RBCC Red Blood Cell Collection

GH1 [Confidence: low (only semi-automatic identification from reviews)]
Somatotropin (Growth hormone; GH; GH-N; Growth hormone 1; Pituitary growth hormone; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01241
ID SOMA_HUMAN Reviewed; 217 AA.
AC P01241; A6NEF6; Q14405; Q16631; Q5EB53; Q9HBZ1; Q9UMJ7; Q9UNL5;
read moreDT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-1992, sequence version 2.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Somatotropin;
DE AltName: Full=Growth hormone;
DE Short=GH;
DE Short=GH-N;
DE AltName: Full=Growth hormone 1;
DE AltName: Full=Pituitary growth hormone;
DE Flags: Precursor;
GN Name=GH1;
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] (ISOFORM 1).
RX PubMed=386281; DOI=10.1093/nar/7.2.305;
RA Roskam W., Rougeon F.;
RT "Molecular cloning and nucleotide sequence of the human growth hormone
RT structural gene.";
RL Nucleic Acids Res. 7:305-320(1979).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=377496; DOI=10.1126/science.377496;
RA Martial J.A., Hallewell R.A., Baxter J.D., Goodman H.M.;
RT "Human growth hormone: complementary DNA cloning and expression in
RT bacteria.";
RL Science 205:602-607(1979).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), AND POSSIBLE
RP ALTERNATIVE SPLICING.
RX PubMed=6269091; DOI=10.1093/nar/9.15.3719;
RA Denoto F.M., Moore D.D., Goodman H.M.;
RT "Human growth hormone DNA sequence and mRNA structure: possible
RT alternative splicing.";
RL Nucleic Acids Res. 9:3719-3730(1981).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7169009;
RA Seeburg P.H.;
RT "The human growth hormone gene family: nucleotide sequences show
RT recent divergence and predict a new polypeptide hormone.";
RL DNA 1:239-249(1982).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2744760; DOI=10.1016/0888-7543(89)90271-1;
RA Chen E.Y., Liao Y.C., Smith D.H., Barrera-Saldana H.A., Gelinas R.E.,
RA Seeburg P.H.;
RT "The human growth hormone locus: nucleotide sequence, biology, and
RT evolution.";
RL Genomics 4:479-497(1989).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Pituitary;
RA Gu J., Huang Q.-H., Li N., Xu S.-H., Han Z.-G., Fu G., Chen Z.;
RT "A novel gene expressed in human pituitary.";
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=18473352; DOI=10.1002/humu.20767;
RA Sedman L., Padhukasahasram B., Kelgo P., Laan M.;
RT "Complex signatures of locus-specific selective pressures and gene
RT conversion on human growth hormone/chorionic somatomammotropin
RT genes.";
RL Hum. Mutat. 29:1181-1193(2008).
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 [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Pituitary;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 5).
RC TISSUE=Pituitary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-26.
RX PubMed=3912261; DOI=10.1016/0378-1119(85)90319-1;
RA Gray G.L., Baldridge J.S., McKeown K.S., Heyneker H.L., Chang C.N.;
RT "Periplasmic production of correctly processed human growth hormone in
RT Escherichia coli: natural and bacterial signal sequences are
RT interchangeable.";
RL Gene 39:247-254(1985).
RN [13]
RP PROTEIN SEQUENCE OF 27-217.
RX PubMed=5810834; DOI=10.1016/0003-9861(69)90489-5;
RA Li C.H., Dixon J.S., Liu W.-K.;
RT "Human pituitary growth hormone. XIX. The primary structure of the
RT hormone.";
RL Arch. Biochem. Biophys. 133:70-91(1969).
RN [14]
RP PROTEIN SEQUENCE OF 27-217, AND SEQUENCE REVISION.
RX PubMed=5144027; DOI=10.1016/S0003-9861(71)80060-7;
RA Li C.H., Dixon J.S.;
RT "Human pituitary growth hormone. 32. The primary structure of the
RT hormone: revision.";
RL Arch. Biochem. Biophys. 146:233-236(1971).
RN [15]
RP SEQUENCE REVISION.
RX PubMed=4675454;
RA Bewley T.A., Dixon J.S., Li C.H.;
RT "Sequence comparison of human pituitary growth hormone, human
RT chorionic somatomammotropin, and ovine pituitary growth and lactogenic
RT hormones.";
RL Int. J. Pept. Protein Res. 4:281-287(1972).
RN [16]
RP PROTEIN SEQUENCE OF 27-61 AND 102-124.
RX PubMed=5279046;
RA Niall H.D.;
RT "Revised primary structure for human growth hormone.";
RL Nature New Biol. 230:90-91(1971).
RN [17]
RP SEQUENCE REVISION TO 119-120 AND 157-159.
RX PubMed=5279528; DOI=10.1073/pnas.68.4.866;
RA Niall H.D., Hogan M.L., Sauer R., Rosenblum I.Y., Greenwood F.C.;
RT "Sequences of pituitary and placental lactogenic and growth hormones:
RT evolution from a primordial peptide by gene reduplication.";
RL Proc. Natl. Acad. Sci. U.S.A. 68:866-869(1971).
RN [18]
RP SEQUENCE REVISION.
RA Niall H.D.;
RT "The chemistry of the human lactogenic hormones.";
RL (In) Griffiths K. (eds.);
RL Prolactin and carcinogenesis, Proc. fourth tenovus workshop prolactin,
RL pp.13-20, Alpha Omega Alpha Press, Cardiff (1972).
RN [19]
RP PROTEIN SEQUENCE OF 27-79 (ISOFORM 2).
RX PubMed=7462247;
RA Chapman G.E., Rogers K.M., Brittain T., Bradshaw R.A., Bates O.J.,
RA Turner C., Cary P.D., Crane-Robinson C.;
RT "The 20,000 molecular weight variant of human growth hormone.
RT Preparation and some physical and chemical properties.";
RL J. Biol. Chem. 256:2395-2401(1981).
RN [20]
RP PROTEIN SEQUENCE OF 46-80 (ISOFORM 2).
RX PubMed=7356479; DOI=10.1016/0006-291X(80)90363-0;
RA Lewis U.J., Bonewald L.F., Lewis L.J.;
RT "The 20,000-dalton variant of human growth hormone: location of the
RT amino acid deletions.";
RL Biochem. Biophys. Res. Commun. 92:511-516(1980).
RN [21]
RP DEAMIDATION AT GLN-163 AND ASN-178.
RX PubMed=7028740;
RA Lewis U.J., Singh R.N., Bonewald L.F., Seavey B.K.;
RT "Altered proteolytic cleavage of human growth hormone as a result of
RT deamidation.";
RL J. Biol. Chem. 256:11645-11650(1981).
RN [22]
RP INVOLVEMENT IN IGHD1A.
RX PubMed=8364549; DOI=10.1093/hmg/2.7.1073;
RA Igarashi Y., Ogawa M., Kamijo T., Iwatani N., Nishi Y., Kohno H.,
RA Masumura T., Koga J.;
RT "A new mutation causing inherited growth hormone deficiency: a
RT compound heterozygote of a 6.7 kb deletion and a two base deletion in
RT the third exon of the GH-1 gene.";
RL Hum. Mol. Genet. 2:1073-1074(1993).
RN [23]
RP PHOSPHORYLATION AT SER-132 AND SER-176.
RC TISSUE=Pituitary;
RX PubMed=14997482; DOI=10.1002/pmic.200300584;
RA Giorgianni F., Beranova-Giorgianni S., Desiderio D.M.;
RT "Identification and characterization of phosphorylated proteins in the
RT human pituitary.";
RL Proteomics 4:587-598(2004).
RN [24]
RP REVIEW.
RX PubMed=10393484; DOI=10.1159/000053128;
RA Baumann G.;
RT "Growth hormone heterogeneity in human pituitary and plasma.";
RL Horm. Res. 51 Suppl. 1:2-6(1999).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Pituitary;
RX PubMed=16807684; DOI=10.1007/s11102-006-8916-x;
RA Beranova-Giorgianni S., Zhao Y., Desiderio D.M., Giorgianni F.;
RT "Phosphoproteomic analysis of the human pituitary.";
RL Pituitary 9:109-120(2006).
RN [26]
RP 3D-STRUCTURE MODELING.
RX PubMed=3447173; DOI=10.1002/prot.340020209;
RA Cohen F.E., Kuntz I.D.;
RT "Prediction of the three-dimensional structure of human growth
RT hormone.";
RL Proteins 2:162-166(1987).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
RX PubMed=1549776; DOI=10.1126/science.1549776;
RA de Vos A.M., Ultsch M., Kossiakoff A.A.;
RT "Human growth hormone and extracellular domain of its receptor:
RT crystal structure of the complex.";
RL Science 255:306-312(1992).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=7984244; DOI=10.1038/372478a0;
RA Somers W., Ultsch M., de Vos A.M., Kossiakoff A.A.;
RT "The X-ray structure of a growth hormone-prolactin receptor complex.";
