/2/2003
terry: 12/30/2002
tkritzer: 12/18/2002
tkritzer: 12/17/2002
terry: 12/13/2002
alopez: 12/10/2002
terry: 12/10/2002
mgross: 12/4/2002
terry: 11/27/2002
terry: 11/22/2002
carol: 11/12/2002
cwells: 8/19/2002
carol: 8/15/2002
alopez: 8/7/2002
cwells: 8/1/2002
terry: 7/31/2002
mgross: 6/5/2002
terry: 6/4/2002
alopez: 5/8/2002
terry: 5/8/2002
alopez: 3/13/2002
alopez: 2/5/2002
carol: 2/4/2002
mcapotos: 2/1/2002
terry: 1/22/2002
alopez: 1/22/2002
terry: 1/17/2002
alopez: 1/11/2002
cwells: 1/10/2002
mgross: 12/21/2001
terry: 12/11/2001
cwells: 11/20/2001
cwells: 11/14/2001
carol: 9/13/2001
mcapotos: 8/30/2001
cwells: 8/16/2001
cwells: 8/13/2001
terry: 8/8/2001
mcapotos: 7/23/2001
mcapotos: 7/20/2001
mcapotos: 7/17/2001
carol: 7/11/2001
mcapotos: 7/5/2001
cwells: 6/20/2001
cwells: 6/19/2001
cwells: 6/15/2001
terry: 6/13/2001
mcapotos: 6/8/2001
cwells: 6/6/2001
cwells: 6/1/2001
terry: 5/30/2001
alopez: 3/29/2001
terry: 3/28/2001
alopez: 3/13/2001
alopez: 3/12/2001
mcapotos: 3/12/2001
carol: 3/8/2001
cwells: 3/6/2001
cwells: 3/5/2001
mcapotos: 2/9/2001
alopez: 2/6/2001
mcapotos: 1/9/2001
alopez: 1/9/2001
mcapotos: 1/4/2001
mcapotos: 1/2/2001
terry: 12/18/2000
mcapotos: 12/5/2000
mcapotos: 12/4/2000
mcapotos: 12/1/2000
mcapotos: 11/27/2000
mcapotos: 11/8/2000
mcapotos: 11/7/2000
mgross: 11/1/2000
terry: 10/30/2000
mcapotos: 10/12/2000
mcapotos: 9/22/2000
mcapotos: 9/15/2000
mcapotos: 9/5/2000
alopez: 8/30/2000
terry: 8/30/2000
carol: 8/29/2000
terry: 8/21/2000
carol: 8/3/2000
terry: 7/26/2000
mcapotos: 7/17/2000
mcapotos: 7/13/2000
terry: 6/30/2000
alopez: 6/16/2000
terry: 6/9/2000
mgross: 5/31/2000
carol: 5/22/2000
carol: 5/16/2000
alopez: 5/9/2000
alopez: 5/8/2000
alopez: 5/5/2000
mcapotos: 5/3/2000
mcapotos: 4/28/2000
terry: 4/10/2000
mgross: 4/10/2000
terry: 3/24/2000
mgross: 3/13/2000
mgross: 3/9/2000
terry: 2/16/2000
mcapotos: 2/14/2000
mcapotos: 2/8/2000
terry: 2/8/2000
carol: 2/2/2000
terry: 2/1/2000
mgross: 2/1/2000
terry: 1/12/2000
mgross: 1/5/2000
alopez: 12/9/1999
terry: 12/9/1999
carol: 11/24/1999
terry: 11/18/1999
alopez: 11/10/1999
terry: 11/3/1999
jlewis: 9/17/1999
terry: 9/8/1999
carol: 6/30/1999
kayiaros: 6/30/1999
kayiaros: 6/29/1999
carol: 5/20/1999
mgross: 2/24/1999
carol: 2/23/1999
terry: 2/20/1999
dkim: 12/15/1998
alopez: 12/11/1998
dkim: 12/10/1998
alopez: 12/8/1998
terry: 11/16/1998
carol: 11/9/1998
terry: 11/4/1998
terry: 8/20/1998
carol: 8/20/1998
terry: 8/17/1998
terry: 7/24/1998
alopez: 7/6/1998
terry: 6/30/1998
alopez: 6/16/1998
terry: 6/12/1998
terry: 6/3/1998
terry: 6/1/1998
alopez: 5/21/1998
alopez: 5/19/1998
terry: 5/13/1998
dholmes: 4/17/1998
carol: 4/14/1998
terry: 3/27/1998
psherman: 3/24/1998
dholmes: 3/6/1998
mark: 2/26/1998
terry: 2/26/1998
mark: 2/25/1998
terry: 2/16/1998
alopez: 2/11/1998
dholmes: 2/6/1998
terry: 11/6/1997
alopez: 10/13/1997
alopez: 10/10/1997
alopez: 10/9/1997
mark: 10/8/1997
terry: 10/6/1997
terry: 7/10/1997
alopez: 7/10/1997
carol: 6/23/1997
jenny: 6/23/1997
alopez: 6/17/1997
jenny: 6/5/1997
terry: 5/28/1997
mark: 5/16/1997
terry: 5/12/1997
mark: 5/1/1997
terry: 5/1/1997
alopez: 4/21/1997
alopez: 4/17/1997
terry: 4/11/1997
jenny: 4/8/1997
terry: 4/4/1997
jenny: 4/3/1997
terry: 3/31/1997
mark: 3/2/1997
terry: 2/28/1997
joanna: 1/15/1997
terry: 1/2/1997
terry: 12/30/1996
jamie: 12/4/1996
mark: 11/27/1996
terry: 11/19/1996
terry: 11/8/1996
jamie: 10/23/1996
jamie: 10/16/1996
terry: 9/4/1996
terry: 9/3/1996
terry: 8/22/1996
mark: 7/22/1996
carol: 7/18/1996
carol: 7/17/1996
mark: 6/12/1996
terry: 6/6/1996
mark: 5/8/1996
terry: 5/3/1996
terry: 4/15/1996
mark: 3/11/1996
terry: 3/11/1996
mark: 3/6/1996
terry: 2/29/1996
mark: 2/22/1996
terry: 2/12/1996
terry: 2/6/1996
mark: 1/28/1996
terry: 1/25/1996
terry: 1/24/1996
mark: 1/20/1996
mark: 1/17/1996
terry: 1/16/1996
mark: 11/13/1995
terry: 10/26/1995
carol: 3/2/1995
davew: 8/16/1994
jason: 6/7/1994
warfield: 4/21/1994

MIM 162210
*RECORD*
*FIELD* NO
162210
*FIELD* TI
#162210 NEUROFIBROMATOSIS, FAMILIAL SPINAL
;;FSNF
*FIELD* TX
A number sign (#) is used with this entry because familial spinal
read moreneurofibromatosis is caused by mutation in the neurofibromin gene (NF1;
613113).

CLINICAL FEATURES

Pulst et al. (1991) reported 2 families with spinal neurofibromatosis.
The first family also had cafe-au-lait spots, whereas the second family
had no cafe-au-lait spots. Other signs of neurofibromatosis I (NF1;
162200) or neurofibromatosis type II (NF2; 101000), such as cutaneous
tumors, Lisch nodules, or acoustic tumors, were absent in both families.
The transmission pattern was consistent with autosomal dominant
inheritance, with at least 1 instance of male-to-male transmission in
both families.

Poyhonen et al. (1997) described a family in which 7 members in 3
generations had spinal neurofibromatosis. The affected adults showed, at
the ages of 32, 37, 38, and 61 years, respectively, multiple spinal
neurofibromas symmetrically affecting all spinal roots. Two patients
were operated on for histopathologically proven cervical spinal
neurofibromas. All patients had cafe-au-lait spots, 1 had several
freckles in the axillary area, and 2 had possible dermal neurofibromas,
but iris Lisch nodules were not present. Other signs of
neurofibromatosis type I and type II were absent. Several patients had
lower extremity weakness.

Ars et al. (1998) reported a 3-generation family in which 5 members, all
female, had spinal neurofibromatosis. All presented with multiple spinal
neurofibromas and cafe-au-lait spots. The oldest affected patient was a
58-year-old woman who had developed progressive paraparesis of her legs
and right arm at age 45 years. She had multiple cafe-au-lait spots, but
no cutaneous neurofibromas. Her affected daughter was a 34-year-old
woman who had surgery at 16 years of age to remove a mediastinal
neurofibroma. She had multiple cafe-au-lait spots and 3 cutaneous
neurofibromas. At age 23 years, she developed signs of progressive
spastic paraparesis. Another 24-year-old daughter had multiple
cafe-au-lait spots and a history of surgical resection of a plexiform
neurofibroma on the right arm. Multiple intra- and extraspinal
neurofibromas were demonstrated. A third woman in the second generation,
aged 21 years, had multiple cafe-au-lait spots and Lisch nodules, as
well as spinal tumors. An affected member of the third generation, a
12-year-old girl, had multiple cafe-au-lait spots and Lisch nodules.
Spinal MRI showed multiple bilateral tumors from C2 to D4 and 2
paravertebral masses.

Kaufmann et al. (2001) reported 2 unrelated families with spinal
neurofibromatosis but without cafe-au-lait macules. The 32-year-old
proposita in the first family had an intrathoracic upper mediastinal
tumor detected at age 17 years. Subsequent MRI examinations detected
multiple tumors of the psoas muscle and cervical and lumbar spine. Two
of the spinal tumors were surgically excised and identified as a
schwannoma and neurofibroma. In addition, a subcutaneous neurofibroma
and a subcutaneous schwannoma were excised. Tumors in the CNS typical of
NF2 were not found. She had no cafe-au-lait macules, intertriginous
freckling, or Lisch nodules. There were no signs of mental retardation
or scoliosis. The 31-year-old proposita from the second family observed
multiple painful intradermal tumors of the extremities and trunk at the
age of 17 years, 1 of which was identified as a neurofibroma. Another
tumor, identified histologically as a schwannoma, was excised from the
thoracic spine at age 29 years. Multiple spinal tumors were identified
by MRI scans in all segments of the spine, especially in C5/C6. Other
symptoms typical of NF1, such as cafe-au-lait macules, freckles, Lisch
nodules, scoliosis, or tumors of the CNS, were not found. The patient's
mother had 2 lumbar hyperpigmentations and presented with acute lumbago.
MRI scan showed enlarged spinal nerves in all segments of the spine.

MAPPING

Using genetic linkage analysis with DNA markers tightly linked to the
NF1 and NF2 loci, Pulst et al. (1991) determined that the likely
location for the mutation in a family with spinal neurofibromatosis and
cafe-au-lait spots was in the NF1 gene with odds of 97:1, whereas the
mutation in a second family, with spinal neurofibromatosis but without
cafe-au-lait spots, was excluded from the NF1 locus with odds of more
than 100,000:1. However, markers for the NF2 locus were uninformative in
the unlinked family.

Linkage study of the affected family reported by Poyhonen et al. (1997)
suggested close linkage to the NF1 locus and excluded linkage with the
NF2 locus. DNA analysis of histopathologically verified spinal
neurofibromas in 2 patients showed no evidence of loss of heterozygosity
(LOH) at 17q11.2. Poyhonen et al. (1997) suggested that the disorder was
a clinically distinct form of neurofibromatosis with extensive spinal
involvement and cafe-au-lait macules which may be allelic to classic
NF1.

MOLECULAR GENETICS

In affected members of a family with spinal neurofibromatosis, Ars et
al. (1998) identified a frameshift mutation in the NF1 gene
(613113.0018).

In affected members of 2 families with spinal neurofibromas but no
cafe-au-lait macules, Kaufmann et al. (2001) identified 2 different
mutations in the NF1 gene (613113.0028 and 613113.0029, respectively).
Both NF1 mutations caused a reduction in neurofibromin of approximately
50%, with no truncated protein present in the cells. The findings
demonstrated that typical NF1 null mutations can result in a phenotype
that is distinct from classical NF1, showing only a small spectrum of
the NF1 symptoms, such as multiple spinal tumors, but not completely
fitting the current clinical criteria for spinal NF. Kaufmann et al.
(2001) suggested that the spinal NF phenotype may be caused by a
modifying gene that partially compensates for the effects of
neurofibromin deficiency.

In 4 affected members of the family with spinal NF and cafe-au-lait
spots reported by Pulst et al. (1991), Messiaen et al. (2003) identified
a mutation in the NF1 gene (613113.0037). In affected members of the
family with spinal NF reported by Poyhonen et al. (1997), Messiaen et
al. (2003) identified a mutation in the NF1 gene (613113.0038).

*FIELD* RF
1. Ars, E.; Kruyer, H.; Gaona, A.; Casquero, P.; Rosell, J.; Volpini,
V.; Serra, E.; Lazaro, C.; Estivill, X.: A clinical variant of neurofibromatosis
type 1: familial spinal neurofibromatosis with a frameshift mutation
in the NF1 gene. Am. J. Hum. Genet. 62: 834-841, 1998.

2. Kaufmann, D.; Muller, R.; Bartelt, B.; Wolf, M.; Kunzi-Rapp, K.;
Hanemann, C. O.; Fahsold, R.; Hein, C.; Vogel, W.; Assum, G.: Spinal
neurofibromatosis without cafe-au-lait macules in two families with
null mutations of the NF1 gene. Am. J. Hum. Genet. 69: 1395-1400,
2001.

3. Messiaen, L.; Riccardi, V.; Peltonen, J.; Maertens, O.; Callens,
T.; Karvonen, S. L.; Leisti, E.-L.; Koivunen, J.; Vandenbroucke, I.;
Stephens, K.; Poyhonen, M.: Independent NF1 mutations in two large
families with spinal neurofibromatosis. J. Med. Genet. 40: 122-126,
2003.

4. Poyhonen, M.; Leisti, E.-L.; Kytola, S.; Leisti, J.: Hereditary
spinal neurofibromatosis: a rare form of NF1? J. Med. Genet. 34:
184-187, 1997.

5. Pulst, S.-M.; Riccardi, V. M.; Fain, P.; Korenberg, J. R.: Familial
spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 41:
1923-1927, 1991.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Lisch nodules (iris hamartomas) may or may not be present

SKIN, NAILS, HAIR:
[Skin];
Neurofibromas may or may not be present;
Cafe-au-lait spots may or may not be present;
Freckling may or may not be present

NEUROLOGIC:
[Central nervous system];
Spinal nerve root neurofibromas, symmetric, multiple;
Neurofibromas can occur at cervical, thoracic, lumbar, and sacral
levels;
Paraparesis;
Lower extremity weakness

MISCELLANEOUS:
Spinal tumors are necessary for diagnosis;
Other features of neurofibromatosis type I (NF1, 162200) may or
may not be present;
Allelic disorder to NF1

MOLECULAR BASIS:
Caused by mutation in the neurofibromin gene (NF1, 162200.0018)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/21/2004

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 10/21/2004

*FIELD* CN
Cassandra L. Kniffin - reorganized: 10/25/2004
Cassandra L. Kniffin - updated: 10/21/2004
Victor A. McKusick - updated: 1/11/2002

*FIELD* CD
Victor A. McKusick: 9/16/1992

*FIELD* ED
wwang: 05/23/2011
carol: 11/23/2009
tkritzer: 10/25/2004
ckniffin: 10/21/2004
alopez: 1/11/2002
mimadm: 12/2/1994
carol: 10/26/1993
carol: 9/16/1992

MIM 193520
*RECORD*
*FIELD* NO
193520
*FIELD* TI
#193520 WATSON SYNDROME
;;PULMONIC STENOSIS WITH CAFE-AU-LAIT SPOTS;;
CAFE-AU-LAIT SPOTS WITH PULMONIC STENOSIS
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Watson syndrome is caused by mutation in the NF1 gene (613113) on
chromosome 17q11.2.

DESCRIPTION

Watson syndrome is an autosomal dominant disorder characterized by
pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability
(Watson, 1967), and short stature (Partington et al., 1985). Most
affected individuals have relative macrocephaly and Lisch nodules and
about one-third of those affected have neurofibroma (Allanson et al.,
1991).

CLINICAL FEATURES

Watson (1967) described 15 persons from 2 generations of each of 3
families with pulmonic stenosis (8/15), cafe-au-lait spots (15/15) and
low normal or dull intelligence (12/15). There were 8 males and 7
females; male-to-male transmission was noted. There were no signs of
neurofibromata.