RL Nature 372:478-481(1994).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RA Chantalat L., Chirgadze N.Y., Jones N., Korber F., Navaza J.,
RA Pavlovsk A.G., Wlodawer A.;
RT "The crystal-structure of wild-type growth-hormone at 2.5-A
RT resolution.";
RL Protein Pept. Lett. 2:333-340(1995).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=8943276; DOI=10.1074/jbc.271.50.32197;
RA Sundstroem M., Lundqvist T., Roedin J., Giebel L.B., Milligan D.,
RA Norstedt G.;
RT "Crystal structure of an antagonist mutant of human growth hormone,
RT G120R, in complex with its receptor at 2.9-A resolution.";
RL J. Biol. Chem. 271:32197-32203(1996).
RN [31]
RP VARIANT KWKS CYS-103.
RX PubMed=8552145; DOI=10.1056/NEJM199602153340704;
RA Takahashi Y., Kaji H., Okimura Y., Goji K., Abe H., Chihara K.;
RT "Short stature caused by a mutant growth hormone.";
RL N. Engl. J. Med. 334:432-436(1996).
RN [32]
RP ERRATUM.
RA Takahashi Y., Kaji H., Okimura Y., Goji K., Abe H., Chihara K.;
RL N. Engl. J. Med. 334:1207-1207(1996).
RN [33]
RP VARIANT IGHD1B ALA-3, AND VARIANT IGHD2 HIS-209.
RX PubMed=9152628;
RA Miyata I., Cogan J.D., Prince M.A., Kamijo T., Ogawa M.,
RA Phillips J.A. III;
RT "Detection of growth hormone gene defects by dideoxy fingerprinting
RT (ddF).";
RL Endocr. J. 44:149-154(1997).
RN [34]
RP VARIANT KWKS GLY-138.
RX PubMed=9276733; DOI=10.1172/JCI119627;
RA Takahashi Y., Shirono H., Arisaka O., Takahashi K., Yagi T., Koga J.,
RA Kaji H., Okimura Y., Abe H., Tanaka T., Chihara K.;
RT "Biologically inactive growth hormone caused by an amino acid
RT substitution.";
RL J. Clin. Invest. 100:1159-1165(1997).
RN [35]
RP VARIANT CYS-105.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [36]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [37]
RP VARIANT IGHD2 HIS-209.
RX PubMed=11502836; DOI=10.1210/jc.86.8.3941;
RA Deladoey J., Stocker P., Mullis P.E.;
RT "Autosomal dominant GH deficiency due to an Arg183His GH-1 gene
RT mutation: clinical and molecular evidence of impaired regulated GH
RT secretion.";
RL J. Clin. Endocrinol. Metab. 86:3941-3947(2001).
RN [38]
RP VARIANTS IGHD1B ALA-3; PRO-16; ASN-37; CYS-42; ILE-53; ARG-67; ASP-73;
RP PHE-97; LYS-100; LEU-117; CYS-134; ARG-134 AND ALA-201, AND VARIANT
RP ILE-136.
RX PubMed=12655557; DOI=10.1002/humu.10168;
RA Millar D.S., Lewis M.D., Horan M., Newsway V., Easter T.E.,
RA Gregory J.W., Fryklund L., Norin M., Crowne E.C., Davies S.J.,
RA Edwards P., Kirk J., Waldron K., Smith P.J., Phillips J.A. III,
RA Scanlon M.F., Krawczak M., Cooper D.N., Procter A.M.;
RT "Novel mutations of the growth hormone 1 (GH1) gene disclosed by
RT modulation of the clinical selection criteria for individuals with
RT short stature.";
RL Hum. Mutat. 21:424-440(2003).
RN [39]
RP VARIANT SHORT STATURE MET-205, AND VARIANTS ALA-3 AND ILE-136.
RX PubMed=15001589; DOI=10.1210/jc.2003-030652;
RA Lewis M.D., Horan M., Millar D.S., Newsway V., Easter T.E.,
RA Fryklund L., Gregory J.W., Norin M., Del Valle C.-J.,
RA Lopez-Siguero J.P., Canete R., Lopez-Canti L.F., Diaz-Torrado N.,
RA Espino R., Ulied A., Scanlon M.F., Procter A.M., Cooper D.N.;
RT "A novel dysfunctional growth hormone variant (Ile179Met) exhibits a
RT decreased ability to activate the extracellular signal-regulated
RT kinase pathway.";
RL J. Clin. Endocrinol. Metab. 89:1068-1075(2004).
RN [40]
RP VARIANT SHORT STATURE SER-79, AND CHARACTERIZATION OF VARIANT SHORT
RP STATURE SER-79.
RX PubMed=15713716; DOI=10.1210/jc.2004-1838;
RA Besson A., Salemi S., Deladoeey J., Vuissoz J.-M., Eble A.,
RA Bidlingmaier M., Buergi S., Honegger U., Flueck C., Mullis P.E.;
RT "Short stature caused by a biologically inactive mutant growth hormone
RT (GH-C53S).";
RL J. Clin. Endocrinol. Metab. 90:2493-2499(2005).
RN [41]
RP CHARACTERIZATION OF VARIANT KWKS CYS-103.
RX PubMed=17519310; DOI=10.1210/jc.2006-2238;
RA Petkovic V., Besson A., Thevis M., Lochmatter D., Eble A., Fluck C.E.,
RA Mullis P.E.;
RT "Evaluation of the biological activity of a growth hormone (GH) mutant
RT (R77C) and its impact on GH responsiveness and stature.";
RL J. Clin. Endocrinol. Metab. 92:2893-2901(2007).
CC -!- FUNCTION: Plays an important role in growth control. Its major
CC role in stimulating body growth is to stimulate the liver and
CC other tissues to secrete IGF-1. It stimulates both the
CC differentiation and proliferation of myoblasts. It also stimulates
CC amino acid uptake and protein synthesis in muscle and other
CC tissues.
CC -!- SUBUNIT: Monomer, dimer, trimer, tetramer and pentamer, disulfide-
CC linked or non-covalently associated, in homopolymeric and
CC heteropolymeric combinations. Can also form a complex either with
CC GHBP or with the alpha2-macroglobulin complex.
CC -!- INTERACTION:
CC P10912:GHR; NbExp=3; IntAct=EBI-1026046, EBI-286316;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist;
CC Name=1; Synonyms=22 kDa;
CC IsoId=P01241-1; Sequence=Displayed;
CC Name=2; Synonyms=20 kDa variant;
CC IsoId=P01241-2; Sequence=VSP_006200;
CC Name=3;
CC IsoId=P01241-3; Sequence=VSP_006201;
CC Name=4;
CC IsoId=P01241-4; Sequence=VSP_006202;
CC Name=5;
CC IsoId=P01241-5; Sequence=VSP_045642;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Growth hormone deficiency, isolated, 1A (IGHD1A)
CC [MIM:262400]: An autosomal recessive, severe deficiency of growth
CC hormone leading to dwarfism. Patients often develop antibodies to
CC administered growth hormone. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Growth hormone deficiency, isolated, 1B (IGHD1B)
CC [MIM:612781]: An autosomal recessive deficiency of growth hormone
CC leading to short stature. Patients have low but detectable levels
CC of growth hormone, significantly retarded bone age, and a positive
CC response and immunologic tolerance to growth hormone therapy.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Kowarski syndrome (KWKS) [MIM:262650]: A syndrome
CC clinically characterized by short stature associated with
CC bioinactive growth hormone, normal or slightly increased growth
CC hormone secretion, pathologically low insulin-like growth factor 1
CC levels, and normal catch-up growth on growth hormone replacement
CC therapy. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Growth hormone deficiency, isolated, 2 (IGHD2)
CC [MIM:173100]: An autosomal dominant deficiency of growth hormone
CC leading to short stature. Clinical severity is variable. Patients
CC have a positive response and immunologic tolerance to growth
CC hormone therapy. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- PHARMACEUTICAL: Available under the names Nutropin or Protropin
CC (Genentech), Norditropin (Novo Nordisk), Genotropin (Pharmacia
CC Upjohn), Humatrope (Eli Lilly) and Saizen or Serostim (Serono).
CC Used for the treatment of growth hormone deficiency and for
CC Turner's syndrome.
CC -!- MISCELLANEOUS: Circulating GH shows a great heterogeneity due to
CC alternative splicing, differential post-translational
CC modifications of monomeric forms, oligomerization, optional
CC binding to 2 different GH-binding proteins, and potentially
CC proteolytic processing.
CC -!- SIMILARITY: Belongs to the somatotropin/prolactin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GH1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Growth hormone entry;
CC URL="http://en.wikipedia.org/wiki/Growth_hormone";
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DR EMBL; V00519; CAA23778.1; -; mRNA.
DR EMBL; V00520; CAA23779.1; -; Genomic_DNA.
DR EMBL; M13438; AAA98618.1; -; Genomic_DNA.