Partington et al. (1985) described a father (aged 57 years), his
daughter (aged 20) and his son (aged 18), all with pulmonary stenosis,
cafe-au-lait spots, and dull intelligence. The daughter also had soft
tissue limitation of movement of the knees and ankles and the father had
ectasia of the coronary arteries. None had neurofibromas, Lisch nodules,
lentigines, or deafness. Partington et al. (1985) contended that the
Watson syndrome is distinct from both neurofibromatosis I (NF1; 162200)
and the LEOPARD syndrome (151100). Although it was not obvious from the
original description, short stature is a universal feature of the Watson
syndrome.

Allanson et al. (1989) reviewed the 2 largest reported families
including members of the extended family who had not previously been
examined. They expanded the clinical phenotype to include relative
macrocephaly and Lisch nodules in most affected individuals and
neurofibromata in at least 4 family members. Allanson et al. (1991)
extended their review to an additional family. Neurofibromas were found
in about one-third of affected persons.

MAPPING

Because of clinical similarities between Watson syndrome and
neurofibromatosis, Allanson et al. (1991) performed linkage studies in
families with Watson syndrome, using probes known to flank the NF1 gene
on chromosome 17. Tight linkage with Watson syndrome was found (maximum
lod = 3.29 at theta = 0.0).

Upadhyaya et al. (1989, 1990) did a linkage study of a 3-generation
family with Watson syndrome. Close linkage with DNA marker D17S33 was
found; maximum lod = 3.28 at theta = 0.00. This marker is also the
closest marker to NF1. Thus, Watson syndrome and NF1 may be allelic, or
it is possible that pulmonic stenosis is the result of a change in an
adjacent gene.

Using probes flanking the NF1 gene on chromosome 17, Allanson et al.
(1991) found tightest linkage with probe HHH202; maximum lod score =
3.59 at theta = 0.0. They interpreted this to indicate that either the
Watson syndrome and NF1 are allelic or that there is a group of
contiguous genes responsible for the several features of the Watson
syndrome.

Relevant to the question of whether the Watson syndrome is a contiguous
gene syndrome resulting from deletion of both the NF1 gene and a gene
for Noonan syndrome, Sharland et al. (1992), in a linkage study in 11
families with Noonan syndrome in 2 or 3 generations, excluded the
proximal region of 17q as the location of the gene.

MOLECULAR GENETICS

Supporting the conclusion that Watson syndrome is allelic to NF1 is the
finding by Upadhyaya et al. (1992) of an 80-kb deletion in the NF1 gene
(613113.0011) in a patient with Watson syndrome. Similarly, Tassabehji
et al. (1993) demonstrated an almost perfect in-frame tandem duplication
of 42 bases in exon 28 of the NF1 gene in 3 members of a family with
Watson syndrome (613113.0010).

*FIELD* RF
1. Allanson, J. E.; Upadhyaya, M.; Watson, G. H.; Partington, M.;
Harper, P.; Huson, S.: Molecular linkage analysis of Watson syndrome.
(Abstract) Am. J. Hum. Genet. 45 (suppl.): A38 only, 1989.

2. Allanson, J. E.; Upadhyaya, M.; Watson, G. H.; Partington, M.;
MacKenzie, A.; Lahey, D.; MacLeod, H.; Sarfarazi, M.; Broadhead, W.;
Harper, P. S.; Huson, S. M.: Watson syndrome: is it a subtype of
type 1 neurofibromatosis? J. Med. Genet. 28: 752-756, 1991.

3. Partington, M. W.; Burggraf, G. W.; Fay, J. E.; Frontini, E.:
Pulmonary stenosis, cafe au lait spots and dull intelligence: the
Watson syndrome revisited. (Abstract) Proc. Greenwood Genet. Center 4:
105 only, 1985.

4. Sharland, M.; Taylor, R.; Patton, M. A.; Jeffery, S.: Absence
of linkage of Noonan syndrome to the neurofibromatosis type 1 locus. J.
Med. Genet. 29: 188-190, 1992.

5. Tassabehji, M.; Strachan, T.; Sharland, M.; Colley, A.; Donnai,
D.; Harris, R.; Thakker, N.: Tandem duplication within a neurofibromatosis
type I (NF1) gene exon in a family with features of Watson syndrome
and Noonan syndrome. Am. J. Hum. Genet. 53: 90-95, 1993.

6. Upadhyaya, M.; Sarfarazi, M.; Broadhead, W.; Huson, S. M.; Allanson,
J.; Fryer, A. E.; Harper, P. S.: Linkage of Watson's syndrome to
chromosome 17 markers. (Abstract) Cytogenet. Cell Genet. 51: 1094
only, 1989.

7. Upadhyaya, M.; Sarfarazi, M.; Huson, S.; Broadhead, W.; Allanson,
J.; Fryer, A.; Harper, P. S.: Linkage of Watson's syndrome to chromosome
17 markers. (Abstract) J. Med. Genet. 27: 209 only, 1990.

8. Upadhyaya, M.; Shen, M.; Cherryson, A.; Farnham, J.; Maynard, J.;
Huson, S. M.; Harper, P. S.: Analysis of mutations at the neurofibromatosis
1 (NF1) locus. Hum. Molec. Genet. 1: 735-740, 1992.

9. Watson, G. H.: Pulmonary stenosis, cafe-au-lait spots, and dull
intelligence. Arch. Dis. Child. 42: 303-307, 1967.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Head];
Relative macrocephaly;
[Eyes];
Lisch nodules

CARDIOVASCULAR:
[Heart];
Pulmonary valvular stenosis

SKIN, NAILS, HAIR:
[Skin];
Multiple cafe-au-lait spots;
Neurofibromas;
Axillary freckling

NEUROLOGIC:
[Central nervous system];
Low IQ

MISCELLANEOUS:
Allelic to neurofibromatosis-1 (NF1, 162200)

MOLECULAR BASIS:
Caused by mutations in the neurofibromin gene (NF1, 162200.0010)

*FIELD* CN
Kelly A. Przylepa - revised: 12/9/2003

*FIELD* CD
John F. Jackson: 10/22/1997

*FIELD* ED
terry: 02/12/2009
joanna: 12/9/2003
joanna: 10/22/1997

*FIELD* CN
Iosif W. Lurie - updated: 6/26/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 11/23/2009
carol: 11/20/2009
terry: 6/11/1999
terry: 6/3/1998
carol: 6/26/1996
mimadm: 6/7/1995
carol: 7/14/1993
carol: 2/2/1993
carol: 1/13/1993
carol: 5/26/1992
supermim: 3/16/1992

MIM 601321
*RECORD*
*FIELD* NO
601321
*FIELD* TI
#601321 NEUROFIBROMATOSIS-NOONAN SYNDROME; NFNS
;;NOONAN-NEUROFIBROMATOSIS SYNDROME;;
read moreNEUROFIBROMATOSIS WITH NOONAN PHENOTYPE
*FIELD* TX
A number sign (#) is used with this entry because some cases of
neurofibromatosis-Noonan syndrome are caused by mutation in the
neurofibromin gene (NF1; 613113).

Allelic disorders include classic neurofibromatosis type I (162200) and
Watson syndrome (193520).

CLINICAL FEATURES

Allanson et al. (1985) reported 4 unrelated patients with
neurofibromatosis who had manifestations of Noonan syndrome (163950),
including short stature, ptosis, midface hypoplasia, webbed neck,
learning disabilities, and muscle weakness. Family history was negative
in each case. Average paternal and maternal ages were 37 and 28 years,
respectively, at the birth of the patients, suggesting new dominant
mutation. The chromosomes, including prometaphase preparations in 3 of
the 4, were normal. The authors suggested that this is a distinct
entity. Opitz and Weaver (1985) likewise favored the distinctness of
what they called the neurofibromatosis-Noonan syndrome. They suggested
that males are more likely to have fusiform swelling of nerve strands,
while females more often show the classic neurofibromata seen in von
Recklinghausen disease (NF1). Lisch nodules of the iris were uncommon,
whereas there was a strong tendency to develop retroperitoneal or
visceral (ganglio-) neurofibromatosis.

Abuelo and Meryash (1988) described an 18-year-old man with
neurofibromatosis and classic manifestations of Noonan syndrome,
including atrial septal defect of the secundum type and valvular and
supravalvular pulmonic stenosis, for which cardiac surgery was
performed. The father also had neurofibromatosis and was described by
the authors as having 'some of the characteristics of Noonan syndrome,'
which were only 'prominent nasolabial folds and apparently low-set
ears.' The authors suggested several possibilities to explain the
combination of features: (1) a mutation at a locus different from that
of NF1 on chromosome 17; (2) an allele at the NF1 locus; (3) a
coincidence of 2 relatively frequent conditions; or (4) associated
disorders due to mutations at closely linked loci. In connection with
the last possibility, it is of note that Abuelo and Meryash (1988) found
no abnormality in the prophase chromosome analysis, performed with
special attention to chromosome 17, in their propositus.

Meinecke (1987) and Quattrin et al. (1987) concluded that it was
uncertain whether neurofibromatosis with Noonan syndrome-like features
was a distinct entity.

Edman Ahlbom et al. (1995) reported a family in which 4 individuals
spanning 2 generations had Noonan syndrome and cafe-au-lait spots.
Dysmorphic features included hypertelorism, epicanthal folds,
downslanting palpebral fissures, high peaks of the upper vermilion
border, and low-set ears. They also had pulmonary stenosis, cardiac
conduction defect, short stature, short neck, and widely spaced nipples.
Intelligence was normal. Nystrom et al. (2009) reported follow-up of the
family reported by Edman Ahlbom et al. (1995) and included additional
affected family members. The Noonan syndrome facial phenotype was found
in several family members but was less evident in others. All except 1
fulfilled the criteria for NF1, with cafe-au-lait spots, Lisch nodules,
and axillary freckling. None had visible plexiform neurofibromas, but 2
had growing mandibles, suggestive of giant cell lesions. Upon
reevaluation, Nystrom et al. (2009) concluded that the phenotype in this
family was consistent with NFNS.

Colley et al. (1996) examined 94 persons with neurofibromatosis for
features of the Noonan syndrome and found that 12, including some
familial cases, had diagnostic criteria of the Noonan syndrome. One of
the families showed independent segregation of NF1 and Noonan syndrome;
in other families, half of those affected with NF1 had manifestations of
the Noonan syndrome. However, linkage of the Noonan syndrome gene to
chromosome 12 (Jamieson et al., 1994) suggested that the genes for NF1
and Noonan syndrome are neither allelic nor contiguous. Colley et al.
(1996) suggested that some alterations of the NF1 gene may predispose to
the Noonan syndrome phenotype, but considered it unlikely that a
neurofibromatosis-Noonan syndrome phenotype is a distinct disorder or
occurs as part of classic Noonan syndrome.

Bahuau et al. (1996, 1998) reported a 4-generation family in which 8
members had NF1/Noonan syndrome, 2 had NF1 only, and 2 had NS only.
Linkage analysis showed tight linkage of the neurofibromatosis phenotype
to the NF1 gene, whereas the Noonan phenotype was not linked to the NF1
gene. However, cosegregation of the 2 phenotypes suggested 2 genetically
linked but distinct loci. Molecular analysis identified a heterozygous
truncating mutation in the NF1 gene in all 10 patients with features of
NF1, but not in the 2 patients with Noonan syndrome only. The findings
suggested the presence of another locus for Noonan syndrome on 17q
distinct from the NF1 gene.

Klopfenstein et al. (1999) reported 2 unrelated boys with
neurofibromatosis-Noonan syndrome who developed acute lymphoblastic
leukemia.

Stevenson et al. (2006) provided follow-up on the family reported by
Carey et al. (1997) in which a mother and 4 of 5 offspring had NFNS. All
5 patients had multiple cafe-au-lait spots and relative macrocephaly
consistent with NF1. None had neurofibromas. Variable features of Noonan
syndrome included short stature (in 3 of 5 patients), speech delay (3),
ptosis (5), downslanted palpebral fissures (2), telecanthus (3), malar
hypoplasia (3), posteriorly angulated ears (4), broad neck (4), pectus
anomaly (4), and pulmonic stenosis (3).

MOLECULAR GENETICS

In affected members of a family with NFNS, Carey et al. (1997)
identified a 3-bp deletion in exon 17 of the NF1 gene (162200.0033).

Baralle et al. (2003) used comparative sequence analysis to examine the
NF1 gene in 6 patients with NFNS and identified mutations in 2: a 3-bp
deletion in exon 25 (162200.0034) in 1 and a 2-bp insertion in exon 23-2
(162200.0035) in the other. The PTPN11 gene (176876), which had been
recognized as the cause of more than 50% of Noonan syndrome cases, was
also examined in 4 cases of NFNS, and no mutations were found.

To answer the question of whether NFNS represents a variable
manifestation of either NF1 or NS or is a distinct clinical entity, De
Luca et al. (2005) screened a cohort with clinically well-characterized
NFNS for mutations in the entire coding sequence of the NF1 and PTPN11
genes, which are responsible for classic neurofibromatosis and Noonan
syndrome, respectively. Heterozygous NF1 defects were identified in 16
of the 17 unrelated subjects studied, thus providing evidence that
mutations in NF1 represent the major molecular event underlying this
condition. A particularly high prevalence of in-frame defects affecting
exons 24 and 25, which encode a portion of the GAP-related domain of the
protein, was observed. On the other hand, no defect in PTPN11 was
observed and no lesion affecting exons 11 through 27 of the NF1 gene was
identified in 100 PTPN11 mutation-negative subjects with NS, providing
further evidence that NFNS and NS are genetically distinct disorders.
These results supported the view that NFNS is a variant of NF1 and is
caused by mutations of the NF1 gene, some of which have been
demonstrated to cause classic NF1 in other individuals.

De Luca et al. (2005) pointed out that some of the mutations identified
in patients with NFNS have also been reported in NF1 without any
features suggestive of NS. From a molecular point of view, the clinical
overlap between NFNS and NS is not surprising: the NF1 and PTPN11 gene
products, neurofibromin and SHP2, elicit their modulatory role through a
common pathway.

Although Edman Ahlbom et al. (1995) excluded linkage to the NF1 locus in
a family with Noonan syndrome and cafe-au-lait spots, Nystrom et al.
(2009) used direct sequencing to identify a heterozygous NF1 mutation
(L1390F; 613113.0045) in affected members of this family.

- Cooccurrence of NF1 And PTPN11 Mutations

Bertola et al. (2005) reported the occurrence of mutations in both NF1
(162200.0043) and PTPN11 (176876.0023) in a patient with
neurofibromatosis type I and Noonan syndrome. This is probably a rare
event accounting for a minority of these cases.

Thiel et al. (2009) reported another patient with features of both
neurofibromatosis I and Noonan syndrome who had mutations in both the
NF1 (162200.0044) and PTPN11 (176876.0027) genes. The PTPN11 mutation
occurred de novo, and the NF1 mutation was inherited from the patient's
mother, who had mild features of neurofibromatosis I, including the
absence of optic gliomas. The proband developed bilateral optic gliomas
before age 2 years, suggesting an additive effect of the 2 mutations on
the Ras pathway. The proband also had short stature, delayed
development, sternal abnormalities, and valvular pulmonary stenosis.

*FIELD* RF
1. Abuelo, D. N.; Meryash, D. L.: Neurofibromatosis with fully expressed
Noonan syndrome. Am. J. Med. Genet. 29: 937-941, 1988.

2. Allanson, J. E.; Hall, J. G.; Van Allen, M. I.: Noonan phenotype
associated with neurofibromatosis. Am. J. Med. Genet. 21: 457-462,
1985.

3. Bahuau, M.; Flintoff, W.; Assouline, B.; Lyonnet, S.; Le Merrer,
M.; Prieur, M.; Guilloud-Bataille, M.; Feingold, N.; Munnich, A.;
Vidaud, M.; Vidaud, D.: Exclusion of allelism of Noonan syndrome
and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis
association. Am. J. Med. Genet. 66: 347-355, 1996.

4. Bahuau, M.; Houdayer, C.; Assouline, B.; Blanchet-Bardon, C.; Le
Merrer, M.; Lyonnet, S.; Giraud, S.; Recan, D.; Lakhdar, H.; Vidaud,
M.; Vidaud, D.: Novel recurrent nonsense mutation causing neurofibromatosis
type 1 (NF1) in a family segregating both NF1 and Noonan syndrome. Am.
J. Med. Genet. 75: 265-272, 1998.