DR EMBL; J03071; AAA52549.1; -; Genomic_DNA.
DR EMBL; AF185611; AAG09699.1; -; mRNA.
DR EMBL; AF110644; AAD48584.1; -; mRNA.
DR EMBL; EU421712; ABZ88713.1; -; Genomic_DNA.
DR EMBL; AC127029; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94233.1; -; Genomic_DNA.
DR EMBL; BC062475; AAH62475.1; -; mRNA.
DR EMBL; BC075012; AAH75012.1; -; mRNA.
DR EMBL; BC075013; AAH75013.1; -; mRNA.
DR EMBL; BC090045; AAH90045.1; -; mRNA.
DR EMBL; CD106566; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; M14398; AAA52554.1; -; mRNA.
DR PIR; A93731; STHU.
DR RefSeq; NP_000506.2; NM_000515.3.
DR RefSeq; NP_072053.1; NM_022559.2.
DR RefSeq; NP_072054.1; NM_022560.2.
DR RefSeq; XP_005257275.1; XM_005257218.1.
DR RefSeq; XP_005257276.1; XM_005257219.1.
DR UniGene; Hs.655229; -.
DR PDB; 1A22; X-ray; 2.60 A; A=27-217.
DR PDB; 1AXI; X-ray; 2.10 A; A=27-217.
DR PDB; 1BP3; X-ray; 2.90 A; A=27-217.
DR PDB; 1HGU; X-ray; 2.50 A; A=27-217.
DR PDB; 1HUW; X-ray; 2.00 A; A=27-217.
DR PDB; 1HWG; X-ray; 2.50 A; A=27-217.
DR PDB; 1HWH; X-ray; 2.90 A; A=27-217.
DR PDB; 1KF9; X-ray; 2.60 A; A/D=27-217.
DR PDB; 3HHR; X-ray; 2.80 A; A=27-216.
DR PDBsum; 1A22; -.
DR PDBsum; 1AXI; -.
DR PDBsum; 1BP3; -.
DR PDBsum; 1HGU; -.
DR PDBsum; 1HUW; -.
DR PDBsum; 1HWG; -.
DR PDBsum; 1HWH; -.
DR PDBsum; 1KF9; -.
DR PDBsum; 3HHR; -.
DR ProteinModelPortal; P01241; -.
DR SMR; P01241; 27-216.
DR DIP; DIP-1022N; -.
DR IntAct; P01241; 3.
DR STRING; 9606.ENSP00000312673; -.
DR PhosphoSite; P01241; -.
DR DMDM; 134703; -.
DR PaxDb; P01241; -.
DR PRIDE; P01241; -.
DR Ensembl; ENST00000323322; ENSP00000312673; ENSG00000259384.
DR Ensembl; ENST00000351388; ENSP00000343791; ENSG00000259384.
DR Ensembl; ENST00000458650; ENSP00000408486; ENSG00000259384.
DR GeneID; 2688; -.
DR KEGG; hsa:2688; -.
DR UCSC; uc002jdk.3; human.
DR CTD; 2688; -.
DR GeneCards; GC17M061994; -.
DR HGNC; HGNC:4261; GH1.
DR HPA; CAB025646; -.
DR HPA; HPA043715; -.
DR MIM; 139250; gene.
DR MIM; 173100; phenotype.
DR MIM; 262400; phenotype.
DR MIM; 262650; phenotype.
DR MIM; 612781; phenotype.
DR neXtProt; NX_P01241; -.
DR Orphanet; 231662; Isolated growth hormone deficiency type IA.
DR Orphanet; 231671; Isolated growth hormone deficiency type IB.
DR Orphanet; 231679; Isolated growth hormone deficiency type II.
DR Orphanet; 629; Short stature due to growth hormone qualitative anomaly.
DR PharmGKB; PA171; -.
DR eggNOG; NOG26152; -.
DR HOVERGEN; HBG011318; -.
DR InParanoid; P01241; -.
DR KO; K05438; -.
DR OMA; CRRFVES; -.
DR OrthoDB; EOG7F7W9X; -.
DR PhylomeDB; P01241; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P01241; -.
DR ChiTaRS; GH1; human.
DR EvolutionaryTrace; P01241; -.
DR GenomeRNAi; 2688; -.
DR NextBio; 10614; -.
DR PRO; PR:P01241; -.
DR ArrayExpress; P01241; -.
DR Bgee; P01241; -.
DR CleanEx; HS_GH1; -.
DR Genevestigator; P01241; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005131; F:growth hormone receptor binding; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070977; P:bone maturation; IDA:BHF-UCL.
DR GO; GO:0015758; P:glucose transport; IDA:MGI.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; TAS:Reactome.
DR GO; GO:0010535; P:positive regulation of activation of JAK2 kinase activity; IDA:BHF-UCL.
DR GO; GO:0043568; P:positive regulation of insulin-like growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; TAS:BHF-UCL.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IDA:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IDA:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IDA:BHF-UCL.
DR GO; GO:0042523; P:positive regulation of tyrosine phosphorylation of Stat5 protein; IDA:BHF-UCL.
DR GO; GO:0032355; P:response to estradiol stimulus; IDA:BHF-UCL.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR012351; 4_helix_cytokine_core.
DR InterPro; IPR001400; Somatotropin.
DR InterPro; IPR018116; Somatotropin_CS.
DR PANTHER; PTHR11417; PTHR11417; 1.
DR Pfam; PF00103; Hormone_1; 1.
DR PRINTS; PR00836; SOMATOTROPIN.
DR SUPFAM; SSF47266; SSF47266; 1.
DR PROSITE; PS00266; SOMATOTROPIN_1; 1.
DR PROSITE; PS00338; SOMATOTROPIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond; Dwarfism;
KW Hormone; Metal-binding; Pharmaceutical; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1 26
FT CHAIN 27 217 Somatotropin.
FT /FTId=PRO_0000032988.
FT METAL 44 44 Zinc (By similarity).
FT METAL 200 200 Zinc (By similarity).
FT MOD_RES 132 132 Phosphoserine.
FT MOD_RES 163 163 Deamidated glutamine; by deterioration.
FT MOD_RES 176 176 Phosphoserine.
FT MOD_RES 178 178 Deamidated asparagine; by deterioration.
FT DISULFID 79 191
FT DISULFID 208 215
FT VAR_SEQ 58 97 Missing (in isoform 5).
FT /FTId=VSP_045642.
FT VAR_SEQ 58 72 Missing (in isoform 2).
FT /FTId=VSP_006200.
FT VAR_SEQ 111 148 Missing (in isoform 3).
FT /FTId=VSP_006201.
FT VAR_SEQ 117 162 Missing (in isoform 4).
FT /FTId=VSP_006202.
FT VARIANT 3 3 T -> A (in IGHD1B; could be a neutral
FT polymorphism; dbSNP:rs2001345).
FT /FTId=VAR_011917.
FT VARIANT 16 16 L -> P (in IGHD1B; suppresses secretion).
FT /FTId=VAR_015801.
FT VARIANT 37 37 D -> N (in IGHD1B).
FT /FTId=VAR_015802.
FT VARIANT 42 42 R -> C (in IGHD1B; reduced secretion).
FT /FTId=VAR_015803.
FT VARIANT 53 53 T -> I (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015804.
FT VARIANT 67 67 K -> R (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015805.
FT VARIANT 73 73 N -> D (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015806.
FT VARIANT 79 79 C -> S (in short stature; idiopathic
FT autosomal; affects binding affinity of GH
FT for GHR and the potency of GH to activate
FT the JAK2/STAT5 signaling pathway).
FT /FTId=VAR_032702.
FT VARIANT 97 97 S -> F (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015807.
FT VARIANT 100 100 E -> K (in IGHD1B).
FT /FTId=VAR_015808.
FT VARIANT 103 103 R -> C (in KWKS; loss of activity; no
FT difference in the binding affinity or
FT bioactivity between wild-type and mutant;
FT no difference found in the extent of
FT subcellular localization within
FT endoplasmic reticulum Golgi or secretory
FT vesicles between wild-type and mutant;
FT reduced capability of the mutant to
FT induce GHR/GHBP gene transcription rate
FT when compared to wild-type).
FT /FTId=VAR_015809.
FT VARIANT 105 105 S -> C (in dbSNP:rs6174).
FT /FTId=VAR_011918.
FT VARIANT 117 117 Q -> L (in IGHD1B; reduced secretion).
FT /FTId=VAR_015810.
FT VARIANT 134 134 S -> C (in IGHD1B).
FT /FTId=VAR_015811.
FT VARIANT 134 134 S -> R (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015812.
FT VARIANT 136 136 V -> I (in dbSNP:rs5388).
FT /FTId=VAR_011919.
FT VARIANT 138 138 D -> G (in KWKS; loss of activity).
FT /FTId=VAR_015813.
FT VARIANT 201 201 T -> A (in IGHD1B; reduced ability to
FT activate the JAK/STAT pathway).
FT /FTId=VAR_015814.
FT VARIANT 205 205 I -> M (in short stature; idiopathic
FT autosomal).
FT /FTId=VAR_032703.
FT VARIANT 209 209 R -> H (in IGHD2).
FT /FTId=VAR_015815.
FT CONFLICT 35 35 L -> P (in Ref. 1; CAA23778).
FT CONFLICT 40 40 M -> S (in Ref. 3; CAA23779).
FT HELIX 32 61
FT HELIX 64 72
FT HELIX 73 75
FT TURN 80 83
FT HELIX 90 94
FT HELIX 98 110
FT TURN 111 114
FT HELIX 115 119
FT HELIX 120 125
FT TURN 129 133
FT HELIX 136 154
FT HELIX 163 166
FT STRAND 178 180
FT HELIX 182 209
FT TURN 212 216
SQ SEQUENCE 217 AA; 24847 MW; 72CC15AF4ED1C51A CRC64;
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEA
YIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE LLRISLLLIQ SWLEPVQFLR
SVFANSLVYG ASDSNVYDLL KDLEEGIQTL MGRLEDGSPR TGQIFKQTYS KFDTNSHNDD
ALLKNYGLLY CFRKDMDKVE TFLRIVQCRS VEGSCGF
//