5. Baralle, D.; Mattocks, C.; Kalidas, K.; Elmslie, F.; Whittaker,
J.; Lees, M.; Ragge, N.; Patton, M. A.; Winter, R. M.; ffrench-Constant,
C.: Different mutations in the NF1 gene are associated with neurofibromatosis-Noonan
syndrome (NFNS). Am. J. Med. Genet. 119A: 1-8, 2003.

6. Bertola, D. R.; Pereira, A. C.; Passetti, F.; de Oliveira, P. S.;
Messiaen, L.; Gelb, B. D.; Kim, C. A.; Krieger, J. E.: Neurofibromatosis-Noonan
syndrome: molecular evidence of the concurrence of both disorders
in a patient. Am. J. Med. Genet. A136: 242-245, 2005.

7. Carey, J. C.; Stevenson, D. A.; Ota, M.; Neil, S.; Viskochil, D.
H.: Is there an NF/Noonan syndrome: Part 2. Documentation of the
clinical and molecular aspects of an important family. (Abstract) Proc.
Greenwood Genet. Center 17: 152-153, 1997.

8. Colley, A.; Donnai, D.; Evans, D. G. R.: Neurofibromatosis/Noonan
phenotype: a variable feature of type 1 neurofibromatosis. Clin.
Genet. 49: 59-64, 1996.

9. De Luca, A.; Bottillo, I.; Sarkozy, A.; Carta, C.; Neri, C.; Bellacchio,
E.; Schirinzi, A.; Conti, E.; Zampino, G.; Battaglia, A.; Majore,
S.; Rinaldi, M. M.; Carella, M.; Marino, B.; Pizzuti, A.; Digilio,
M. C.; Tartaglia, M.; Dallapiccola, B.: NF1 gene mutations represent
the major molecular event underlying neurofibromatosis-Noonan syndrome. Am.
J. Hum. Genet. 77: 1092-1101, 2005.

10. Edman Ahlbom, B.; Dahl, N.; Zetterqvist, P.; Anneren, G.: Noonan
syndrome with cafe-au-lait spots and multiple lentigines syndrome
are not linked to the neurofibromatosis type 1 locus. Clin. Genet. 48:
85-89, 1995.

11. Jamieson, C. R.; van der Burgt, I.; Brady, A. F.; van Reen, M.;
Elsawi, M. M.; Hol, F.; Jeffery, S.; Patton, M. A.; Mariman, E.:
Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Nature
Genet. 8: 357-360, 1994.

12. Klopfenstein, K. J.; Sommer, A.; Ruymann, F. B.: Neurofibromatosis-Noonan
syndrome and acute lymphoblastic leukemia: a report of two cases. J.
Pediat. Hemat. Oncol. 21: 158-160, 1999.

13. Meinecke, P.: Evidence that the neurofibromatosis-Noonan syndrome
is a variant of von Recklinghausen neurofibromatosis. Am. J. Med.
Genet. 26: 741-745, 1987.

14. Nystrom, A. M.; Ekvall, S.; Allanson, J.; Edeby, C.; Elinder,
M.; Holmstrom, G.; Bondeson, M. L.; Anneren, G.: Noonan syndrome
and neurofibromatosis type I in a family with a novel mutation in
NF1. Clin Genet. 76: 524-534, 2009.

15. Opitz, J. M.; Weaver, D. D.: The neurofibromatosis-Noonan syndrome. Am.
J. Med. Genet. 21: 477-490, 1985.

16. Quattrin, T.; McPherson, E.; Putnam, T.: Vertical transmission
of the neurofibromatosis/Noonan syndrome. Am. J. Med. Genet. 26:
645-649, 1987.

17. Stevenson, D. A.; Viskochil, D. H.; Rope, A. F.; Carey, J. C.
: Clinical and molecular aspects of an informative family with neurofibromatosis
type 1 and Noonan phenotype. Clin. Genet. 69: 246-253, 2006.

18. Thiel, C.; Wilken, M.; Zenker, M.; Sticht, H.; Fahsold, R.; Gusek-Schneider,
G.-C.; Rauch, A.: Independent NF1 and PTPN11 mutations in a family
with neurofibromatosis-Noonan syndrome. Am. J. Med. Genet. 149A:
1263-1267, 2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Midface hypoplasia;
Prominent nasolabial folds;
[Ears];
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Hypertelorism;
Downslanted palpebral fissures;
Ptosis;
Epicanthal folds;
Lisch nodules;
[Nose];
Low nasal root;
[Neck];
Webbed neck;
Short neck;
Webbed neck

CARDIOVASCULAR:
[Heart];
Pulmonic stenosis

CHEST:
[External features];
Pectus carinatum superiorly;
Pectus excavatum inferiorly

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
[Spine];
Scoliosis;
[Limbs];
Cubitus valgus

SKIN, NAILS, HAIR:
[Skin];
Cafe-au-lait spots;
Axillary freckling;
Inguinal freckling;
Neurofibromas;
[Hair];
Low posterior hairline;
Frontal upsweep of the hair

NEUROLOGIC:
[Central nervous system];
Speech delay;
Articulation defects;
Developmental delay, mild;
Unidentified bright objects on brain MRI

NEOPLASIA:
Optic glioma;
Neurofibromas;
Low incidence of plexiform neurofibromas

MISCELLANEOUS:
Phenotypic overlap between neurofibromatosis type 1 (162200) and
Noonan syndrome (163950)

MOLECULAR BASIS:
Caused by mutation in the neurofibromin gene (NF1, 613113.0033)

*FIELD* CN
Cassandra L. Kniffin - revised: 1/19/2010

*FIELD* CD
John F. Jackson: 10/3/1997

*FIELD* ED
joanna: 04/26/2013
ckniffin: 12/23/2010
ckniffin: 1/19/2010
alopez: 12/20/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 12/23/2010
Cassandra L. Kniffin - updated: 11/8/2010
Cassandra L. Kniffin - updated: 5/30/2006
Victor A. McKusick - updated: 12/12/2005
Victor A. McKusick - updated: 5/15/2003

*FIELD* CD
Iosif W. Lurie: 6/24/1996

*FIELD* ED
wwang: 01/10/2011
ckniffin: 12/23/2010
wwang: 11/12/2010
ckniffin: 11/8/2010
carol: 11/23/2009
joanna: 2/2/2009
carol: 6/5/2006
ckniffin: 5/30/2006
carol: 4/25/2006
alopez: 12/20/2005
terry: 12/16/2005
terry: 12/12/2005
tkritzer: 5/20/2003
tkritzer: 5/19/2003
terry: 5/15/2003
carol: 6/26/1996

MIM 607785
*RECORD*
*FIELD* NO
607785
*FIELD* TI
#607785 JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
;;LEUKEMIA, JUVENILE MYELOMONOCYTIC
read moreLEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because juvenile
myelomonocytic leukemia (JMML) can be caused by somatic mutations in
specific genes that result in activation of the RAS signaling pathway,
such as PTPN11 (176876), KRAS (190070), NRAS (164790). Somatic mutation
in the CBL gene (165360) has also been reported.

DESCRIPTION

Juvenile myelomonocytic leukemia is an aggressive pediatric
myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)
characterized by malignant transformation in the hematopoietic stem cell
compartment with proliferation of differentiated progeny (Loh et al.,
2009). JMML constitutes approximately 30% of childhood cases of
myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999).
Although JMML is a progressive and often rapidly fatal disease without
hematopoietic stem cell transplantation (HSCT), some patients have been
shown to have a prolonged and stable clinical course without HSCT
(Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a
similar disorder with later onset. Both JMML and CMML have a high
frequency of mutations affecting the RAS signaling pathway and show
hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511)
hyperphosphorylation (Loh et al., 2009).

- Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia

In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due
to somatic mutations in the PTPN11, KRAS, and NRAS genes. Additionally,
both germline and somatic mutations in the CBL gene have been found in
patients with JMML, indicating a frequency of 10 to 15% of JMML patients
overall (Loh et al., 2009). Somatic disruptions of the GRAF gene
(ARHGAP26; 605370) have also been found in patients with JMML.

About 10 to 15% of JMML cases arise in children with neurofibromatosis
type I (NF1; 162200) due to germline mutations in the NF1 gene (613113).
In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or
Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations
in the PTPN11, KRAS2, and CBL genes, respectively, also have an
increased risk of developing JMML.

- Genetic Heterogeneity of Chronic Myelomonocytic Leukemia

Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1
(605590) genes have been found in patients with CMML.

CYTOGENETICS

In a patient with chronic myelomonocytic leukemia (CMML) with a
t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the
HIP1 gene (601767) to the platelet-derived growth factor-beta receptor
gene (PDGFRB; 173410). They identified a chimeric transcript containing
the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The
fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the
transmembrane and tyrosine kinase domains of the PDGFRB gene. The
reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein
product was a 180-kD protein when expressed in a murine hematopoietic
cell line and was constitutively tyrosine phosphorylated. Furthermore,
the fusion gene transformed the same mouse hematopoietic cell line to
interleukin-3-independent growth.

In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et
al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner
fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The
fusion protein included more than 85% of the native rabaptin-5 fused to
the transmembrane and intracellular tyrosine kinase domains of PDGFRB.
Rabaptin-5 is an essential and rate-limiting component of early
endosomal fusion. The new fusion protein links 2 important pathways of
growth regulation.

MOLECULAR GENETICS

- Mutations Associated with Noonan Syndrome and JMML

Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to
Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I;
176876.0011), and that somatic mutations in PTPN11 are associated with
isolated JMML. Jongmans et al. (2005) described a patient with Noonan
syndrome and mild JMML who carried a mutation in the PTPN11 gene
(176876.0011).

Schubbert et al. (2006) described a 3-month-old female with Noonan
syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented
with a JMML-like myeloproliferative disorder. The patient was
heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This
mutation was also present in her buccal cells, but was absent in
parental DNA.

De Filippi et al. (2009) reported a boy who presented in infancy with
JMML and was later noted to have dysmorphic features suggestive of, but
not diagnostic of, Noonan syndrome (see NS6; 613224). Features included
short stature, relative macrocephaly, high forehead, epicanthal folds,
long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and
low scores on performance tasks. Cardiac studies were normal. Genetic
analysis revealed a de novo germline heterozygous mutation in the NRAS
gene (G13D; 164790.0003).

In 3 unrelated patients with a Noonan syndrome-like disorder (613563)
who developed JMML, Perez et al. (2010) identified a heterozygous
germline mutation in the CBL gene (Y371H; 165360.0005). The mutation
occurred de novo in 2 patients and was inherited from an unaffected
father in 1 patient. Leukemia cells of all patients showed somatic loss
of heterozygosity at chromosome 11q23, including the CBL gene. The
findings indicated that germline heterozygous mutations in the CBL gene
are associated with predisposition for the development of JMML.

In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009)
identified 25 homozygous and 2 heterozygous mutations in the CBL gene.
The mutations were located throughout the linker and RING finger
domains, and Y371H was the most common mutation. Leukemic cells from 3
patients examined in detail had acquired isodisomy of chromosome 11q
including the CBL gene. Each of these 3 patients had a heterozygous
germline CBL mutation, whereas their tumor cells had homozygous
mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high
levels of STAT5 (601511) in response to GM-CSF. These findings indicated
that reduplication of an inherited CBL mutation in a pluripotent
hematopoietic stem cell confers a selective advantage for the homozygous
state. Loh et al. (2009) estimated the frequency of CBL mutations to be
10 to 15% of JMML patients overall. They did not find CBL mutations in
JMML patients with known PTPN11/RAS mutation, indicating that CBL and
PTPN11/RAS mutations are mutually exclusive. The finding that
heterozygous germline mutations may predispose to development of JMML
suggested that CBL acts as a tumor suppressor gene.

- Isolated Juvenile or Chronic Myelomonocytic Leukemia

Jankowska et al. (2009) identified recurrent areas of somatic copy
number-neutral loss of heterozygosity (LOH) and deletions of chromosome
4q24 in patients with MDS/MPD. Subsequent analysis identified somatic
mutations in the TET2 gene (612839) in 6 of 17 cases of chronic
myelomonocytic leukemia.

Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene
in 29 (42%) of 69 CMML.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified somatic ASXL1 mutations were also found in 19 (43%) of 44
chronic myelomonocytic leukemia samples.

Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from
patients with CMML, which shares features with JMML.

Muramatsu et al. (2010) identified uniparental disomy of 11q23 in
leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the
CBL gene identified somatic mutations in 5 (10%) of 49 patients.
Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and
KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively.
None of the patients had mutations in the TET2 gene (612839), which had
previously been shown to be present in a significant proportion of
patients with MDS/MPD, including CMML (see Jankowska et al., 2009).
Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al.
(2010) did not have any of the known pathogenic defects.

Klinakis et al. (2011) identified novel somatic-inactivating Notch (see
190198) pathway mutations in a fraction of patients with CMML.
Inactivation of Notch signaling in mouse hematopoietic stem cells
resulted in aberrant accumulation of granulocyte/monocyte progenitors,
extramedullary hematopoiesis, and the induction of CMML-like disease.
Transcriptome analysis revealed that Notch signaling regulates an
extensive myelomonocytic-specific gene signature, through the direct
suppression of gene transcription by the Notch target Hes1 (139605).
Klinakis et al. (2011) concluded that their studies identified a novel
role for Notch signaling during early hematopoietic stem cell
differentiation and suggested that the Notch pathway can play both
tumor-promoting and -suppressive roles within the same tissue.

Sakaguchi et al. (2013) performed whole-exome sequencing for paired
tumor-normal DNA from 13 individuals with JMML (cases), followed by deep
sequencing of 8 target genes in 92 tumor samples. JMML was characterized
by a paucity of gene mutations (0.85 nonsilent mutations per sample)
with somatic or germline RAS pathway involvement in 82 cases (89%). The
SETBP1 (611060) and JAK3 (600173) mutations were among common targets
for secondary mutations. Mutations in JAK3 were often subclonal, and
Sakaguchi et al. (2013) hypothesized that they may be involved in the
progression rather than the initiation of leukemia; these mutations
associated with poor clinical outcomes.

- Exclusion Studies

Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a
cause of JMML in 16 specimens obtained from patients with the disorder
who did not have mutations in the KRAS, NRAS, or PTPN11 genes.

GENOTYPE/PHENOTYPE CORRELATIONS

Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS
gly12-to-ser (G12S) mutation who showed spontaneous improvement of
hematologic abnormalities lasting for 2 to 4 years with neither
intensive therapy nor HSCT. They suggested that the mild course
correlated with the G12S RAS mutation and recommended that patients
found to have this mutation receive close follow-up but no chemotherapy.
Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007)
as premature. They reviewed 50 patients with JMML who were not given
HSCT within the first 3 years after diagnosis; of these, 17 survived
without treatment from 4 to 21 years. Six of 7 carried a RAS mutation
different from R12S.

*FIELD* RF
1. Abdel-Wahab, O.; Mullally, A.; Hedvat, C.; Garcia-Manero, G.; Patel,
J.; Wadleigh, M.; Malinge, S.; Yao, J.; Kilpivaara, O.; Bhat, R.;
Huberman, K.; Thomas, S.; and 12 others: Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:
144-147, 2009.

2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.

3. Flotho, C.; Kratz, C. P.; Bergstrasser, E.; Hasle, H.; Stary, J.;
Trebo, M.; van den Heuvel-Eibrink, M. M.; Wojcik, D.; Zecca, M.; Locatelli,
F.; Niemeyer, C. M.: Genotype-phenotype correlation in cases of juvenile
myelomonocytic leukemia with clonal RAS mutations. (Letter) Blood 111:
966-967, 2008.

4. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
N.; Birnbaum, D.: Mutations of polycomb-associated gene ASXL1 in
myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
J. Haemat. 145: 788-800, 2009.

5. Hasle, H.; Arico, M.; Basso, G.; Biondi, A.; Rajnoldi, A. C.; Creutzig,
U.; Fenu, S.; Fonatsch, C.; Haas, O. A.; Harbott, J.; Kardos, G.;
Kerndrup, G.; and 11 others: Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia associated with
complete or partial monosomy 7. Leukemia 13: 376-385, 1999.