MIM 139250
*RECORD*
*FIELD* NO
139250
*FIELD* TI
*139250 GROWTH HORMONE 1; GH1
;;GH;;
GROWTH HORMONE, NORMAL; GHN;;
GROWTH HORMONE, PITUITARY
read more*FIELD* TX

DESCRIPTION

Growth hormone (GH) is synthesized by acidophilic or somatotropic cells
of the anterior pituitary gland. Human growth hormone has a molecular
mass of 22,005 and contains 191 amino acid residues with 2 disulfide
bridges (Niall et al., 1971).

CLONING

By 1977, not only had the amino acid sequence of GH been determined, but
the sequence of nucleotides in the structural gene for GH had been
determined as well (Baxter et al., 1977).

By molecular cloning of cDNA, Masuda et al. (1988) demonstrated that the
20-kD variant of human GH is produced by the same gene (GHN or GH1) as
the 22-kD form, and that a process of alternative splicing is involved.

Chen et al. (1989) sequenced the entire 66,500 bp of the GH gene
cluster. The expression of the 5 genes in this cluster was examined by
screening pituitary and placenta cDNA libraries, using gene-specific
oligonucleotides. According to this analysis, the GHN gene is
transcribed exclusively in the pituitary, whereas the other 4 genes
(CSL, 603515; CSA, 150200; GHV, 139240; and CSB, 118820) are expressed
only in placental tissues. The CSL gene carries a G-to-A transition in a
sequence used by the other 4 genes as an intronic 5-prime splice donor
site. The mutation results in a different splicing pattern and, hence,
in a novel sequence of the CSL gene mRNA and the deduced polypeptide.

GH and CSH (CSA) have 191 amino acid residues and show about 85%
homology in amino acid sequence (Owerbach et al., 1980). Their messenger
RNAs have more than 90% homology.

GENE FUNCTION

Human GH binds 2 GHR (600946) molecules and induces signal transduction
through receptor dimerization. Sundstrom et al. (1996) noted that at
high concentrations, GH acts as an antagonist because of a large
difference in affinities at the respective binding sites. This
antagonist action can be enhanced further by reducing binding in the
low-affinity binding site. A possible mechanism by which mutant,
biologically inactive GH may have its effect is to act as an antagonist
to the binding of normal GH to its receptor, GHR.

The regulation of GH synthesis and release is modulated by a family of
genes that include the transcription factors PROP1 (601538) and PIT1
(173110). PROP1 and PIT1 regulate differentiation of pituitary cells
into somatotrophs, which synthesize and release GH. Genes that are
important in the release of GH include the GHRH (139190) and GHRHR
(139191) genes. After GHRH is synthesized and released from the
hypothalamus, it travels to the anterior pituitary where it binds to
GHRHR, resulting in transduction of a signal into the somatotroph which
promotes release of presynthesized GH that is stored in secretory
granules. Other gene products that are important in GH synthesis and
release are GHR and the growth hormone-binding proteins (GHBP). The
GHBPs are derived from the membrane bound receptor (GHR) and they remain
bound to GH in the circulation. Following binding of GH to 2 GHR
molecules, the signal to produce IGF1 (147440) is transduced. The GH
molecules that are bound to membrane-anchored GH receptors can be
released into the circulation by excision of the extracellular portion
of the GHR molecules. At this point, the extracellular portion of the
GHR, which is referred to as the GHBP, serves to stabilize GH in the
circulation. The final genes in the GH synthetic pathway include IGF1
and its receptor (IGF1R; 147370), whose products stimulate growth in
various tissues including bones and muscle (Phillips, 1995; Rimoin and
Phillips, 1997).

Boguszewski et al. (1997) investigated the proportion of circulating
non-22-kD GH1 isoforms in prepubertal children with short stature
(height less than -2 SD score) of different etiologies. The study groups
consisted of 17 girls with Turner syndrome (TS), aged 3 to 13 years; 25
children born small for gestational age (SGA) without postnatal catch-up
growth, aged 3 to 13 years; and 24 children with idiopathic short
stature (ISS), aged 4 to 15 years. The results were compared with those
from 23 prepubertal healthy children of normal stature (height +/- 2 SD
score), aged 4 to 13 years. Serum non-22-kD GH levels, expressed as a
percentage of the total GH concentration, were determined by the 22-kD
GH exclusion assay. The median proportion of non-22-kD GH isoforms was
8.1% in normal children; it was increased in children born SGA (9.8%; P
= 0.05) and in girls with TS (9.9%; P = 0.01), but not in children with
ISS (8.9%). In children born SGA, the proportion of non-22-kD GH
isoforms directly correlated with different estimates of spontaneous GH
secretion and inversely correlated with height SD score. The authors
concluded that the ratio of non-22-kD GH isoforms in the circulation may
have important implications for normal and abnormal growth.

Mendlewicz et al. (1999) studied the contributions of genetic and
environmental factors in the regulation of the 24-hour GH secretion. The
24-hour profile of plasma GH was obtained at 15-minute intervals in 10
pairs of monozygotic and 9 pairs of dizygotic normal male twins, aged 16
to 34 years. A major genetic effect was evidenced on GH secretion during
wakefulness (heritability estimate of 0.74) and, to a lesser extent, on
the 24-hour GH secretion. Significant genetic influences were also
identified for slow-wave sleep and height. These results suggested that
human GH secretion in young adulthood is markedly dependent on genetic
factors.

Hindmarsh et al. (1999) studied GH secretory patterns in the elderly by
constructing 24-hour serum GH profiles in 45 male and 38 female
volunteers, aged 59.4 to 73.0 years, and related patterns to IGF1,
IGFBP3 (146732), and GH-binding protein levels; body mass index; and
waist/hip ratio. There was a highly significant difference in mean
24-hour serum GH concentrations in females compared to males as a result
of significantly higher trough GH levels in females. Peak values were
not significantly different. Serum IGF1 levels were significantly higher
in males. Peak GH values were related to serum IGF1 levels, whereas
trough GH levels were not. GH was secreted with a dominant periodicity
of 200 minutes in males and 280 minutes in females. GH secretion
assessed by ApEn was more disordered in females, and increasing disorder
was associated with lower IGF1 levels. Body mass index was negatively
related to GH in both sexes. In males, trough values were the major
determinant, whereas in females, the peak value was the major
determinant. Trough GH levels were inversely related in both sexes to
waist/hip ratio and to increasing secretory disorder. These data
demonstrated a sexually dimorphic pattern of GH secretion in the
elderly.

De Groof et al. (2002) evaluated the GH/IGF1 axis and the levels of
IGF-binding proteins (IGFBPs), IGFBP3 protease, glucose, insulin
(176730), and cytokines in 27 children with severe septic shock due to
meningococcal sepsis during the first 3 days after admission. The median
age was 22 months. Significant differences were found between
nonsurvivors and survivors for the levels of total IGF1, free IGF1,
IGFBP1 (146730), IGFBP3 protease activity, IL6 (147620), and TNFA
(191160). The pediatric risk of mortality score correlated significantly
with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with
levels of total IGFI and free IGFI. Levels of GH and IGFBP1 were
extremely elevated in nonsurvivors, whereas total and free IGFI levels
were markedly decreased and were accompanied by high levels of the
cytokines IL6 and TNFA.

In rodents and humans there is a sexually dimorphic pattern of GH
secretion that influences the serum concentration of IGF1. Geary et al.
(2003) studied the plasma concentrations of IGF1, IGF2 (147470), IGFBP3,
and GH in cord blood taken from the offspring of 987 singleton Caucasian
pregnancies born at term and related these values to birth weight,
length, and head circumference. Cord plasma concentrations of IGF1,
IGF2, and IGFBP3 were influenced by factors related to birth size:
gestational age at delivery, mode of delivery, maternal height, and
parity of the mother. Plasma GH concentrations were inversely related to
the plasma concentrations of IGF1 and IGFBP3; 10.2% of the variability
in cord plasma IGF1 concentration and 2.7% for IGFBP3 was explained by
sex of the offspring and parity. Birth weight, length, and head
circumference measurements were greater in males than females (P less
than 0.001). Mean cord plasma concentrations of IGF1 and IGFBP3 were
significantly lower in males than females. Cord plasma GH concentrations
were higher in males than females, but no difference was noted between
the sexes for IGF2. After adjustment for gestational age, parity, and
maternal height, cord plasma concentrations of IGF1 and IGFBP3 along
with sex explained 38.0% of the variability in birth weight, 25.0% in
birth length, and 22.7% in head circumference.

Ho et al. (2002) noted that the human GH gene cluster encompasses GHN,
which is expressed primarily in pituitary somatotropes, and 4 genes,
CSA, CSB, CSL, and GHV, which are expressed specifically in
syncytiotrophoblast cells lining the placental villi. A multicomponent
locus control region (LCR) is required for transcriptional activation in
both pituitary and placenta. In addition, 2 genes overlap with the GH
LCR: SCN4A (603967) on the 5-prime end and CD79B (147245) on the 3-prime
end. Ho et al. (2002) studied mice carrying an 87-kb human transgene
encompassing the GH LCR and most of the GH gene cluster. By deleting a
fragment of the transgene, they showed that a single determinant of the
human GH LCR located 14.5 kb 5-prime to the GHN promoter has a critical,
specific, and nonredundant role in facilitating promoter trans factor
binding and activating GHN transcription. Ho et al. (2002) found that
this same determinant plays an essential role in establishing a 32-kb
acetylated domain that encompasses the entire GH LCR and the contiguous
GHN promoter. These data supported a model for long-range gene
activation via LCR-mediated targeting and extensive spreading of core
histone acetylation.

Using mice carrying the 87-kb human GH transgene, Ho et al. (2006) found
that insertion of a Pol II terminator within the GH LCR blocked
transcription of the CD79B gene adjacent to the LCR and repressed GHN
expression. However, the insertion had little effect on acetylation
within the GH locus. Selective elimination of CD79B also repressed GHN
expression. Ho et al. (2006) concluded that Pol II tracking and histone
acetylation are not linked and that transcription, but not translation,
of the CD79B gene is required for GHN expression.

In addition to expression in pituitary and placenta and functions in
growth and reproduction, prolactin (PRL; 176760), GH, and placental
lactogen (CSH1; 150200) are expressed in endothelial cells and have
angiogenic effects. Ge et al. (2007) found that BMP1 (112264) and
BMP1-like proteinases processed PRL and GH in vitro and in vivo to
produce approximately 17-kD N-terminal fragments with antiangiogenic
activity.

GENE STRUCTURE

The GH, PL (CSH1), and PRL genes contain 5 exons separated by 4 introns.
The introns occur at the same sites, supporting evolutionary homology
(Baxter, 1981). All 5 genes in the GH gene cluster are in the same
transcriptional orientation (Ho et al., 2002).

Baxter (1981) found evidence for the existence of at least 3 GH and 3
CSH, also called placental lactogen (PL), genes on chromosome 17.
Whether they are situated GH:GH:GH:PL:PL:PL or arranged
GH:PL:GH:PL:GH:PL was not clear.

BIOCHEMICAL FEATURES

- Crystal Structure

Sundstrom et al. (1996) crystallized a GH antagonist mutant, gly120 to
arg, with its receptor as a 1-to-1 complex and determined the crystal
structure at 2.9-angstrom resolution. The 1-to-1 complex with the
agonist is remarkably similar to the native GHR 1-to-2 complex. A
comparison between the 2 structures revealed only minimal differences in
the conformations of the hormone or its receptor in the 2 complexes.

EVOLUTION

Owerbach et al. (1980) estimated that the GH and CSH genes diverged
about 50 to 60 million years ago, whereas the PRL and GH genes diverged
about 400 million years ago.

Human PL and human GH are more alike than are rat GH and human GH. (PL
has more growth-promoting effects than milk-producing effects.) Baxter
(1981) proposed that in evolution the prolactin gene diverged early from
the gene that was the common progenitor of the GH and PL genes.
(Placental lactogen was the official Endocrine Society designation;
Grumbach (1981) promoted the term chorionic somatomammotropin, which has
functional legitimacy.)

MAPPING

By a combination of restriction mapping and somatic cell hybridization,
Owerbach et al. (1980) assigned genes for growth hormone, chorionic
somatomammotropin (CSH), and a third growth hormone-like gene (GH2;
139240) to the growth hormone gene cluster that is assigned to
chromosome 17.

Lebo (1980) corroborated the assignment of the GH gene to chromosome 17
by the technique of fluorescence-activated chromosome sorting. George et
al. (1981) assigned the genes for GH and CSH to the 17q21-qter region.

Ruddle (1982) found that the GH family of genes is between galactokinase
(604313) and thymidine kinase (TK1; 188300), with galactokinase being
closer to the centromere.

Harper et al. (1982) used in situ hybridization to assign the GH gene
cluster to 17q22-q24. A gene copy number experiment showed that both
genes are present in about 3 copies per haploid genome. The sequence of
genes in the GH gene cluster is thought to be GHN--CSL--CSA--GHV--CSB
(Phillips, 1983). Normal growth hormone (GHN, referred to now as GH1)
encodes GH. CSA and CSB both encode chorionic somatomammotropin. GHV, or
growth hormone variant, is now designated GH2.

Xu et al. (1988) assigned the growth hormone complex to 17q23-q24 by in
situ hybridization.

MOLECULAR GENETICS

Using GH cDNA as a specific DNA probe in Southern blot analyses,
Phillips et al. (1981) found that the GHN (GH1) gene was deleted in 2
families with type IA growth hormone deficiency (Illig type; 262400). On
the other hand, the GH genes of persons with type IB (612781) (in 6
families) had normal restriction patterns. Two affected sibs in 2 of the
6 families were discordant for 2 restriction markers closely linked to
the GH cluster.

Braga et al. (1986) reported the cases of a son and daughter of
first-cousin Italian parents who had isolated growth hormone deficiency
(IGHD) resulting from homozygosity for a 7.6-kb deletion within the GH
gene cluster. Both developed antibodies in response to treatment with
human GH, but in neither was there interference with growth. The
deletion affected not only the structural gene for GH (GH1) but also
sequences adjacent to CSL.

Goossens et al. (1986) described a double deletion in the GH gene
cluster in cases of inherited growth hormone deficiency. A total of
about 40 kb of DNA was absent due to 2 separate deletions flanking the
CSL gene (603515). Two affected sibs were homozygous. The parents were
'Romany of French origin' (i.e., French gypsies) and related as first
cousins once removed. Restriction patterns in them were consistent with
heterozygosity.

Vnencak-Jones et al. (1988) described the molecular basis of deletions
within the human GH gene cluster in 9 unrelated patients. Their results
suggested that the presence of highly repetitive DNA sequences flanking
the GH1 gene predisposed to unequal recombinant events through
chromosomal misalignment.

In a Chinese family, He et al. (1990) found that 2 sibs with GH
deficiency had a deletion of approximately 7.1 kb of DNA. The parents,
who were related as second cousins, were heterozygous but of normal
stature. The affected children had not received exogenous GH, but the
authors suspected that their disorder represented IGHD type IA.

Akinci et al. (1992) described a Turkish family in which 3 children had
IGHD type IA. A homozygous deletion of approximately 45 kb encompassing
the GH1, CSL, CSA, and GH2 genes was found. The end points of the
deletion lay within 2 regions of highly homologous DNA sequence situated
5-prime to the GH1 gene and 5-prime to the CSB gene. The parents, who
were consanguineous, were both heterozygous for the deletion.

Mullis et al. (1992) analyzed GH1 DNA from circulating lymphocytes of 78
subjects with severe IGHD. The subjects analyzed were broadly grouped
into 3 different populations: 32 north European, 22 Mediterranean, and
24 Turkish. Of the 78 patients, 10 showed a GH1 deletion; 8 had a 6.7-kb
deletion, and the remaining 2 had a 7.6-kb GH1 deletion. Five of the 10
subjects developed anti-hGH antibodies to hGH replacement followed by a
stunted growth response. Parental consanguinity was found in all
families, and heterozygosity for the corresponding deletion was present
in each parent. The proportion of deletion cases was about the same in
each of the 3 population groups.

Phillips and Cogan (1994) tabulated mutations found in the GH gene.

Takahashi et al. (1996) reported the case of a boy with short stature
and heterozygosity for a mutant GH gene (139250.0008). In this child,
the GH not only could not activate the GH receptor (GHR; 600946) but
also inhibited the action of wildtype GH because of its greater affinity
for GHR and GH-binding protein (GHBP), which is derived from the
extracellular domain of the GHR. Thus, a dominant-negative effect was
observed. See Kowarski syndrome, 262650.