6. Jankowska, A. M.; Szpurka, H.; Tiu, R. V.; Makishima, H.; Afable,
M.; Huh, J.; O'Keefe, C. L.; Ganetzky, R.; McDevitt, M. A.; Maciejewski,
J. P.: Loss of heterozygosity 4q24 and TET2 mutations associated
with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410,
2009.

7. Jongmans, M.; Sistermans, E. A.; Rikken, A.; Nillesen, W. M.; Tamminga,
R.; Patton, M.; Maier, E. M.; Tartaglia, M.; Noordam, K.; van der
Burgt, I.: Genotypic and phenotypic characterization of Noonan syndrome:
new data and review of the literature. Am. J. Med. Genet. 134A:
165-170, 2005.

8. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; Oh, P.; Haeno, H.; Buonamici,
S.; van De Walle, I.; Cathelin, S.; Trimarchi, T.; Araldi, E.; Liu,
C.; Ibrahim, S.; Beran, M.; Zavadil, J.; Efstratiadis, A.; Taghon,
T.; Michor, F.; Levine, R. L.; Aifantis, I.: A novel tumour-suppressor
function for the Notch pathway in myeloid leukaemia. Nature 473:
230-233, 2011.

9. Loh, M. L.; Sakai, D. S.; Flotho, C.; Kang, M.; Fliegauf, M.; Archambeault,
S.; Mullighan, C. G.; Chen, L.; Bergstraesser, E.; Bueso-Ramos, C.
E.; Emanuel, P. D.; Hasle, H.; and 9 others: Mutations in CBL occur
frequently in juvenile myelomonocytic leukemia. Blood 114: 1859-1863,
2009.

10. Magnusson, M. K.; Meade, K. E.; Brown, K. E.; Arthur, D. C.; Krueger,
L. A.; Barrett, A. J.; Dunbar, C. E.: Rabaptin-5 is a novel fusion
partner to platelet-derived growth factor beta receptor in chronic
myelomonocytic leukemia. Blood 98: 2518-2525, 2001.

11. Matsuda, K.; Shimada, A.; Yoshida, N.; Ogawa, A.; Watanabe, A.;
Yajima, S.; Iizuka, S.; Koike, K.; Yanai, F.; Kawasaki, K.; Yanagimachi,
M.; Kikuchi, A.; and 10 others: Spontaneous improvement of hematologic
abnormalities in patients having juvenile myelomonocytic leukemia
with specific RAS mutations. Blood 109: 5477-5480, 2007.

12. Muramatsu, H.; Makishima, H.; Jankowska, A. M.; Cazzolli, H.;
O'Keefe, C.; Yoshida, N.; Xu, Y.; Nishio, N.; Hama, A.; Yagasaki,
H.; Takahashi, Y.; Kato, K.; Manabe, A.; Kojima, S.; Maciejewski,
J. P.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations
are pathogenic in juvenile myelomonocytic leukemia. Blood 115: 1969-1975,
2010.

13. Niemeyer, C. M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi,
A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.;
Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van't Veer-Korthof,
E. T.; van Wering, E.; Zimmermann, M.; European Working Group on
Myelodysplastic Syndromes in Childhood (EWOG-MDS): Chronic myelomonocytic
leukemia in childhood: a retrospective analysis of 110 cases. Blood 89:
3534-3543, 1997.

14. Perez, B.; Mechinaud, F.; Galambrun, C.; Ben Romdhane, N.; Isidor,
B.; Philip, N.; Derain-Court, J.; Cassinat, B.; Lachenaud, J.; Kaltenbach,
S.; Salmon, A.; Desiree, C.; Pereira, S.; Menot, M. L.; Royer, N.;
Fenneteau, O.; Baruchel, A.; Chomienne, C.; Verloes, A.; Cave, H.
: Germline mutations of the CBL gene define a new genetic syndrome
with predisposition to juvenile myelomonocytic leukaemia. J. Med.
Genet. 47: 686-691, 2010.

15. Ross, T. S.; Bernard, O. A.; Berger, R.; Gilliland, D. G.: Fusion
of huntingtin interacting protein 1 to platelet-derived growth factor-beta
receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:
4419-4426, 1998.

16. Sakaguchi, H.; Okuno, Y.; Muramatsu, H.; Yoshida, K.; Shiraishi,
Y.; Takahashi, M.; Kon, A.; Sanada, M.; Chiba, K.; Tanaka, H.; Makishima,
H.; Wang, X.; and 10 others: Exome sequencing identifies secondary
mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature
Genet. 45: 937-941, 2013.

17. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.

18. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.

19. Yoshida, N.; Yagasaki, H.; Takahashi, Y.; Kudo, K.; Manabe, A.;
Kojima, S.: Mutation analysis of SIPA1 in patients with juvenile
myelomonocytic leukemia. (Letter) Brit. J. Haematol. 142: 845-846,
2008.

*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 5/25/2011
Ada Hamosh - updated: 5/23/2011
Cassandra L. Kniffin - updated: 5/3/2011
Carol A. Bocchini - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/9/2009
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005

*FIELD* CD
Victor A. McKusick: 5/14/2003

*FIELD* ED
alopez: 01/28/2014
carol: 12/8/2011
carol: 11/29/2011
ckniffin: 10/24/2011
wwang: 8/9/2011
ckniffin: 8/1/2011
wwang: 6/2/2011
ckniffin: 5/31/2011
ckniffin: 5/25/2011
alopez: 5/24/2011
terry: 5/23/2011
wwang: 5/19/2011
ckniffin: 5/3/2011
carol: 11/23/2009
terry: 6/19/2009
terry: 6/1/2009
carol: 6/1/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 7/31/2008
alopez: 3/3/2006
terry: 2/24/2006
tkritzer: 4/27/2005
terry: 4/14/2005
terry: 7/30/2003
alopez: 6/3/2003
alopez: 5/15/2003
alopez: 5/14/2003

MIM 613113
*RECORD*
*FIELD* NO
613113
*FIELD* TI
*613113 NEUROFIBROMIN 1; NF1
;;NEUROFIBROMIN
*FIELD* TX

DESCRIPTION

The NF1 gene encodes neurofibromin, a cytoplasmic protein that is
read morepredominantly expressed in neurons, Schwann cells, oligodendrocytes, and
leukocytes. It is a multidomain molecule with the capacity to regulate
several intracellular processes, including the RAS (see 190020)-cyclic
AMP pathway, the ERK (600997)/MAP (see 600178) kinase cascade, adenylyl
cyclase, and cytoskeletal assembly (summary by Trovo-Marqui and Tajara,
2006).

CLONING

Buchberg et al. (1990) sequenced a portion of the murine NF1 gene and
showed that the predicted amino acid sequence is nearly the same as the
corresponding region of the human NF1 gene product. Computer searches
identified homology between the mouse NF1 gene and the Ira1 and Ira2
genes identified in Saccharomyces cerevisiae, which negatively regulate
the RAS-cyclic AMP pathway. RAS proteins are involved in the control of
proliferation and differentiation in mammalian cells. Their activity is
modulated by their ability to bind and hydrolyze guanine nucleotides.
GTP-binding activates RAS, whereas GTP hydrolysis inactivates RAS.
Mutant forms of RAS found in human tumors have greatly decreased GTPase
activity, resulting in accumulation of RAS in the GTP-bound active form.

Xu et al. (1990) extended the known open reading frame of the human NF1
gene by cDNA walking and sequencing. The new sequence predicted 2,485
amino acids of the NF1 peptide. A 360-residue region showed significant
similarity to the catalytic domains of both human and bovine
GTPase-activating protein (GAP; 139150). Xu et al. (1990) suggested that
NF1 encodes a cytoplasmic GAP-like protein that may be involved in the
control of cell growth by interacting with proteins such as the RAS gene
product.

Marchuk et al. (1991) reported an extensive cDNA walk resulting in the
cloning of the complete coding region of the NF1 transcript. Analysis of
the sequences revealed an open reading frame of 2,818 amino acids,
although alternatively spliced products may code for different protein
isoforms.

To study the NF1 gene product, Gutmann et al. (1991) raised antibodies
against both fusion proteins and synthetic peptides. A specific protein
of about 250 kD was identified by both immunoprecipitation and
immunoblotting. The protein was found in all tissues and cell lines
examined and was detected in human, rat, and mouse tissues. Based on the
homology between the NF1 gene product and members of the GAP
superfamily, the name NF1-GAP-related protein (NF1-GRD) was suggested.
DeClue et al. (1991) raised rabbit antisera to a bacterially synthesized
peptide corresponding to the GAP-related domain of NF1 (NF1-GRD). The
sera specifically detected a 280-kD protein in lysates of HeLa cells.
This protein corresponded to the NF1 gene product, as shown by several
criteria. NF1 was present in a large molecular mass complex in
fibroblast and schwannoma cell lines and appeared to associate with a
very large (400-500 kD) protein in both cell lines.

Daston et al. (1992) raised antibodies against peptides coded by
portions of the NF1 cDNA. These antibodies specifically recognized a
220-kD protein, called neurofibromin, in both human and rat spinal cord.
Neurofibromin was most abundant in the nervous system. Immunostaining of
tissue sections indicated that neurons, oligodendrocytes, and
nonmyelinating Schwann cells contained neurofibromin, whereas astrocytes
and myelinating Schwann cells did not.

Trovo-Marqui and Tajara (2006) stated that 4 splicing exons (9a, 10a-2,
23a, and 48a) are responsible for the production of 5 human
neurofibromin isoforms (II, 3, 4 9a and 10a-2), which exhibit
differential expression in distinct tissues. Neurofibromin II, named
GRD2 (domain II-related GAP), is the result of the insertion of exon
23a, is expressed in Schwann cells, and has a reduced capacity of acting
as GAP. Neurofibromins 3 and 4, which contain exon 48a and both exons
23a and 48a, respectively, are expressed in muscle tissue, mainly in
cardiac and skeleton muscles. Neurofibromin 9a (also called 9br) is the
result of the inclusion of exon 9a and shows limited neuronal
expression. Isoform 10a is the result of insertion of exon 10a, which
introduces a transmembrane domain. This isoform has been observed in the
majority of human tissues analyzed.

GENE STRUCTURE

Xu et al. (1990) found that 3 active genes, called OMGP (164345), EVI2B
(158381), and EVI2A (158380), lie within an intron of NF1 but in
opposite orientation.

Xu et al. (1992) found a pseudogene of the AK3L1 gene (103030) in an
intron of the NF1 gene. It appeared to be a processed pseudogene since
it lacked introns and contained a polyadenylate tract; it nevertheless
retained coding potential because the open reading frame was not
impaired by any observed base substitutions.

Heim et al. (1994) cited evidence that the NF1 gene spans approximately
350 kb of genomic DNA, encodes an mRNA of 11 to 13 kb, and contains at
least 56 exons.

Li et al. (1995) showed that the 5-prime end of the NF1 gene is embedded
in a CpG island containing a NotI restriction site and that the
remainder of the gene lies in the adjacent 35-kb NotI fragment. In their
efforts to develop a comprehensive screen for NF1 mutations, they
isolated genomic DNA clones that together contain the entire NF1 cDNA
sequence. They identified all intron-exon boundaries of the coding
region and established that it contains at least 59 exons. The 3-prime
untranslated region of the NF1 gene was found to span approximately 3.5
kb and to be continuous with the stop codon.

Trovo-Marqui and Tajara (2006) stated that the NF1 gene contains 61
exons.

MAPPING

Barker et al. (1987) demonstrated that the gene responsible for
neurofibromatosis (NF1; 162200) is located in the pericentromeric region
of chromosome 17.

Wallace et al. (1990) identified a large transcript from the candidate
NF1 region on chromosome 17q11.2 that was disrupted in 3 patients with
neurofibromatosis type I. The changes disrupted expression of the NF1
transcript in all 3 patients, consistent with the hypothesis that it
acts as a tumor suppressor.

- Pseudogenes

Legius et al. (1992) characterized an NF1-related locus on chromosome
15. The nonprocessed NF1 pseudogene (NF1P1) can produce additional
fragments in Southern blotting, pulsed field gel, and PCR experiments
with some NF1 cDNA probes or oligonucleotides. In addition, certain
regions of the NF1 gene cross-hybridize with a locus on chromosome 14.
These loci can cause confusion in the mutation analysis of patients with
NF1.

Numerous NF1 pseudogenes have been identified in the human genome. Those
in 2q21, 14q11, and 22q11 form a subset with a similar genomic
organization and a high sequence homology. By PCR and fluorescence in
situ hybridization, Luijten et al. (2001) studied the extent of the
homology of the regions surrounding these NF1 pseudogenes. They found
that a fragment of at least 640 kb is homologous between the 3 regions.
Based on previous studies and these new findings, they proposed a model
for the spreading of the NF1 pseudogene-containing regions. A fragment
of approximately 640 kb was first duplicated in chromosome region 2q21
and transposed to 14q11. Subsequently, this fragment was duplicated in
14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11,
with a length of about 430 kb, was further duplicated to a variable
extent in 14q11. In addition, Luijten et al. (2001) identified sequences
that may facilitate the duplication and transposition of the 640-kb and
430-kb fragments.

GENE FUNCTION

DeClue et al. (1992) presented evidence implicating the NF1 protein as a
tumor suppressor gene product that negatively regulates p21(ras) (see
190020) and defined a 'positive' growth role for RAS activity in NF1
malignancies.

Basu et al. (1992) presented evidence supporting the hypothesis that NF1
is a tumor-suppressor gene whose product acts upstream of the RAS
proteins. They showed that the RAS proteins in malignant tumor cell
lines from patients with NF1 were in a constitutively activated state as
measured by the ratio of the guanine nucleotides bound to them, i.e.,
the ratio of GTP (active) to GDP (inactive). Transforming mutants of
p21(ras) bind large amounts of GTP, whereas wildtype p21(ras) is almost
entirely GDP-bound.

Nakafuku et al. (1993) took advantage of the yeast RAS system to isolate
mutants in the RAS GTPase activating protein-related domain of the NF1
gene product (NF1-GRD) that can act as antioncogenes specific for
oncogenic RAS. They demonstrated that these mutant NF1-GRDs, when
expressed in mammalian cells, were able to induce morphologic reversion
of RAS-transformed NIH 3T3 cells.

Johnson et al. (1993) stated that in schwannoma cell lines from patients
with neurofibromatosis, loss of neurofibromin is associated with
impaired regulation of GTP/RAS. They analyzed other neural crest-derived
tumor cell lines and showed that some melanoma and neuroblastoma cell
lines established from tumors occurring in patients without
neurofibromatosis also contained reduced or undetectable levels of
neurofibromin, with concomitant genetic abnormalities of the NF1 locus.
In contrast to the schwannoma cell lines, however, GTP/RAS was
appropriately regulated in the melanoma and neuroblastoma lines that
were deficient in neurofibromin, even when HRAS (190020) was
overexpressed. These results demonstrated that some neural crest tumors
not associated with neurofibromatosis have acquired somatically
inactivated NF1 genes and suggested a tumor-suppressor function for
neurofibromin that is independent of RAS GTPase activation.

Silva et al. (1997) cited several studies that suggested a role of
neurofibromin in brain function. The expression of the NF1 gene is
largely restricted to neuronal tissues in the adult. This
GTPase-activating protein may act as a negative regulator of
neurotrophin (see BDNF; 113505)-mediated signaling. They also noted
immunohistochemical studies that suggested that activation of astrocytes
may be common in the brain of NF1 patients.

In a review of the molecular neurobiology of human cognition, Weeber and
Sweatt (2002) presented an overview of the RAS-ERK-CREB pathway,
including the function of NF1. The authors discussed publications that
implicated dysfunction of this signal transduction cascade in cognitive
defects, including mental retardation caused by mutation in the NF1
gene.

Vogel et al. (1995) used a targeted disruption of the NF1 gene in mice
to examine the role of neurofibromin in the acquisition of neurotrophin
dependence in embryonic neurons. They showed that both neural crest- and
placode-derived sensory neurons isolated from NF1 -/- embryos develop,
extend neurites, and survive in the absence of neurotrophins, whereas
their wildtype counterparts die rapidly unless nerve growth factor
(162030) or BDNF is added to the culture medium. Moreover, NF1 -/-
sympathetic neurons survive for extended periods and acquire mature
morphology in the presence of NGF-blocking antibodies. These results
were considered by Vogel et al. (1995) as consistent with a model
wherein neurofibromin acts as a negative regulator of
neurotrophin-mediated signaling for survival of embryonic peripheral
neurons.