Splicing of pre-mRNA transcripts is regulated by consensus sequences at
intron boundaries and the branch site. In vitro studies showed that the
small introns of some genes also require intron splice enhancers (ISE)
to modulate splice site selection. An autosomal dominant form of
isolated growth hormone deficiency (IGHD II; 173100) can be caused by
mutations in intron 3 (IVS3) of the GH1 gene that cause exon 3 skipping,
resulting in truncated GH1 gene products that prevent secretion of
normal GH. Some of these GH1 mutations are located 28 to 45 nucleotides
into IVS3 (which is 92 nucleotides long). McCarthy and Phillips (1998)
localized this ISE by quantitating the effects of deletions within IVS3
on skipping of exon 3. The importance of individual nucleotides to ISE
function was determined by analyzing the effects of point mutants and
additional deletions. The results showed that (1) an ISE with a
G(2)X(1-4)G(3) motif resides in IVS3 of the GH1 gene; (2) both runs of
Gs are required for ISE function; (3) a single copy of the ISE regulates
exon 3 skipping; and (4) ISE function can be modified by an adjacent AC
element. The findings revealed a new mechanism by which mutations can
cause inherited human endocrine disorders and suggested that (1) ISEs
may regulate splicing of transcripts of other genes, and (2) mutations
of these ISEs or of the transacting factors that bind them may cause
other genetic disorders.

Hasegawa et al. (2000) studied polymorphisms in the GH1 gene that were
associated with altered GH production. The subjects included 43
prepubertal short children with GHD without gross pituitary
abnormalities, 46 short children with normal GH secretion, and 294
normal adults. A polymorphism in intron 4 (A or T at nucleotide 1663,
designated P1) was identified. Two additional polymorphic sites (T or G
at nucleotide 218, designated P2, and G or T at nucleotide 439,
designated P3) in the promoter region of the GH1 gene were also
identified and matched with the P1 polymorphism (A or T, respectively)
in more than 90% of the subjects. P1, P2, and P3 were considered to be
associated with GH production. For example, the allele frequency of T at
P2 in prepubertal short children with GHD without gross pituitary
abnormalities (58%) was significantly different from that in short
children with normal GH secretion and normal adults (37% and 44%,
respectively). Furthermore, significant differences were observed in
maximal GH peaks in provocative tests, IGF1 (147440) SD scores, and
height SD scores in children with the T/T or G/G genotypes at P2. In the
entire study group, significant differences in IGF1 SD scores and height
SD scores were observed between the T/T and G/G genotypes at P2.
Hasegawa et al. (2000) concluded that GH secretion is partially
determined by polymorphisms in the GH1 gene, explaining some of the
variations in GH secretion and height.

Dennison et al. (2004) examined associations between common SNPs in the
GH1 gene and weight in infancy, adult bone mass and bone loss rates, and
circulating GH profiles. Genomic DNA was examined for 2 SNPs in the GH
gene, 1 in the promoter region and 1 in intron 4. Homozygotes at loci
GH1 A5157G and T6331A displayed low baseline bone density and
accelerated bone loss; there was also a significant (P = 0.04)
interaction among weight at 1 year, GH1 genotype, and bone loss rate.
There was a graded association between alleles and circulating GH
concentration among men. The authors concluded that common diversity in
the GH1 region predisposes to osteoporosis via effects on the level of
GH expression.

The proximal promoter region of the GH1 gene is highly polymorphic,
containing at least 15 SNPs. This variation is manifest in 40 different
haplotypes, the high diversity being explicable in terms of gene
conversion, recurrent mutation, and selection. Horan et al. (2003)
showed by functional analysis that 12 haplotypes were associated with a
significantly reduced level of reporter gene expression, whereas 10
haplotypes were associated with a significantly increased level. The
former tended to be more prevalent in the general population than the
latter (p less than 0.01), possibly as a consequence of selection.
Haplotype partitioning identified 6 SNPs as major determinants of GH1
gene expression, which is influenced by an LCR located between 14.5 and
32 kb upstream of the GH1 gene (Jones et al., 1995). Horan et al. (2003)
used a series of LCR-GH1 proximal promoter constructs to demonstrate
that the LCR enhanced proximal promoter activity by up to 2.8-fold
depending upon proximal promoter haplotype, and that the activity of a
given proximal promoter haplotype was also differentially enhanced by
different LCR haplotypes. The genetic basis of interindividual
differences in GH1 gene expression thus appeared to be extremely
complex.

Millar et al. (2003) sought to identify subtle mutations in the GH1
gene, which had been regarded as a comparatively rare cause of short
stature, in 3 groups: 41 individuals selected for short stature, reduced
height velocity, and bone age delay, 11 individuals with short stature
and IGHD, and 154 controls. Heterozygous mutations were identified in
all 3 groups but disproportionately in the individuals with short
stature, both with and without IGHD. Twenty-four novel GH1 gene lesions
were found. Fifteen novel GH1 gene mutations were considered to be of
probable phenotypic significance. Although most such lesions may be
insufficient on their own to account for the observed clinical
phenotype, they were considered likely to play a contributory role in
the etiology of short stature.

In a screen of the GH1 gene for mutations in a group of 74 children with
familial short stature, Lewis et al. (2004) identified 4 mutations, 2 of
which were novel: an ile179-to-met (I179M) substitution and a
single-basepair substitution in the promoter region. Resistance to
proteolysis and secretion from rat pituitary cells of I179M GH were
consistent with a lack of significant misfolding. Receptor binding
studies were normal, but molecular modeling studies suggested that the
I179M substitution might perturb interactions between GH and the GH
receptor loop containing residue trp169, thereby affecting signal
transduction. In contrast to its ability to activate STAT5 (601511)
normally, activation of ERK (see 176948) by the I179M variant was
reduced to half that observed with wildtype. The subject exhibited
normal GH secretion after pharmacologic stimulation. That the I179M
variant did not cosegregate with the short stature phenotype in the
family strongly suggested to Lewis et al. (2004) that this variant was
on its own insufficient to fully account for the observed clinical
phenotype.

Cogan et al. (1995, 1997) and Moseley et al. (2002) described 3
mutations (139250.0016; 139250.0011; 139250.0012) that are not located
at the 5-prime splice site in intron 3 but still alter splicing of GH1
to cause increased production of a 17.5-kD isoform. All 3 mutations
reside within purine-rich sequences that resemble exonic and intronic
splicing enhancers (ESE and ISE). Since splicing enhancers often
activate specific splice sites to facilitate exon definition, Ryther et
al. (2003) considered that the splicing defects caused by these
mutations could be due to a defect in exon definition, resulting in exon
skipping. They showed that overexpression of the dominant-negative
17.5-kD isoform also destroyed the majority of somatotrophs, leading to
anterior pituitary hypoplasia in transgenic mice. They demonstrated that
dual splicing enhancers are required to ensure exon 3 definition to
produce full-length 22-kD hormone. They also showed that splicing
enhancer mutations that weaken exon 3 recognition produce variable
amounts of the 17.5-kD isoform, a result that could potentially explain
the clinical variability observed in IGHD II. Noncanonical splicing
mutations that disrupt splicing enhancers, such as those represented by
the 3 mutations discussed, demonstrate the importance of enhancer
elements in regulating alternative splicing to prevent human disease.

Mullis et al. (2005) studied a total of 57 subjects with IGHD type II
(173100) belonging to 19 families with different splice site as well as
missense mutations within the GH1 gene. The subjects presenting with a
splice site mutation within the first 2 bp of intervening sequence 3
(5-prime IVS +1/+2 bp; 139250.0009) leading to a skipping of exon 3 were
more likely to present in the follow-up with other pituitary hormone
deficiencies. In addition, although the patients with missense mutations
had been reported to be less affected, a number of patients presenting
with a missense GH form showed some pituitary hormone impairment. The
development of multiple hormonal deficiencies is not age-dependent, and
there is a clear variability in onset, severity, and progression, even
within the same families. Mullis et al. (2005) concluded that the
message of clinical importance from these studies is that the pituitary
endocrine status of all such patients should continue to be monitored
closely over the years because further hormonal deficiencies may evolve
with time.

Shariat et al. (2008) studied a 4-generation family segregating
autosomal dominant growth hormone deficiency and identified a
heterozygous missense mutation in the GH gene (EX3+1G-A; 139250.0025) in
affected individuals. Analysis of the effects of this variant as well as
G-T and G-C changes at the first nucleotide of exon 3 illustrated the
multiple mechanisms by which changes in sequence can cause disease:
splice site mutations, splicing enhancer function, messenger RNA decay,
missense mutations, and nonsense mutations. The authors noted that for
IGHD II, only exon skipping leads to production of the dominant-negative
isoform, with increasing skipping correlating with increasing disease
severity.

Horan et al. (2006) observed an association between 4 core promoter
haplotypes in the GH1 gene and increased risk for hypertension and
stroke in a study of 111 hypertensive patients and 155 stroke patients.
The association was more significant for females than males. Horan et
al. (2006) also observed an association between an isoform of the GHR
gene lacking exon 3 (GHRd3) and hypertension in female stroke patients.
The authors postulated a complex interaction between variants in the GH1
and GHR genes involving height.

Giordano et al. (2008) studied the contribution to IGHD of genetic
variations in the GH1 gene regulatory regions. The T allele of a G-to-T
polymorphism at position -57 (dbSNP rs2005172), within the vitamin
D-responsive element, showed a positive significant association when
comparing patients with normal (P = 0.006) or short stature (P = 0.0011)
controls. The genotype -57TT showed an odds ratio of 2.93 (1.44-5.99)
and 2.99 (1.42-6.31), respectively. Giordano et al. (2008) concluded
that the common -57G-T polymorphism contributes to IGHD susceptibility,
indicating that it may have a multifactorial etiology.

ANIMAL MODEL

By Southern analysis of DNA from mouse-rat somatic cell hybrids, Cooke
et al. (1986) found that the GH gene is on rat chromosome 10 and the PRL
gene (176760) is on rat chromosome 17. Thus, in the rat, as in man,
these genes are on different chromosomes even though they show an
evolutionary relationship.

Morgan et al. (1987) showed that retrovirus-mediated gene transfer can
be used to introduce a recombinant human GH1 gene into cultured human
keratinocytes. The transduced keratinocytes secreted biologically active
GH into the culture medium. When grafted as an epithelial sheet onto
athymic mice, these cultured keratinocytes reconstituted a
normal-appearing epidermis from which, however, human growth hormone
could be extracted. Transduced epidermal cells may be a general vehicle
for the delivery of gene products by means of grafting.

Smith et al. (1997) demonstrated a role of GH in retinal
neovascularization, which is the major cause of untreatable blindness.
They found that retinal neovascularization was inhibited in transgenic
mice expressing a GH antagonist gene and in normal mice given an
inhibitor of GH secretion. In these mice retinal neovascularization was
inhibited in inverse proportion to serum levels of GH and IGF1.
Inhibition was reversed with exogenous IGF1 administration. GH
inhibition did not diminish hypoxia-stimulated retinal vascular
endothelial growth factor (VEGF; 192240) or VEGF receptor (VEGFR;
191306) expression. Smith et al. (1997) suggested that systemic
inhibition of GH or IGF1, or both, may have therapeutic potential in
preventing some forms of retinopathy.

Growth hormones from primates are unique in that they are able to bind
with and activate both primate and nonprimate GHRs, whereas GHs from
nonprimates are ineffective in primates. Behncken et al. (1997)
investigated the basis of primate specificity of binding by the GHR.
They examined the interaction between GHR residues arg43 (primate) or
leu43 (nonprimate) and their complementary hormone residues asp171
(primate) and his170 (nonprimate). They found that the interaction
between arg43 and his170/171 is sufficient to explain virtually all of
the primate species specificity.

In mouse preadipocytes, Wolfrum et al. (2003) found that Foxa2 (600288)
inhibited adipocyte differentiation by activating transcription of
preadipocyte factor-1 (DLK1; 176290), and that expression of both Foxa2
and Dlk1 was enhanced by growth hormone in primary preadipocytes.
Wolfrum et al. (2003) suggested that the antiadipogenic activity of
growth hormone is mediated by Foxa2.

Using GH-deficient Socs2 (605117) -/- mice, Greenhalgh et al. (2005)
demonstrated that the Socs2 -/- phenotype is dependent upon the presence
of endogenous GH. Treatment with exogenous GH induced excessive growth
in terms of overall body weight, body and bone lengths, and the weight
of internal organs and tissues. Microarray analysis on liver RNA
extracts after exogenous GH administration revealed a heightened
response to GH. The conserved C-terminal SOCS-box motif was essential
for all inhibitory function. SOCS2 was found to bind 2 phosphorylated
tyrosines on the GH receptor, and mutation analysis of these amino acids
showed that both were essential for SOCS2 function. Greenhalgh et al.
(2005) concluded that SOCS2 is a negative regulator of GH signaling.

*FIELD* AV
.0001
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IA
GH1, 2-BP DEL, FS132TER

Igarashi et al. (1993) identified a Japanese patient with growth
retardation (IGHD IA; 262400) with a compound heterozygous pattern
consisting of total deletion of 1 GH1 gene and retention of a GH1 gene
of apparently normal size. DNA sequence analysis demonstrated deletion
of 2 bases of exon 3 of 1 GH1 allele of the mother and the patient. The
father carried a 6.7-kb deletion (139250.0003), present also on the
patient's paternal allele. The patient was a 13-year-old female, the
offspring of healthy, nonconsanguineous parents. GH therapy, begun at
the age of 9 years and 2 months, resulted in catch-up growth without
development of anti-GH antibodies. Deletion of the 2 bases in exon 3 was
predicted to introduce a termination codon after the codon of amino acid
residue 131 in exon 4.

.0002
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IA
GH1, TRP20TER

In a Turkish family with IGHD IA (262400), Cogan et al. (1993) found a
G-to-A transition converting codon 20 from tryptophan (TGG) to stop
(TAG) in the signal peptide of GH1. The mutation resulted in termination
of translation after residue 19 of the signal peptide and no production
of mature GH. Patients homozygous for the mutation had no detectable GH
and produced anti-GH antibodies in response to exogenous GH treatment.

.0003
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IA
GH1, 6.7-KB DEL

Duquesnoy et al. (1990) described the cases of 2 sibs with IGHD IA
(262400) who were found to be compound heterozygotes for deletion and
frameshift mutations of the GH1 gene. Southern blot analysis showed them
to be heterozygous for a 6.7-kb GH deletion; DNA sequence analysis
demonstrated deletion of a cytosine at position 371, resulting in a
frameshift within the signal peptide coding region which prevented the
synthesis of any mature GH protein (139250.0004). The patients presented
with severe growth failure, and after an initial growth response to
treatment with exogenous GH, developed high titers of anti-GH
antibodies.

Vnencak-Jones et al. (1990) and Igarashi et al. (1993) also described
patients with 6.7-kb deletions deleting 1 GH1 allele.

.0004
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IA
GH1, 1-BP DEL, 371C

See 139250.0003 and Duquesnoy et al. (1990).

.0005
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IB
GH1, IVS4, G-C, +1

In a consanguineous Saudi Arabian family with IGHD IB (612781), Cogan et
al. (1993) detected a G-to-C transversion of the first base of the donor
splice site of intron 4 as the basis of growth hormone deficiency. The
effect of this mutation on mRNA splicing was determined by transfecting
the mutant gene into cultured mammalian cells and DNA sequencing the
resulting GH cDNAs. Mutation was found to cause the activation of a
cryptic splice site 73 bases upstream of the exon 4 donor splice site.
The altered splicing resulted in loss of amino acids 103 to 126 of exon
4 and created a frameshift that altered the amino acids encoded by exon
5.

.0006
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IB
GH1, IVS4, G-T, +1

In another consanguineous Saudi family with IGHD IB (612781), Phillips
and Cogan (1994) found a mutation at the same nucleotide as that
described in 139250.0005. A G-to-T transversion in the first base of the
donor splice site of intron 4 had the same effect on splicing as the
G-to-C transversion. Patients homozygous for these 2 different defects
in 2 different families responded well to exogenous GH treatment and did
not develop anti-GH antibodies. Analogous splicing mutations occurred in
the beta-globin gene, causing milder forms of beta-thalassemia called
beta-plus-thalassemia.

.0007
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, T-C, +6

Phillips and Cogan (1994) demonstrated a T-to-C transition in the sixth
base of the donor splice site of intron 3 in a Turkish family with IGHD
II (173100). The mutant GH gene was transfected into cultured mammalian
cells, and the GH mRNA transcripts were analyzed by direct sequencing of
their corresponding cDNAs. The mutation was found to inactivate the
donor splice site of intron 3, resulting in alternative use of the donor
splice site of intron 2 in conjunction with the acceptor site of intron
3. This alternative splicing pattern deleted or skipped exon 3,
resulting in the loss of amino acids 32 to 71 from the corresponding
mature GH protein products. All affected members of the family were
heterozygous for the mutation and had low but measurable GH levels after
stimulation. All responded well to treatment with exogenous GH. The
mechanism of the dominant-negative effect is unknown; the mutant GH
allele may inactivate the normal GH allele by formation of GH dimers or
disruption of normal intracellular protein transport.

.0008
KOWARSKI SYNDROME
GH1, ARG77CYS

Takahashi et al. (1996) reported a patient with short stature in whom
the bioactivity of growth hormone was below the normal range (Kowarski
syndrome; 262650). The patient was heterozygous for a C-to-T transition
in the GH1 gene that converted codon 77 from CGC (arg) to TGC (cys)
(R77C). Isoelectric focusing of the proband's serum revealed the
presence of an abnormal growth hormone peak in addition to the normal
peak. Further studies demonstrated that the child's growth hormone not
only could not activate the growth hormone receptor but also inhibited
the action of wildtype growth hormone because of its greater affinity
for growth hormone-binding protein and growth hormone receptor.

Petkovic et al. (2007) identified heterozygosity for the R77C mutation
in a Syrian boy with short stature and partial GH insensitivity. His
mother and grandfather had the same mutation and showed partial GH
insensitivity with modest short stature. Functional analyses showed no
differences in the binding affinity or bioactivity between wildtype and
GH-R77C, nor were differences found in the extent of subcellular
localization within endoplasmic reticulum, Golgi, or secretory vesicles
between wildtype and GH-R77C. There was, however, a reduced capability
of GH-R477C to induce GHR/GHBP gene transcription rate when compared to
wildtype GH. Petkovic et al. (2007) concluded that reduced GHR/GHBP
expression might be a cause of the partial GH insensitivity with delay
in growth in this family.