For the most part the NF1 tumor suppressor acts through the interaction
of its GRD with the product of the RAS protooncogene. Skuse et al.
(1996) discovered an mRNA editing site within the NF1 mRNA. Editing at
this site changes a cytidine at nucleotide 2914 to a uridine, creating
an in-frame translation stop codon. The edited transcript, if
translated, would produce a protein truncated in the N-terminal region
of the GRD, thereby inactivating the NF1 tumor-suppressor function.
Analysis of RNA from a variety of cell lines, tumors, and peripheral
blood cells revealed that the NF1 mRNA undergoes editing, to different
extents, in every cell type studied. Three tumors analyzed as part of
their study, an astrocytoma, a neurofibroma, and a neurofibrosarcoma,
each had levels of NF1 mRNA editing substantially higher than did
peripheral blood leukocytes. To investigate the role played by editing
in NF1 tumorigenesis, Cappione et al. (1997) analyzed RNA from 19 NF1
and 4 non-NF1 tumors. (The authors referred to the editing site as
nucleotide 3916.) They observed varying levels in NF1 mRNA editing in
different tumors, with a higher range of editing in more malignant
tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous
neurofibromas). Plexiform neurofibromas had an intermediate range of
levels of NF1 mRNA editing. The constitutional levels of NF1 mRNA
editing varied slightly in NF1 individuals but were consistent with the
levels observed in non-NF1 individuals. In every case, there was a
greater level of NF1 mRNA editing in the tumor than in the nontumor
tissue from the same patient. These results suggested to Cappione et al.
(1997) that inappropriately high levels of NF1 mRNA editing indeed plays
a role in NF1 tumorigenesis and that editing may result in the
functional equivalent of biallelic inactivation of the NF1 tumor
suppressor.

Mukhopadhyay et al. (2002) studied C-to-U RNA editing in peripheral
nerve sheath tumor samples (PNSTs) from 34 patients with NF1. Whereas
most showed low levels of RNA editing, 8 of the 34 tumors demonstrated 3
to 12% C-to-U editing of NF1 RNA. These tumors demonstrated 2
distinguishing characteristics. First, these PNSTs expressed APOBEC1
(600130) mRNA, the catalytic deaminase of the holoenzyme that edits APOB
(107730) RNA. Second, NF1 RNA from these PNSTs contained increased
proportions of an alternatively spliced exon, 23A, downstream of the
edited base in which editing occurs preferentially. These findings,
together with results of both in vivo and in vitro experiments with
APOBEC1, strongly suggested an important mechanistic linkage between NF1
RNA splicing and C-to-U editing and provided a basis for understanding
the heterogeneity of posttranscriptional regulation of NF1 expression.

The NF1 tumor suppressor protein is thought to restrict cell
proliferation by functioning as a Ras-specific guanosine
triphosphatase-activating protein. However, The et al. (1997) found that
Drosophila homozygous for null mutations of an NF1 homolog show no
obvious signs of perturbed RAS1-mediated signaling. Loss of NF1 resulted
in a reduction in size of larvae, pupae, and adults. This size defect
was not modified by manipulating RAS1 signaling but was restored by
expression of activated adenosine 3-prime, 5-prime-monophosphate
-dependent protein kinase (PKA; see 176911). Thus, NF1 and PKA appear to
interact in a pathway that controls the overall growth of Drosophila.
Guo et al. (1997) showed, from a study of Drosophila NF1 mutants, that
NF1 is essential for the cellular response to the neuropeptide PACAP38
(pituitary adenylyl cyclase-adenosine activating polypeptide) at the
neuromuscular junction. The peptide induced a 3-prime,
5-prime-monophosphate (cAMP) pathway. This response was eliminated in
NF1 mutants. NF1 appeared to regulate the rutabaga-encoded adenylyl
cyclase rather than the RAS-RAF pathway. Moreover, the NF1 defect was
rescued by the exposure of cells to pharmacologic treatment that
increased concentrations of cAMP.

Gutmann (2001) reviewed the functions of neurofibromin and merlin, the
product of the NF2 gene (607379), in tumor suppression and cell-cell
signaling, respectively.

Trovo-Marqui and Tajara (2006) provided a detailed review of
neurofibromin and its role in neurofibromatosis.

MOLECULAR GENETICS

- Neurofibromatosis Type I

Using pulsed field gel electrophoresis, Upadhyaya et al. (1990)
identified a 90-kb deletion in the proximal portion of 17q in 1 of 90
unrelated patients with neurofibromatosis I. Viskochil et al. (1990)
detected deletions of 190, 40, and 11 kb in the gene located at the 17q
translocation breakpoint in 3 patients with NF1.

In an NF1 patient, Wallace et al. (1991) identified an insertion of an
Alu sequence in an intron of the NF1 gene, resulting in deletion of the
downstream exon during splicing and a frameshift (613113.0001).

Cawthon et al. (1990) identified 2 different point mutations in the NF1
gene (L348P; 613113.0003 and R365X; 613113.0004) in patients with NF1.

Upadhyaya et al. (1992) identified multiple germline NF1 mutations (see,
e.g., 613113.0006-613113.0009) in patients with NF1.

Weiming et al. (1992) identified mutations in the NF1 gene in at most 3%
of NF1 subjects in an analysis that covered 17% of the coding sequence
by SSCP and a larger region by Southern blotting. The results suggested
that most NF1 mutations lie elsewhere in the coding sequence or outside
it.

Collins (1993) developed FISH techniques to detect large deletions in
the NF1 gene.

By denaturing gradient gel electrophoresis (DGGE), Valero et al. (1994)
screened 70 unrelated NF1 patients for mutations in exons 29 and 31. Of
the 4 mutations that were identified, 3 consisted of C-to-T transitions
resulting in nonsense mutations: 2 in exon 29 (5242C-T; 613113.0004 and
5260C-T) and 1 in exon 31 (5839C-T). The fourth mutation consisted of a
2-bp deletion in exon 31, 5843delAA, resulting in a premature stop
codon. The 5839C-T mutation had previously been reported in 3
independent studies, suggesting that this position is a mutation hotspot
within the NF1 gene. It occurs in a CpG residue.

Heim et al. (1994) stated that although mutations had been sought in
several hundred NF1 patients, by August 1994, only 70 germline mutations
had been reported in a total of 78 individuals; only the R1947X
(613113.0012) mutation had been seen in as many as 6 unrelated patients.
NF1 mutations that had been identified included 14 large (more than 25
bp) deletions, 3 large insertions, 18 small (less than 25 bp) deletions,
8 small insertions, 6 nonsense mutations, 14 missense mutations, and 7
intronic mutations. At least 56 (80%) of the 70 mutations potentially
encode a truncated protein because of premature translation termination.

Abernathy et al. (1997) stated that about half of NF1 cases represent
new mutations and fewer than 100 constitutional mutations had been
reported. They used a combined heteroduplex/SSCP approach to search for
mutations in the NF1 gene in a set of 67 unrelated NF1 patients and
identified 26 mutations and/or variants in 45 of the 59 exons tested.
Disease-causing mutations were found in 19% (13 of 67) of cases studied.
The mutations included splice mutations, insertions, deletions, and
point changes.

Maynard et al. (1997) screened exon 16 of the NF1 gene in 465 unrelated
NF1 patients. Nine novel mutations were identified: 3 nonsense, 2
single-base deletions, 1 7-bp duplication, 2 missense, and 1 recurrent
splice site mutation. No mutations had been reported previously in exon
16, which is the largest exon (441 bp) of NF1. The previous absence of
mutation identification in exon 16 suggested to the authors that codons
in this region may have a lower propensity to mutate.

Stop, or nonsense, mutations can have a number of effects. In the case
of several genes, they affect mRNA metabolism and reduce the amount of
detectable mRNA. Also, in the NF1 gene, a correlation between a high
proportion of stop mutations and unequal expression of the 2 alleles is
demonstrable. A second, less common outcome is that mRNA containing a
nonsense mutation is translated and results in a truncated protein. A
third possible outcome is an abnormally spliced mRNA induced by a
premature-termination codon (PTC) in the skipped exon. This was
demonstrated in several disease genes, including the CFTR gene (Hull et
al., 1994) and the fibrillin gene (Dietz et al., 1993). Hoffmeyer et al.
(1998) characterized several stop mutations localized within a few
basepairs in exons 7 and 37 of the NF1 gene and noticed complete
skipping of either exon in some cases. Because skipping of exons 7 and
37 does not lead to a frameshift, premature termination codons are
avoided. Hoffmeyer et al. (1998) found that some other stop mutations in
the same general region did not lead to a skip. Calculations of
minimum-free-energy structures of the respective regions suggested that
both changes in the secondary structure of mRNA and creation or
disruption of exonic sequences relevant for the splicing process may in
fact cause these different splice phenomena observed in the NF1 gene.

Mutation analysis in NF1 has been hampered by the large size of the gene
(350 kb with 60 exons), the high rate of new mutations, lack of
mutational clustering, and the presence of numerous homologous loci.
Mutation detection methods based on the direct analysis of the RNA
transcript of the gene permit the rapid screening of large multiexonic
genes. However, detection of frameshift or nonsense mutations can be
limited by instability of the mutant mRNA species due to
nonsense-mediated decay. To determine the frequency of this allelic
exclusion, Osborn and Upadhyaya (1999) analyzed total lymphocyte RNA
from 15 NF1 patients with known truncation mutations and a panel of 40
NF1 patients with unknown mutations. The level of expression of the
mutant message was greatly reduced in 2 of the 15 samples (13%), and in
3 of the 18 informative samples from the panel of 40. A coupled RT-PCR
and protein truncation test method was subsequently applied to screen
RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide
bands were identified and characterized in 21 samples (53%); each of
these had a different mutation. The mutations were uniformly distributed
across the gene, and 14 represented novel changes, providing further
information on the germline mutational spectrum of the NF1 gene.

The mutation rate in the NF1 gene is one of the highest known in humans,
with approximately 50% of all NF1 patients presenting with novel
mutations (review by Huson and Hughes, 1994). Despite the high frequency
of this disorder in all populations, relatively few mutations had been
identified at the molecular level, with most unique to 1 family. A
limited number of mutation 'hotspots' had been identified: R1947X in
exon 31 (613113.0012), and the 4-bp region between nucleotides 6789 and
6792 in exon 37, both implicated in about 2% of NF1 patients (review by
Upadhyaya and Cooper (1998)). Messiaen et al. (1999) identified another
mutation hotspot in exon 10b. By analyzing 232 unrelated NF1 patients,
they identified 9 mutations in exon 10b, indicating that this exon is
mutated in almost 4% of NF1 patients. Two mutations, Y489C (613113.0023)
and L508P (613113.0024), were recurrent, whereas the others were unique.
The authors suggested that since 10b shows the highest mutation rate of
any of the 60 NF1 exons, it should be given priority in mutation
analysis.

Fahsold et al. (2000) performed a mutation screen of the NF1 gene in
more than 500 unrelated patients with NF1. For each patient, the whole
coding sequence and all splice sites were studied for aberrations,
either by the protein truncation test (PTT), temperature-gradient gel
electrophoresis (TGGE) of genomic PCR products, or, most often, by
direct genomic sequencing of all individual exons. Of the variants
found, they concluded that 161 different ones were novel.
Mutation-detection efficiencies of the various screening methods were
similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for direct sequencing.
Of all sequence variants found, less than 20% represented C-to-T or
G-to-A transitions within a CpG dinucleotide, and only 6 different
mutations also occurred in NF1 pseudogenes, with 5 being typical C-to-T
transitions in a CpG. Thus, neither frequent deamination of
5-methylcytosines nor interchromosomal gene conversion can account for
the high mutation rate of the NF1 gene. As opposed to the truncating
mutations, the 28 (10.1%) missense or single-amino-acid-deletion
mutations identified clustered in 2 distinct regions, the GAP-related
domain and an upstream gene segment comprising exons 11 to 17. The
latter forms a so-called cysteine/serine-rich domain with 3 cysteine
pairs suggestive of ATP binding, as well as 3 potential cAMP-dependent
protein kinase recognition sites obviously phosphorylated by PKA.
Coincidence of mutated amino acids and those conserved between human and
Drosophila strongly suggested significant functional relevance of this
region, with major roles played by exons 12a and 15 and part of exon 16.

Ars et al. (2000) applied a whole NF1 cDNA screening methodology to the
study of 80 unrelated NF1 patients and identified 44 different
mutations, 32 being novel, in 52 of the patients. Mutations were
detected in 87% of the familial cases and in 51% of the sporadic ones.
At least 15 of the 80 NF1 patients (19%) had recurrence of a previously
observed mutation. The study showed that in 50% of the patients in whom
the mutations were identified, these resulted in splicing alterations.
Most of the splicing mutations did not involve the conserved AG/GT
dinucleotides of the donor and acceptor splice sites. One frameshift, 2
nonsense, and 2 missense mutations were also responsible for alterations
in mRNA splicing. Location and type of mutation within the NF1 gene and
its putative effect at the protein level did not indicate any
relationship to any specific clinical feature of NF1. The high
proportion of aberrant spliced transcripts detected in NF1 patients
stressed the importance of studying mutations at both the genomic and
RNA level. Ars et al. (2000) raised the possibility that part of the
clinical variability in NF1 is related to mutations affecting mRNA
splicing, which is the most common molecular defect in NF1.

Messiaen et al. (2000) studied 67 unrelated NF1 patients fulfilling the
NIH diagnostic criteria (Stumpf et al., 1988; Gutmann et al., 1997), 29
familial and 38 sporadic cases, using a cascade of complementary
techniques. They performed a protein truncation test starting from
puromycin-treated EBV cell lines and, if no mutation was found,
continued with heteroduplex, FISH, Southern blot, and cytogenetic
analysis. The authors identified the germline mutation in 64 of 67
patients, and 32 of the mutations were novel. The mutation spectrum
consisted of 25 nonsense, 12 frameshift, 19 splice mutations, 6 missense
and/or small in-frame deletions, 1 deletion of the entire NF1 gene, and
a translocation t(14;17)(q32;q11.2). Their data suggested that exons
10a-10c and 37 are mutation-rich regions and that together with some
recurrent mutations they may account for almost 30% of the mutations in
classic NF1 patients. Messiaen et al. (2000) found a high frequency of
unusual splice mutations outside of the AG/GT 5-prime and 3-prime splice
sites. As some of these mutations formed stable transcripts, it remained
possible that a truncated neurofibromin was formed.

Skuse and Cappione (1997) reviewed the possible molecular basis of the
wide clinical variability in NF1 observed even among affected members of
the same family (Huson et al., 1989). The complexities of alternative
splicing and RNA editing may be involved. Skuse and Cappione (1997)
suggested that the classical 2-hit model for tumor suppressor
inactivation used to explain NF1 tumorigenesis can be expanded to
include post-transcriptional mechanisms that regulate NF1 gene
expression. Aberrations in these mechanisms may play a role in the
observed clinical variability.

Eisenbarth et al. (2000) described a systematic approach of searching
for somatic inactivation of the NF1 gene in neurofibromas. In the course
of these studies, they identified 2 novel intragenic polymorphisms: a
tetranucleotide repeat and a 21-bp duplication. Among 7 neurofibromas
from 4 different NF1 patients, they detected 3 tumor-specific point
mutations and 2 LOH events. The results suggested that small subtle
mutations occur with similar frequency to that of LOH in benign
neurofibromas and that somatic inactivation of the NF1 gene is a general
event in these tumors. Eisenbarth et al. (2000) concluded that the
spectrum of somatic mutations occurring in various tumors from
individual NF1 patients may contribute to the understanding of variable
expressivity of the NF1 phenotype.

Klose et al. (1998) identified a novel missense mutation in the NF1 gene
(R1276P; 613113.0022) in a patient with a classic multisymptomatic NF1
phenotype, including a malignant schwannoma. The mutation specifically
abolished the Ras-GTPase-activating function of neurofibromin. The
authors suggested that therapeutic approaches aimed at the reduction of
the Ras-GTP levels in neural crest-derived cells may relieve NF1
symptoms.

Kluwe et al. (1999) stated that plexiform neurofibroma can be found in
about 30% of NF1 patients, often causing severe clinical symptoms. They
examined 14 such tumors from 10 NF1 patients for loss of heterozygosity
at the NF1 gene using 4 intragenic polymorphic markers. LOH was found in
8 tumors from 5 patients, and was suspected in 1 additional tumor from
another patient. They interpreted these findings as suggesting that loss
of the second allele, and thus inactivation of both alleles of the NF1
gene, is associated with the development of plexiform neurofibromas. The
14 plexiform neurofibromas were also examined for mutation in the TP53
gene; no mutations were found.

Faravelli et al. (1999) reported a family in which 7 members developed
brain tumors which in 4 were confirmed as gliomas. Three of these
individuals had a clinical history strongly suggestive of NF1. Two
individuals with very mild features of NF1 insufficient to meet
diagnostic criteria carried a splice site mutation in intron 29 of the
NF1 gene, creating a frameshift and premature protein termination.
Faravelli et al. (1999) noted the unusually high incidence of brain
tumors in this family with the NF1 phenotype and suggested that some
cases of familial glioma may be explained by mutations in the NF1 gene.

Kluwe et al. (2003) examined 20 patients with spinal tumors from 17
families for clinical symptoms associated with NF1 and for NF1
mutations. Typical NF1 features were found in 12 patients from 11
families. Typical NF1 mutations were found in 10 of the 11 index
patients in this group, including 8 truncating mutations, 1 missense
mutation, and 1 deletion of the entire NF1 gene. Eight patients from 6
families had no or only a few additional NF1-associated symptoms besides
multiple spinal tumors, which were distributed symmetrically in all
cases and affected all 38 nerve roots in 6 patients. Only mild NF1
mutations were found in 4 of the 6 index patients in the latter group,
including 1 splicing mutation, 2 missense mutations, and 1 nonsense
mutation in exon 47 at the 3-prime end of the gene. The data indicated
that patients with spinal tumors can have various NF1 symptoms and NF1
mutations; however, patients with no or only a few additional NF1
symptoms may be a subgroup or may have a distinct form of NF1, probably
associated with milder NF1 mutations or other genetic alterations.

The underestimates of NF1 gene mutations in neurofibromatosis type I
have been attributed to the large size of the NF1 gene, the considerable
frequency of gross deletions, and the common occurrence of splicing
defects that are only detectable by cDNA analysis. A number of splicing
errors do not affect the canonical GT splice donor or AG splice
acceptor, or create novel splice sites, but may exert their effect by
means of an altered interaction between an exonic splice enhancer (ESE)
and mRNA splicing factors (Messiaen et al., 2000; Liu et al., 2001).
Colapietro et al. (2003) reported skipping of exon 7 and sequence
alterations in ESEs in a patient with severe NF1 (613113.0036).

The analysis of somatic NF1 gene mutations in neurofibromas from NF1
patients shows that each neurofibroma results from an individual second
hit mutation; thus, factors that influence somatic mutation rates may be
regarded as potential modifiers of NF1. Wiest et al. (2003) performed a
mutation screen of numerous neurofibromas from 2 NF1 patients and found
a predominance of point mutations, small deletions, and insertions as
second hit mutations in both patients. Seven novel mutations were
reported. Together with the results of studies that showed LOH as the
predominant second hit in neurofibromas of other patients, these results
suggest that in different patients different factors may influence the
somatic mutation rate and thereby the severity of the disease.

Not only can mutations in nucleotides at the ends of introns result in
abnormalities of splicing, but nonsense, missense, and even
translationally silent mutations have been shown to cause exon skipping.
The analysis of individual mutations of this kind can shed light on
basic pre-mRNA splicing mechanisms. Using cDNA-based mutation detection
analysis, Zatkova et al. (2004) identified 1 missense and 6 nonsense
mutations (e.g., 613113.0042) that lead to different extents of
exon-lacking transcripts in NF1 patients. They confirmed
mutation-associated exon skipping in a heterologous hybrid minigene
context. Because of evidence that the disruption of functional ESE
sequences is frequently the mechanism underlying mutation-associated
exon skipping, Zatkova et al. (2004) examined the wildtype and mutant
NF1 sequences with 2 available ESE prediction programs. Either or both
programs predicted the disruption of ESE motifs in 6 of the 7 analyzed
mutations. To ascertain the function of the predicted ESEs, Zatkova et
al. (2004) quantitatively measured their ability to rescue splicing of
an enhancer-dependent exon, and found that all 7 mutant ESEs had reduced
splicing enhancement activity compared to the wildtype sequences. The
results suggested that the wildtype sequences function as ESE elements,
whose disruption is responsible for the mutation-associated exon
skipping observed in NF1 patients. Furthermore, this study illustrated
the utility of ESE prediction programs for delineating candidate
sequences that may serve as ESE elements.

In a girl with aniridia (106210), microphthalmia, microcephaly, and
cafe-au-lait macules, Henderson et al. (2007) identified heterozygous
mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and
OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and
PAX6 mutations, had NF1 with typical eye defects; in addition, although
her eyes were of normal size, she had small corneas, and also had
cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal
hypoplasia with normal-sized pupils. The proband's father, who had
multiple ocular defects (MCOPS5; 610125), had previously been studied by
Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation.
Henderson et al. (2007) noted that the proband's phenotype was
surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause
a variety of severe developmental defects.

Sabbagh et al. (2009) examined the phenotypic correlations between
affected relatives in 750 NF1 patients from 275 multiplex families
collected through the NF-France Network. Twelve NF1-related clinical
features, including 5 quantitative traits (number of cafe-au-lait spots
of small size and of large size, and number of cutaneous, subcutaneous,
and plexiform neurofibromas) and 7 binary ones, were scored. All
clinical features studied, with the exception of neoplasms, showed
significant familial aggregation after adjusting for age and sex. For
most of them, patterns of familial correlations indicated a strong
genetic component with no apparent influence of the constitutional NF1
mutation. Heritability estimates of the 5 quantitative traits ranged
from 0.26 to 0.62. Nine tag SNPs in NF1 were genotyped in 1,132
individuals from 313 NF1 families. No significant deviations of
transmission of any of the NF1 variants to affected offspring was found
for any of the 12 clinical features examined, based on single marker or
haplotype analysis. Sabbagh et al. (2009) concluded that genetic
modifiers, unlinked to the NF1 locus, contribute to the variable
expressivity of the disease.

- Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML; 607785) is a pediatric
myelodysplastic syndrome that is associated with neurofibromatosis type
I. The NF1 gene regulates the growth of immature myeloid cells by
accelerating guanosine triphosphate hydrolysis on RAS proteins. Side et
al. (1998) undertook a study to determine if the NF1 gene is involved in
the pathogenesis of JMML in children without a clinical diagnosis of
NF1. An in vitro transcription and translation system was used to screen
JMML marrows from 20 children for NF1 mutations that resulted in a
truncated protein. SSCP analysis was used to detect RAS point mutations
in these samples. Side et al. (1998) confirmed mutations of NF1 in 3
cases of JMML, 1 of which also showed loss of the normal NF1 allele. An
NF1 mutation was detected in normal tissue from the only patient tested,
suggesting that JMML may be the presenting feature of NF1 in some
children. Activating RAS mutations were found in 4 patients; as
expected, none of these samples harbored NF1 mutations. Because 10 to
14% of children with JMML had a clinical diagnosis of NF1, these data
were consistent with the existence of NF1 mutations in approximately 30%
of JMML cases.

The risk of malignant myeloid disorders in young children with NF1 is
200 to 500 times the normal risk. Neurofibromin, the protein encoded by
the NF1 gene, negatively regulates signals transduced by Ras proteins.
Genetic and biochemical data support the hypothesis that NF1 functions
as a tumor-suppressor gene in immature myeloid cells. This hypothesis
was further supported by the demonstration by Side et al. (1997) that
both NF1 alleles were inactivated in bone marrow cells from children
with NF1 complicated by malignant myeloid disorders. Using an in vitro
transcription and translation system, they screened bone marrow samples
from 18 such children for NF1 mutations that cause a truncated protein.
Mutations were confirmed by direct sequencing of genomic DNA from the
patients, and from the affected parents in cases of familial NF1. Side
et al. (1997) found that the normal NF1 allele was absent in bone marrow
samples from 5 of 8 children who had truncating mutations of the NF1
gene.

- Neurofibromatosis-Noonan Syndrome

The overlap syndrome neurofibromatosis-Noonan syndrome (601321) shows
features of both disorders, as was first noted by Allanson et al.
(1985). Colley et al. (1996) examined 94 sequentially identified
patients with NF1 from their genetic register and found Noonan features
in 12. Carey et al. (1997) identified a 3-bp deletion of exon 17 of the
NF1 gene in a family with NFNS (613113.0033). Stevenson et al. (2006)
provided a follow-up of this family. Baralle et al. (2003) identified
mutations in the NF1 gene in 2 patients with the overlap syndrome
(613113.0034 and 613113.0035).

Bertola et al. (2005) provided molecular evidence of the concurrence of
neurofibromatosis and Noonan syndrome in a patient with a de novo
missense mutation in the NF1 gene (613113.0043) and a mutation in the
PTPN11 gene (176876.0023) inherited from her father. The proposita was
noted to have cafe-au-lait spots at birth. Valvar and infundibular
pulmonary stenosis and aortic coarctation were diagnosed at 20 months of
age and surgically corrected at 3 years of age. As illustrated, the
patient had marked hypertelorism and proptosis as well as freckling and
cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a
pilocytic astrocytoma in the suprasellar region involving the optic
chiasm (first presenting symptomatically at 2 years of age), was
partially resected. The father, who was diagnosed with Noonan syndrome,
had downslanting palpebral fissures and prominent nasal labial folds. He
was of short stature (159 cm) and had pectus excavatum.
Electrocardiogram showed left-anterior hemiblock and complete right
bundle branch block.

In a study of 17 unrelated subjects with NFNS, De Luca et al. (2005)
found NF1 gene defects in 16. Remarkably, there was a high prevalence of
in-frame defects affecting exons 24 and 25, which encode a portion of
the GAP-related domain. No defect was observed in PTPN11 (176876), which
is the usual site of mutations causing classic Noonan syndrome. De Luca
et al. (2005) stated that including their study, 18 distinct NF1 gene
mutations had been described in 22 unrelated patients with NFNS.

- Watson Syndrome

Watson syndrome (193520) is an autosomal dominant disorder characterized
by pulmonic stenosis, cafe-au-lait spots, decreased intellectual
ability, and short stature. Most affected individuals have relative
macrocephaly and Lisch nodules and about one-third of those affected
have neurofibromas. Because of clinical similarities between Watson
syndrome and neurofibromatosis, Allanson et al. (1991) performed linkage
studies in families with Watson syndrome, using probes known to flank
the NF1 gene on chromosome 17, and found tight linkage. In a patient
with Watson syndrome, Upadhyaya et al. (1992) identified an 80-kb
deletion in the NF1 gene (613113.0011). Tassabehji et al. (1993)
demonstrated an almost perfect in-frame tandem duplication of 42 bases
in exon 28 of the NF1 gene in 3 members of a family with Watson syndrome
(613113.0010).

- Spinal Neurofibromatosis

In all 5 affected members of 3-generation family with spinal
neurofibromatosis (162210) and cafe-au-lait spots, Ars et al. (1998)
identified a frameshift mutation in the NF1 gene (613113.0018).

In affected members of 2 families with spinal neurofibromas but no
cafe-au-lait macules, Kaufmann et al. (2001) identified 2 different
mutations in the NF1 gene (613113.0028 and 613113.0029, respectively).
Both NF1 mutations caused a reduction in neurofibromin of approximately
50%, with no truncated protein present in the cells. The findings
demonstrated that typical NF1 null mutations can result in a phenotype
that is distinct from classic NF1, showing only a small spectrum of the
NF1 symptoms, such as multiple spinal tumors, but not completely fitting
the current clinical criteria for spinal NF.

- Role in Cancer

Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype
that shares morphologic characteristics with nerve sheath tumors. For
that reason, Gutzmer et al. (2000) analyzed 15 DNMs and 20 melanomas
without morphologic features of desmoplasia or neuroid differentiation
(i.e., common melanomas) for LOH at the NF1 locus and flanking regions.
Allelic loss was detected in 10 of 15 (67%) DNMs but in only 1 of 20
(5%) common melanomas. LOH was most frequently observed at marker IVS38,
located in intron 38 of NF1. These data suggested a role for NF1 in the
pathogenesis of DNM and supported the hypothesis that exon 37 may encode
a functional domain.

The Cancer Genome Atlas Research Network (2008) reported the interim
integrative analysis of DNA copy number, gene expression, and DNA
methylation aberrations in 206 glioblastomas and nucleotide sequence
alterations in 91 of the 206 glioblastomas. The RTK/RAS/PI3K signaling
pathway was altered in 88% of glioblastomas. NF1 was found to be an
important gene in glioblastoma, with mutation or homozygous deletion of
the NF1 gene present in 18% of tumors.

ANIMAL MODEL

See 162200 for a discussion of animal models of neurofibromatosis type
I.

Ruiz-Lozano and Chien (2003) commented on how it is possible to apply
Cre-loxP technology to track the cardiac morphogenic signals mediated by
neurofibromin. A growing list of mouse lines that express Cre in
specific cardiovascular cell lineages was available.

Gene transcription may be regulated by remote enhancer or insulator
regions through chromosome looping. Using a modification of chromosome
conformation capture and fluorescence in situ hybridization, Ling et al.
(2006) found that 1 allele of the Igf2 (147470)/H19 (103280) imprinting
control region (ICR) on mouse chromosome 7 colocalized with 1 allele of
Wsb1 (610091)/Nf1 on chromosome 17. Omission of CCCTC-binding factor
(CTCF; 604167) or deletion of the maternal ICR abrogated this
association and altered Wsb1/Nf1 gene expression. Ling et al. (2006)
concluded that CTCF mediates an interchromosomal association, perhaps by
directing distant DNA segments to a common transcription factory, and
the data provided a model for long-range allele-specific associations
between gene regions on different chromosomes that suggested a framework
for DNA recombination and RNA trans-splicing.

To investigate the function of NF1 in skeletal development, Kolanczyk et
al. (2007) created mice with Nf1 knockout directed to undifferentiated
mesenchymal cells of developing limbs. Inactivation of Nf1 in limbs
resulted in bowing of the tibia, diminished growth, abnormal
vascularization of skeletal tissues, and fusion of the hip joints and
other joint abnormalities. Tibial bowing was caused by decreased
stability of the cortical bone due to a high degree of porosity,
decreased stiffness, and reduction in the mineral content, as well as
hyperosteoidosis. Accordingly, cultured osteoblasts showed increased
proliferation and decreased ability to differentiate and mineralize. The
reduced growth in Nf1-knockout mice was due to reduced proliferation and
differentiation of chondrocytes.

HISTORY

Gervasini et al. (2002) reported a direct tandem duplication of the NF1
gene identified in 17q11.2 by high-resolution FISH. FISH on stretched
chromosomes with locus-specific probes revealed the duplication of the
NF1 gene from the promoter to the 3-prime untranslated region (UTR), but
with at least the absence of exon 22. Duplication was probably present
in the human-chimpanzee-gorilla common ancestor, as demonstrated by the
finding of the duplicated NF1 gene at orthologous chromosome loci. The
authors suggested that the NF1 intrachromosomal duplication may
contribute to the high whole-gene mutation rate by gene conversion. In
contrast to the findings of Gervasini et al. (2002), however,
Kehrer-Sawatzki et al. (2002) studied a female NF1 patient with
reciprocal translocation t(17;22)(q11.2; q11.2) and determined that
there is a single NF1 gene in the 17q11.2 region. Kehrer-Sawatzki and
Messiaen (2003) analyzed another reciprocal translocation, a
t(14;17)(q32;q11.2), described in a large family with NF1, which
disrupted the NF1 gene (Messiaen et al., 2000) and again reported
findings inconsistent with a duplication of the NF1 gene at 17q11.2 as
proposed by Gervasini et al. (2002).

*FIELD* AV
.0001
NEUROFIBROMATOSIS, TYPE I
NF1, ALU INS

In a patient with neurofibromatosis type I (NF1; 162200), Wallace et al.
(1991) demonstrated a de novo heterozygous Alu repetitive element
insertion into an intron of the NF1 gene, which resulted in deletion of
the downstream exon during splicing and consequently shifted the reading
frame. The patient was an isolated case in his family. The insertion,
300-500 bp, began 44 bp upstream of exon 6. This previously undescribed
mechanism of mutation indicated that Alu retrotransposition is an
ongoing process in the human germline. Alu elements had been involved in
the generation of disease mutation by recombination (e.g., in familial
hypercholesterolemia (143890) and ADA deficiency) or point mutation
(e.g., in gyrate atrophy of the choroid and retina 258870; 613349.0023),
but not as a new element.

.0002
NEUROFIBROMATOSIS, TYPE I
NF1, 5-BP DEL

In 2 patients with neurofibromatosis type I (162200), a 35-year-old man
and his daughter, Stark et al. (1991) demonstrated a 5-bp deletion
(CCACC or CACCT) and an adjacent transversion, located about 500 bp
downstream from the region that codes for a functional domain of the NF1
gene product. The mutation was demonstrable by heteroduplex analysis.
The deletion removed the proximal half of a small potential stem-loop
and interrupted the reading frame in exon 1. A severely truncated
protein with a grossly altered carboxy terminus lacking one-third of its
sequence was the predicted consequence. Stark et al. (1992) found that
both alleles were expressed in primary cultures of neurofibroma cells
and melanocytes from a cafe-au-lait macule of the proband, thus
excluding loss of heterozygosity. The authors used the 5-bp deletion for
the presymptomatic diagnosis of the 18-month-old third son of the
proband.

.0003
NEUROFIBROMATOSIS, TYPE I
NF1, LEU348PRO

Cawthon et al. (1990) identified point mutations in a 4-kb sequence of
the transcript of the NF1 gene at a translocation breakpoint associated
with neurofibromatosis type I (162200). One mutant allele contained a
T-to-C transition that caused a leu348-to-pro (L348P) substitution, and
the second harbored a C-to-T insertion that changed an arg365 to a stop
codon (R365X; 613113.0004).

.0004
NEUROFIBROMATOSIS, TYPE I
NF1, ARG365TER

Independently, Cawthon et al. (1990) and Estivill et al. (1991)
identified a new mutation in exon 4 of the NF1 gene; a 1087C-T
transition (numbering of Cawthon et al., 1990), resulting in an
arg365-to-ter (R365X) substitution, in patients with neurofibromatosis I
(162200). Although a different numbering system was used, this is the
same mutation as that found by Valero et al. (1994) and designated
5242C-T in exon 29. They proposed that this site, in a CpG residue, is a
hotspot for mutation in the NF1 gene.

.0005
NEUROFIBROMATOSIS, TYPE I
NF1, LYS1423GLU

In a patient with neurofibromatosis type I (162200) and affected members
of his family, Li et al. (1992) found an AAG-to-GAG transition at codon
1423, resulting in the substitution of glutamic acid for lysine
(K1423E).

The same mutation or a mutation in the same codon leading to
substitution of glutamine for lysine through an A-to-C transversion was
also observed by Li et al. (1992) as a somatic mutation in
adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic
astrocytoma.

.0006
NEUROFIBROMATOSIS, TYPE I
NF1, 1-BP INS, 5662C

In 2 unrelated patients with type I neurofibromatosis (162200),
Upadhyaya et al. (1992) found insertion of a cytosine within codon 1818
that changed the reading frame and resulted in 23 altered amino acids
prior to the inappropriate introduction of a stop codon at amino acid
1841. The insertion created a recognition site for enzyme MnlI. (The
authors incorrectly stated in their abstract and the legend of their
Figure 3 that there was a nucleotide insertion at 'codon 5662.' The
nucleotide insertion at residue 5662 occurs within codon 1818 in their
cDNA clone of NF1, as correctly represented in the sequence shown in
their Figure 3.)

.0007
NEUROFIBROMATOSIS, TYPE I
NF1, 1-BP INS, FS1841TER

In a patient with neurofibromatosis type I (162200), Upadhyaya et al.
(1992) found an insertion of thymidine in codon 1823, resulting in a
shift of the reading frame, the generation of 18 amino acids different
from those of the normal protein, and a gene product that terminated
prematurely at amino acid 1840 by the creation of a stop codon at 1841.

.0008
NEUROFIBROMATOSIS, TYPE I
NF1, LEU2143MET

In a patient with neurofibromatosis type I (162200), Upadhyaya et al.
(1992) found a heterozygous 6639C-A transversion in the NF1 gene,
resulting in a leu2143-to-met (L2143M) substitution.

.0009
NEUROFIBROMATOSIS, TYPE I
NF1, TYR2213ASN

In a patient with neurofibromatosis type I (162200), Upadhyaya et al.
(1992) found a heterozygous 6724T-G transversion in the NF1 gene,
resulting in a tyr2213-to-asn (Y2213N) substitution.

.0010
WATSON SYNDROME
NF1, 42-BP DUP

In a family in which Watson syndrome (193520) had occurred in 3
generations, Tassabehji et al. (1993) demonstrated an almost perfect
in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene.
Unlike the mutations previously described in classic NF1 which result
predominantly in null alleles, the mutation in this family would be
expected to result in a mutant neurofibromin product. The affected
mother had multiple cafe-au-lait patches, freckling in the axillary and
groin, low-set posteriorly rotated ears, a squint, and an IQ of 56. She
had no Lisch nodules or neurofibromata. A daughter, aged 3.5 years, had
multiple cafe-au-lait spots, mild pectus carinatum, hypertelorism with
epicanthic folds, a squint, low-set posteriorly rotated ears, and
moderate global developmental delay. Her twin brother had ptosis, mild
cubitus valgus, bilateral undescended testes, and mild pulmonic valvular
stenosis by echocardiography. Neither child had Lisch nodules or
neurofibromata.

.0011
WATSON SYNDROME
NF1, 80-KB DEL

Upadhyaya et al. (1992) found an 80-kb deletion at the NF1 locus in a
patient with Watson syndrome (193520).

.0012
NEUROFIBROMATOSIS, TYPE I
NF1, ARG1947TER

A C-to-T transition changing arginine-1947 to a stop codon (R1947X) in
the NF1 gene has been described in multiple Caucasian and Japanese
families with neurofibromatosis I (162200), suggesting that this codon,
CGA, is a hotspot for mutation, presumably because it contains a CpG
dinucleotide. (Numbering of codons is based on Marchuk et al. (1991).)
The mutation was described in 3 unrelated Caucasians (Ainsworth et al.,
1993; Cawthon et al., 1990; Estivill et al., 1991); at least 2 of these
cases were sporadic. Horiuchi et al. (1994) reported the same mutation
in 2 unrelated familial cases of NF1. That these represented independent
mutations was indicated by the fact that in the 2 families the affected
individuals differed with regard to a polymorphism located within the
NF1 gene. The frequency of the arg1947-to-ter mutation may be as high as
8% in Japanese and at least 1% in Caucasians. Studying one of the
patients with the arg1947-to-ter mutation, Horiuchi et al. (1994) showed
that both the normal and the mutant allele were transcribed in a
lymphoblastoid cell line.

Heim et al. (1994) referred to the arg1947-to-ter mutation as having
been identified in 6 unrelated patients with NF1.

Lazaro et al. (1995) presented 2 further cases of the arg1947-to-ter
mutation in the NF1 gene. They stated that a total of 9 cases of the
R1947X mutation had been reported, giving a frequency of about 2%. The
mutation occurs within a CpG dinucleotide. They developed an
allele-specific oligonucleotide hybridization assay for the efficient
screening of a large number of samples for this relatively common
recurrent mutation.

In a sample of 56 unrelated Korean patients with NF1, Park et al. (2000)
identified 1 with the R1947X mutation.

.0013
NEUROFIBROMATOSIS, TYPE I
NF1, IVS18DS, G-A, +1

Purandare et al. (1995) identified a G-to-A transition at position +1 of
intron 18 of the NF1 gene in a 41-year-old Caucasian female in whom the
diagnosis of neurofibromatosis (162200) was first made at the age of 28
years when she was admitted to hospital for a grand mal seizure. A son
was also affected. The mutation resulted in skipping of exon 18 which
did not cause a shift in the reading frame but resulted in an in-frame
loss of 123 nucleotides from the mRNA and the corresponding 41 amino
acids from the protein. Purandare et al. (1995) referred to 3 previously
reported splice donor site mutations in the NF1 gene.

.0014
NEUROFIBROMATOSIS, TYPE I
NF1, 2-BP DEL, 1541AG

The arg1947-to-ter mutation (613113.0012) is one of the few recurrent
mutations found in the NF1 gene but is not a frequent recurrence, having
been found in only 6 of 363 patients with NF1 (162200). Robinson et al.
(1996) described a recurrent 2-bp deletion in exon 10c of the NF1 gene
in 2 unrelated patients: one sporadic and another familial case. The
mutation was designated 1541delAG by the authors.

.0015
NEUROFIBROMATOSIS, TYPE I
NF1, MET1035ARG

Wu et al. (1996) suggested that some patients diagnosed with LEOPARD
syndrome (151100) may have a mutation in the NF1 gene, whereas others
may have a mutation in a different gene. They found a de novo M1035R
missense mutation resulting from a T-to-G transversion in exon 18 of the
NF1 gene in a 32-year-old woman with a prior diagnosis of LEOPARD
syndrome, who was found to have NF1 (162200). At birth, a heart murmur
was detected resulting from subvalvular muscular aortic stenosis and
valvular aortic stenosis. The skin showed multiple dark lentigines
together with a few larger cafe-au-lait patches. The same lentigines
were present in the armpits and groin and were not raised. The patient
attended a special school for mildly mentally retarded children. At the
age of 21 years, mitral insufficiency was demonstrated resulting from a
double orifice mitral valve. The patient had macrocrania (head
circumference 58 cm), apparent hypertelorism, and a coarse face with
broad neck. Neurofibromas were not present at the age of 32, and no
Lisch nodules were seen by slit-lamp examination. The mutation was
absent in the parents, who were clinically normal.

.0016
NEUROFIBROMATOSIS, TYPE I
NF1, ARG1391SER

Upadhyaya et al. (1997) identified 14 novel mutations in the GAP-related
domain of neurofibromin in patients with neurofibromatosis I (162200).
One of these mutations was a change at nucleotide 4173 from A to T,
changing codon 1391 from AGA (arg) to AGT (ser) (R1391S). The effect of
this R1391S missense mutation was studied by in vitro expression of a
site-directed mutant and by GAP activity assay. The mutant protein was
found to be some 300-fold less active than wildtype NF1 protein.

.0017
REMOVED FROM DATABASE
.0018
NEUROFIBROMATOSIS, FAMILIAL SPINAL
NF1, 1-BP INS, 8042A

In 5 affected members of a family with spinal neurofibromatosis with
cafe-au-lait macules (162210), Ars et al. (1998) identified a 1-bp
insertion (8042insA) in exon 46 of the NF1 gene. The mutation was
predicted to result in a truncated protein.

.0019
LEUKEMIA, JUVENILE MYELOMONOCYTIC
NF1, TRP1538TER

Among 20 children with juvenile myelomonocytic leukemia (JMML; 607785),
Side et al. (1998) found 3 with truncating mutations in the NF1 gene.
One of the children, a 3-year-old boy, had a G-to-A transition at
nucleotide 4614, which converted codon 1538 from tryptophan to stop in
exon 27a (W1538X).

.0020
LEUKEMIA, JUVENILE MYELOMONOCYTIC
NF1, IVS34, G-A, +18

In a 19-month-old boy with juvenile myelomonocytic leukemia (JMML/Mo7;
607785), Side et al. (1998) found in cloned cDNA aberrant splicing
resulting in a shift in the reading frame. Genomic DNA showed an
alteration (6579,G-A,+18) in the splice donor consensus sequence
flanking exon 34. This mutation introduced an additional 17 nucleotides
containing a novel BglI restriction enzyme site into the patient's cDNA.
Side et al. (1998) identified this restriction site in amplified cDNA
derived from the patient's EBV cell line RNA, thus confirming that this
mutation existed in the germline. Furthermore, loss of heterozygosity
was demonstrated, indicating inactivation of another NF1 allele.

.0021
LEUKEMIA, JUVENILE MYELOMONOCYTIC
NF1, IVS11, A-G, -8

In a 6-month-old boy with JMML (607785), Side et al. (1998) described a
splice mutation. Cloned cDNA showed abnormal splicing of 7 nucleotides
between exons 10c and 11. They had previously found the same mutation in
a child with familial NF1 and myelodysplasia syndrome (Side et al.
(1997)); genomic DNA sequence showed an abnormal splice acceptor
sequence upstream of exon 11 (1642,A-G,-8) creating a cryptic splice
site and consequent frameshift and premature stop codon at codon 555.

.0022
NEUROFIBROMATOSIS, TYPE I
NF1, ARG1276PRO

In a family with a classic multisymptomatic NF1 phenotype (162200),
including a malignant schwannoma, Klose et al. (1998) found an
arg1276-to-pro (R1276P) mutation in the arginine finger of the
GAP-related domain (GRD) of the neurofibromin gene, resulting in
disruption of the most essential catalytic element for Ras-GAP activity.
Klose et al. (1998) presented data demonstrating that the R1276P
mutation, unlike previously reported missense mutations of the GRD
region, did not impair the secondary and tertiary protein structure. It
neither reduced the level of cellular neurofibromin nor influenced its
binding to Ras substantially, but it did completely disable GAP
activity. The findings provided direct evidence that failure of
neurofibromin GAP activity is a critical element in NF1 pathogenesis.
The findings suggested that therapeutic approaches aimed at the
reduction of the Ras-GTP levels in neural crest-derived cells can be
expected to relieve most of the NF1 symptoms. The proband was the first
child of unaffected, nonconsanguineous parents. She developed multiple
cafe-au-lait spots within the first year of life. Her language and motor
development were mildly retarded, and she complained of incoordination
throughout life. Around puberty, multiple cutaneous neurofibromas
developed which worsened at the time of each of her 3 pregnancies. At
the age of 31 years, routine MRI of the brain revealed multiple areas of
increased T2 signal intensity in the midbrain and a small optic glioma.
Because of recurrent paresthesias in her left leg, an MRI scan of the
spine was done 2 years later which revealed multiple schwannomas within
the vertebral foramina. The largest tumor in the lumbar region, with a
volume of approximately 8 ml, was surgically removed. Histologically,
there was no evidence of malignancy at that time. Eight months later,
the patient suffered a relapse with rapid tumor growth. At the time of
reoperation, the retroperitoneal tumor had reached a volume of 800 ml
and showed numerous necrotic and anaplastic areas with a proliferation
rate up to 60%. The patient died of widespread metastatic disease at the
age of 34 years. Her 3 male children, ages 4, 8, and 12 years, all
fulfilled the NF1 diagnostic criteria. The 2 elder sons were
macrocephalic. Language and motor development of all children was
retarded to a similar extent and on the same time scale as in their
mother. A cranial MRI scan in the 2 elder brothers showed increased T2
signal intensities similar to those in their mother.

.0023
NEUROFIBROMATOSIS, TYPE I
NF1, TYR489CYS

Among the 9 NF1 exon 10b mutations identified by Messiaen et al. (1999)
in 232 unrelated patients with neurofibromatosis I (162200), 2 were
recurrent: an A-to-G transition at nucleotide 1466, resulting in a
tyr489-to-cys substitution (Y489C), and a T-to-C transition at
nucleotide 1523, resulting in a leu508-to-pro substitution (L508P;
613113.0024). The Y489C mutation caused skipping of the last 62
nucleotides of exon 10b, while the L508P mutation was undetectable by
the protein truncation test.

.0024
NEUROFIBROMATOSIS, TYPE I
NF1, LEU508PRO

See 613113.0023 and Messiaen et al. (1999).

.0025
NEUROFIBROMATOSIS, TYPE I
NF1, IVS9DS, G-A, +1

In a patient with type I neurofibromatosis (162200), Eisenbarth et al.
(2000) identified a germline G-to-A transition at nucleotide 1260+1, the
splice donor site of intron 9 of the NF1 gene, leading to the inclusion
of 13 bp of intervening sequence into the NF1 messenger. The mutant
allele was present in all tissues tested. In a neurofibroma from this
patient, an additional C-to-T transition at nucleotide 4021
(613113.0026), a presumed 'second hit' somatic mutation, was identified.
Another neurofibroma from the same patient showed a C-to-T transition at
nucleotide 4084 (613113.0027), a presumed further 'second hit' somatic
mutation. Both somatic mutations led to premature stop codons in the NF1
message.

.0026
NEUROFIBROMATOSIS, TYPE I
NF1, GLN1341TER

See 613113.0025 and Eisenbarth et al. (2000).

.0027
NEUROFIBROMATOSIS, TYPE I
NF1, ARG1362TER

See 613113.0025 and Eisenbarth et al. (2000).

.0028
NEUROFIBROMATOSIS, FAMILIAL SPINAL
NF1, LEU2067PRO

In a patient with spinal neurofibromatosis but without cafe-au-lait
macules (162210), Kaufmann et al. (2001) identified a leu2067-to-pro
(L2067P) mutation in exon 33 of the NF1 gene. Her clinically unaffected
61-year-old father had the same NF1 mutation in his blood cells.
Additional molecular investigations to exclude mosaicism were not
feasible and additional clinical investigations through MRI scans could
not be performed. The L2067P mutation yielded an unstable product of
approximately 50% normal neurofibromin levels, indicating functional
haploinsufficiency.

.0029
NEUROFIBROMATOSIS, TYPE I
NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED
NF1, IVS31, A-G, -5

In a patient with neurofibromatosis type I (162200), Fahsold et al.
(2000) identified an A-to-G transition in the NF1 gene splice acceptor
site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to
exon 32 and a premature stop codon at amino acid 1995.

In affected members of a family with spinal neurofibromatosis without
cafe-au-lait macules (162210), Kaufmann et al. (2001) identified the
exon 31 splice site mutation. Noting that the same mutation had been
reported in a patient with classic NF1, the authors concluded that a
modifying gene may compensate for some of the effects of neurofibromin
deficiency. The splice site NF1 mutation resulted in instability of the
neurofibromin protein.

.0030
NEUROFIBROMATOSIS, TYPE I
NF1, DEL

Upadhyaya et al. (2003) described a Portuguese family in which 3 members
had clinical features of NF1 (162200) and each had a different
underlying defect in the NF1 gene. A 12-year-old boy who had multiple
cafe-au-lait spots on his trunk and legs as well as developmental delay
had a heterozygous 1.5-Mb deletion including the entire NF1 gene. The
mutation was associated with the maternally derived chromosomal
haplotype. His 10-year-old brother, who exhibited multiple cafe-au-lait
spots and macrocephaly but whose development was within the normal
range, was heterozygous for a CGA-to-TGA transition in exon 22 of the
NF1 gene, resulting in an arg1241-to-ter mutation (613113.0031). This
mutation had previously been described; its recurrence was thought to
have been mediated by 5-methylcytosine deamination because it occurred
in a hypermutable CpG dinucleotide. The brothers' 26-year-old female
first cousin once removed (a first cousin of their father) exhibited
multiple cafe-au-lait spots, bilateral Lisch nodules, and multiple
dermal neurofibromas. She also showed severe scoliosis and several
plexiform neurofibromas in the clavicular region, but her development
was within the normal range. She was found to carry a frameshift
mutation, 5406insT (613113.0032), in exon 29 of the NF1 gene. None of
the parents had any clinical evidence of NF1 and none had a mutation in
the NF1 gene. There was also no evidence of mosaicism. Upadhyaya et al.
(2003) speculated about the mechanism of this unusual situation.

.0031
NEUROFIBROMATOSIS, TYPE I
NF1, ARG1241TER

Fahsold et al. (2000) described a CGA-to-TGA transition in the NF1 gene,
resulting in an arg1241-to-ter mutation, as the cause of
neurofibromatosis type I (162200). Also see 613113.0030 and Upadhyaya et
al. (2003).

.0032
NEUROFIBROMATOSIS, TYPE I
NF1, 1-BP INS, 5406T

See 613113.0030 and Upadhyaya et al. (2003).

.0033
NEUROFIBROMATOSIS-NOONAN SYNDROME
WATSON SYNDROME, INCLUDED
NF1, 3-BP DEL, 2970AAT

Carey et al. (1997) described a 3-bp deletion in exon 17 of the NF1 gene
in affected members of a family with neurofibromatosis-Noonan syndrome
(601321). The 2970delAAT mutation resulted in deletion of met991. The
clinical features of the 3 subjects were tabulated by De Luca et al.
(2005). Stevenson et al. (2006) reported a follow-up of this family.

Upadhyaya et al. (2007) reported this mutation in 47 affected
individuals from 21 unrelated families with a similar phenotype, lacking
cutaneous neurofibromas or clinically obvious plexiform neurofibromas.
One of the families had been reported by Stevenson et al. (2006);
another was reported by Castle et al. (2003) and had a diagnosis of
Watson syndrome (193520). The in-frame 3-bp deletion in exon 17 was
predicted to result in the loss of 1 of 2 adjacent methionines, either
codon 991 or codon 992, in conjunction with a silent ACA-to-ACG change
of codon 990. These 2 methionine residues are located in a highly
conserved region of neurofibromin and are expected, therefore, to have a
functional role in the protein. This was said to have been the first
study to correlate a specific small mutation of the NF1 gene with the
expression of a particular clinical phenotype.

.0034
NEUROFIBROMATOSIS-NOONAN SYNDROME
NF1, 3-BP DEL, 4312GAA

In a patient with neurofibromatosis-Noonan syndrome (601321), Baralle et
al. (2003) identified a 3-bp deletion, 4312delGAA, in exon 25 of the NF1
gene. The patient was a 6-year-old boy with more than 6 cafe-au-lait
macules. There were no other features of neurofibromatosis type I, but
his mother had a single cafe-au-lait macule and Lisch nodules, low
hairline, and short neck. He had ptosis, epicanthal folds, low posterior
hairline, and low-set ears. On echocardiogram he had pulmonic stenosis.
No neurofibromas were present.

.0035
NEUROFIBROMATOSIS-NOONAN SYNDROME
NF1, 2-BP INS, 4095TG

In a patient with neurofibromatosis-Noonan syndrome (601321), Baralle et
al. (2003) identified a 2-bp insertion, 4095insTG, in exon 23-2 of the
NF1 gene. The patient was a 20-year-old man with 7 cafe-au-lait macules,
axillary freckling, 10 neurofibromas, Lisch nodules, and scoliosis with
a structural cervical vertebral abnormality. He had downslanting
palpebral fissures, ptosis, a short, broad neck, widely spaced nipples,
and an atrial septal defect. He was of short stature and needed extra
help in mainstream school. There was no family history of similar
findings.

.0036
NEUROFIBROMATOSIS TYPE 1
NF1, 20075G-A, 20076C-A

In a patient with severe neurofibromatosis type I (162200), Colapietro
et al. (2003) found a G-to-A transition and a C-to-A transversion at
nucleotide positions 57 and 58, respectively, of the 154-bp long NF1
exon 7, neither of which was present in the proband's parents or 50
healthy controls. RT-PCR analysis showed the expected fragment from exon
4b to 8 together with a shortened one with in-frame skipping of exon 7.
Direct sequencing of genomic DNA revealed 2 exonic heterozygous changes
at nucleotides 20075 (G-A transition) and 20076 (C-A transversion),
which belong to contiguous codons. The first substitution occurred in
the third base of the codon, changing it from CAG to CAA, both encoding
glutamine (Q315Q); the second changed the CTG codon for leucine to the
ATG codon for methionine (L316M). The use of previously established
sequence matrices for the scoring of putative ESE motifs showed that the
adjacent silent and missense mutations were located within highly
conserved overlapping stretches of 7 nucleotides with a close similarity
to the ESE-specific consensus sequences recognized by the SC35 (600813)
and SF2/ASF (600812) arginine/serine-rich (SR) proteins. The combined
occurrence of both consecutive alterations decreased the motif score for
both SR proteins below their threshold levels. As the aberrant
transcript was consistently expressed, a protein lacking 58 amino acids
was predicted. Thus, the contiguous internal exon 7 mutations appear to
have caused exon 7 skipping as a result of the missplicing caused by
abrogation of functional ESEs (see Cartegni et al. (2002) and
Fairbrother et al. (2002)). The male proband in the study of Colapietro
et al. (2003) was the third child of healthy unrelated parents. At the
age of 1 year, he underwent uronephrectomy because of right renal
dysplasia. At the age of 3 years, an optic glioma was identified and
surgically excised. The diagnosis of NF1 was made when he was 9 years
old on the basis of the presence of cafe-au-lait spots, optic glioma,
and Lisch nodules of the iris. Cerebral MRI at the age of 11 years
revealed multiple hamartomas and a right hemisphere cerebral venous
angioma. The patient showed borderline mental retardation, a height in
the 10th percentile, and an occipitofrontal head circumference in the
97th percentile. At the age of 20 years, he showed macrocephaly,
numerous cafe-au-lait spots, small cutaneous neurofibromas, a plexiform
neck neurofibroma, and axillary and inguinal freckling. Scoliosis,
winged scapulae, and bilateral genu valgum were also present.

.0037
NEUROFIBROMATOSIS, TYPE I
NF1, 1-BP DEL, 3775T

In a patient with neurofibromatosis type I (162200), Maris et al. (2002)
identified a 1-bp deletion in the NF1 gene, 3775delT. The mutation was
not present in the patient's parents.

Mosse et al. (2004) showed that the patient originally described by
Maris et al. (2002) was also affected with neuroblastoma (256700) and
Hirschsprung disease (142623), which were caused by a 1-bp deletion in
the PHOX2B gene (676delG; 603851.0007).

.0038
NEUROFIBROMATOSIS, TYPE I
NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED
NF1, LEU357PRO

In a patient with neurofibromatosis type I (162200), Fahsold et al.
(2000) identified a 1070T-C transition in exon 8 of the NF1 gene,
resulting in a leu357-to-pro (L357P) substitution.

In 7 affected members of a family with spinal neurofibromatosis (162210)
originally reported by Poyhonen et al. (1997), Messiaen et al. (2003)
identified the L357P mutation. The mutation was not detected in 200
normal chromosomes.

.0039
NEUROFIBROMATOSIS, FAMILIAL SPINAL
NF1, IVS39DS, A-C, +3

In affected members of a family with spinal neurofibromatosis (162210)
originally reported by Pulst et al. (1991), Messiaen et al. (2003)
identified an A-to-C transversion at position +3 of the donor splice
site of exon 39 of the NF1 gene (7126+3A-C), resulting in the skipping
of exon 39.

.0040
NEUROFIBROMATOSIS, TYPE I
NF1, 1-BP DEL, 4071C

In a patient with neurofibromatosis type I (162200) who had onset of
neurofibromatous neuropathy at the age of 42 years, Ferner et al. (2004)
identified a 1-bp deletion (4071delC) in exon 23.2 of the NF1 gene,
resulting in a premature stop codon. The deletion was predicted to
generate a truncated neurofibromin of 1,383 amino acids. Neuroimaging
studies showed the presence of multiple spinal nerve root neurofibromas.
A high-grade malignant peripheral nerve sheath tumor (MPNST) had been
removed from the left iliac fossa previously, with no recurrence. Benign
flexiform neurofibroma was present in the left abdominal wall.

.0041
NEUROFIBROMATOSIS, TYPE I
NF1, LEU1243PRO

In a patient with neurofibromatosis type I (162200) who had onset of
neurofibromatous neuropathy at the age of 17 years, Ferner et al. (2004)
identified a 1243T-C transition in the NF1 gene, resulting in a
leu1243-to-pro (L1243P) substitution.

.0042
NEUROFIBROMATOSIS, TYPE I
NF1, GLU1904TER

By cDNA-based mutation detection analysis, Zatkova et al. (2004) studied
7 nonsense or missense alleles of NF1 that caused exon skipping and
showed that disruption of exonic splicing enhancer (ESE) elements was
responsible. One of the 7 mutations was a novel nonsense mutation, a
5719G-T transversion, resulting in a glu1904-to-ter (G1904X)
substitution in exon 30. The phenotype was NF1 (162200).

.0043
NEUROFIBROMATOSIS, TYPE I
NF1, LEU844ARG

Bertola et al. (2005) described a 14-year-old girl with
neurofibromatosis type I (162200) and Noonan syndrome (163950) who had a
de novo mutation in the NF1 gene and a mutation in the PTPN11 gene
(176876.0023) inherited from her father. The NF1 mutation was a 2531A-G
transition resulting in a leu844-to-arg substitution. The proband had
pulmonary stenosis and aortic coarctation requiring surgery and also had
a pilocytic astrocytoma in the suprasellar region involving the optic
chiasm and forming the third ventricle. She had cafe-au-lait spots and
axillary freckling typical of neurofibromatosis and marked hypertelorism
characteristic of Noonan syndrome.

.0044
NEUROFIBROMATOSIS, TYPE I
NF1, IVS27DS, G-C, +1

In a mother and son with a mild form of NF1 (162200), Thiel et al.
(2009) identified a heterozygous mutation (4661+1G-C) in intron 27 of
the NF1 gene, resulting in the skipping of exon 27a and potentially
affecting the GAP-related domain. Both patients had cafe-au-lait spots
and mild myopia, but no neurofibromas, Lisch nodules, or optic gliomas.
The daughter of the mother, who also carried the NF1 mutation, was found
to be compound heterozygous with a mutation in the PTPN11 gene (T2I;
176876.0027). In addition to features of neurofibromatosis I, she also
had features of Noonan syndrome (163950), including hypertelorism,
low-set ears, poor growth, sternal deformity, valvular pulmonic
stenosis, and delayed development. The PTPN11 mutation was predicted to
destabilize the inactive form of PTPN11, resulting in increased basal
activity and a gain of function. The girl also developed bilateral optic
gliomas before age 2 years, which may be explained by an additive effect
of both the NF1 and PTPN11 mutations on the Ras pathway. Compound
heterozygosity for mutations in NF1 and PTPN11 were also reported by
Bertola et al. (2005) in a patient with a combination of
neurofibromatosis I and Noonan syndrome.

.0045
NEUROFIBROMATOSIS-NOONAN SYNDROME
NF1, LEU1390PHE

In affected members of a 5-generation family with
neurofibromatosis-Noonan syndrome (601321), Nystrom et al. (2009)
identified a heterozygous 4168C-T transition in exon 24 of the NF1 gene,
resulting in a leu1390-to-phe (L1390F) substitution in the highly
conserved GAP-related domain. The family was originally reported by
Edman Ahlbom et al. (1995) as having Noonan syndrome based on dysmorphic
facial features, short stature, pulmonary stenosis, and short neck. Upon
reevaluation, Nystrom et al. (2009) found that several family members
had cafe-au-lait spots, axillary freckling, Lisch nodules, and multiple
nevi, consistent with NF1, but that all family members lacked dermal and
superficial plexiform neurofibromas. The authors concluded that the
clinical diagnosis was consistent with NFNS. Nystrom et al. (2009)
postulated that the L1390F mutation resulted in impaired GTPase
activity.

.0046
NEUROFIBROMATOSIS, TYPE I
NF1, ARG192TER

In a girl with aniridia (106210), microphthalmia, microcephaly, and
cafe-au-lait macules, Henderson et al. (2007) identified heterozygosity
for a 574C-T transition in exon 4b of the NF1 gene, resulting in an
arg192-to-ter (R192X) substitution, as well as heterozygous mutations in
the PAX6 (R38W; 607108.0026) and OTX2 (Y179X; 600037.0004) genes. Her
mother, who carried the NF1 and PAX6 mutations, had NF1 with the typical
eye defects of retinal fibroma, optic nerve glioma, and gross Lisch
nodules on the iris; in addition, although her eyes were of normal size,
she had eyes were of normal size, she had small corneas, and also had
cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal
hypoplasia with normal-sized pupils. The proband's father, who had
multiple ocular defects (MCOPS5; 610125), had previously been studied by
Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation.
Henderson et al. (2007) noted that the proband's phenotype was
surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause
a variety of severe developmental defects.

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*FIELD* CN
Marla J. F. O'Neill - updated: 2/22/2013
Cassandra L. Kniffin - updated: 12/23/2010
Cassandra L. Kniffin - updated: 11/8/2010
George E. Tiller - updated: 6/23/2010
Patricia A. Hartz - updated: 3/18/2010

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