.0009
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, G-A, +1

Cogan et al. (1995) reported a G-to-A transition of the first base of
the donor splice site of intron 3 (+1G to A) in IGHD II (173100)
subjects from 3 unrelated kindreds from Sweden, North America, and South
Africa. This transition created an NlaIII site that was used to
demonstrate that all affected individuals in all 3 families were
heterozygous for the mutation. In expression studies the transition was
found to destroy the GH intron 3 donor splice site, causing skipping of
exon 3 and loss of amino acids 32 to 71 of the mature GH peptide from
the mutant GH mRNA. Microsatellite analysis indicated that the mutation
arose independently in each family. In 1 family, the finding that
neither grandparent had the mutation suggests that it arose de novo.

Hayashi et al. (1999) identified 2 mutations in Japanese patients with
IGHD II, G-to-A transitions at the first (mutA) and fifth (mutE;
139250.0014) nucleotides of intron 3. GH1 mRNAs skipping exon 3 were
transcribed from both mutant genes. The authors studied the synthesis
and secretion of GH encoded by the mutant GH1 genes and tested whether
inhibition of wildtype GH secretion by mutant products could be
demonstrated in cultured cell lines. A metabolic labeling study in COS-1
cells revealed that a mutant GH with a reduced molecular mass was
synthesized from the mutant mRNAs and retained in the cells for at least
6 hours. On the other hand, the wildtype GH was rapidly secreted into
the medium. Coexpression of mutant and wildtype GH did not result in any
inhibition of wildtype GH secretion in COS-1 or HepG2 cells. However,
coexpression of mutant GH resulted in significant inhibition of wildtype
GH secretion in somatotroph-derived MtT/S cells as well as in
adrenocorticotroph-derived AtT-20 cells, without affecting cell
viability. Hayashi et al. (1999) concluded that the dominant-negative
effect of mutant GH on the secretion of wildtype GH is at least in part
responsible for the pathogenesis of IGHD II. They also suggested that
neuroendocrine cell type-specific mechanisms, including intracellular
storage of the secretory proteins, are involved in the inhibition.

Saitoh et al. (1999) described a 1-year-old Japanese boy and his father
with IGHD II, both of whom had a G-to-A transition of the first base of
the donor splice site of intron 3 of the GH1 gene. The mutation occurred
de novo in the father. No unaffected family members had the mutation.

.0010
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, G-C, +1

Binder and Ranke (1995) reported a G-to-C transversion of the first base
of the donor splice site of intron 3 (+1G to C) in a sporadic case of
IGHD II (173100) in a German patient. This mutation was dominant
negative and arose de novo. They also reported RT-PCR data suggesting
overexpression of the mutant GH1 allele and speculated that the
dominant-negative effect might occur because of this imbalance in
expression of the mutant and normal alleles. However, Binder et al.
(1996) found equal quantities of transcripts in studies using an RNA
protection assay to determine the relative expression of the intron 3 +1
G-to-C mutant and normal GH1 alleles. In normal pituitary, they found 3
GH1 mRNA species with the variant lacking exon 3, which comprised
approximately 5% of the total GH1 mRNA. In contrast, lymphoblasts from
the proband, who was heterozygous for the transition at intron 1,
contained equal amounts of mRNA with or without exon 3. Furthermore,
secreted GH1, measured by enzyme-linked immunosorbent assay, was present
in equal concentrations in media from normal and mutant cells. Thus, GH1
mRNA lacking exon 3 was expressed in proportion to the dosage of the
mutant gene, and dominant-negative effects on GH1 secretion were not
seen in lymphoblasts. Their findings are compatible with a
dominant-negative mechanism involving interaction between normal and
mutant proteins in secretory vesicles of somatotropes, as suggested by
Cogan et al. (1995).

.0011
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, G-A, +28

Cogan et al. (1997) reported 2 intron 3 mutations in 2 unrelated
kindreds with autosomal dominant growth hormone deficiency (173100).
These mutations perturbed splicing and caused exon 3 skipping; however,
the mutations did not occur within the intron 3 branch consensus sites
or the 5-prime or 3-prime splice sites. Instead, these mutations
deranged sequences homologous to XGGG repeats that regulate alternative
mRNA splicing in other genes. Eukaryotic pre-mRNA splicing is regulated
by consensus sequences at the intron boundaries and branch site.
Sirand-Pugnet et al. (1995) demonstrated the importance of an additional
intronic sequence, an (A/U)GGG repeat in chicken beta-tropomyocin that
is a binding site for a protein required for spliceosome assembly. The
mutations found by Cogan et al. (1997) in the third intron of the GH
gene affected a putative, homologous consensus sequence and disturbed
splicing. The first mutation was a G-to-A transition base 28 of intron 3
and the second deleted 18 bp (del+28-45; 139250.0012) of intron 3 of the
human GH gene. The findings suggested that XGGG repeats may regulate
alternative splicing in the human growth hormone gene and that mutations
of these repeats cause growth hormone deficiency by perturbing
alternative splicing.

.0012
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, 18-BP DEL, +28-45

See 139250.0011 and Cogan et al. (1997). McCarthy and Phillips (1998)
presented evidence that this mutation and the G-to-A transition at
position +28 of IVS3 (139250.0011) disturb an intron splice enhancer
(ISE) that is critical for the proper splicing of transcripts of the GH1
gene.

.0013
KOWARSKI SYNDROME
GH1, ASP112GLY

In a child presenting with short stature, Takahashi et al. (1997)
demonstrated a biologically inactive growth hormone (262650) resulting
from a heterozygous single-base substitution (A to G) in exon 4 of the
GH1 gene. This change resulted in an asp112-to-gly amino acid
substitution. At age 3 years, the girl's height was 3.6 standard
deviations below the mean for age and sex. Bone age was delayed by 1.5
years. She had a prominent forehead and a hypoplastic nasal bridge with
normal body proportions. She showed lack of growth hormone action
despite high immunoassayable GH levels in serum and marked catch-up
growth to exogenous GH administration. Results of other studies were
compatible with the production of a bioinactive GH, which prevented
dimerization of the growth hormone receptor, a crucial step in GH signal
transduction.

.0014
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, G-A, +5

In a father and his 2 daughters with autosomal dominant isolated growth
hormone deficiency (173100), Kamijo et al. (1999) found a G-to-A
transition at the fifth base of intron 3 of the GH1 gene. The paternal
grandparents did not show the mutation, indicating that it was a new
mutation in the case of the father. Kamijo et al. (1999) studied 2 other
(sporadic) cases of IGHD II. It is curious and undoubtedly significant
that so many mutations have been found in the splice donor site of IVS3
in cases of isolated growth hormone deficiency type II.

See also 139250.0009 and Hayashi et al. (1999).

.0015
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IB
GH1, IVS4, G-C, +5

Abdul-Latif et al. (2000) identified an extended, highly inbred Bedouin
kindred with IGHD that clinically fulfilled the criteria for type IB
(612781). Molecular studies demonstrated a novel mutation in the GH1
gene: a G-to-C transversion of the fifth base of intron 4, which
appeared to cause GH deficiency through the use of a cryptic splice site
and, consequently, formation of a different protein. Clinical
observations suggested that apparently healthy, non-GH-deficient
individuals in this family were of relatively short stature. Leiberman
et al. (2000) correlated height measurements of potential heterozygotes
with carrier status for the newly identified mutation. Indeed, they
found that carriers of the mutant allele in heterozygous state had
significantly shorter stature than normal homozygotes. They found that
11 of 33 (33%) of heterozygotes, but only 1 of 17 (5.9%) of normal
homozygotes had their height at 2 or more standard deviations below the
mean. Overall, 48.5% of studied heterozygotes were found to be of
appreciably short stature with height at or lower than the 5th centile,
whereas only 5.9% of the normal homozygotes fell into that range (P less
than 0.004).

.0016
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, EX3, A-G, +5

Moseley et al. (2002) reported an A-to-G transition of the fifth base of
exon 3 (exon 3+5A-G) in affected individuals from an IGHD II (173100)
family. This mutation disrupts a (GAA)n exon splice enhancer (ESE) motif
immediately following the weak IVS2 3-prime splice site. The mutation
also destroys a MboII site used to demonstrate heterozygosity in all
affected family members. To determine the effect of ESE mutations on GH
mRNA processing, GH3 cells were transfected with expression constructs
containing the normal ESE, +5A-G, or other ESE mutations, and cDNAs
derived from the resulting GH mRNAs were sequenced. All ESE mutations
studied reduced activation of the IVS2 3-prime splice site and caused
either partial exon 3 skipping, due to activation of an exon 3 +45
cryptic 3-prime splice site, or complete exon 3 skipping. Partial or
complete exon 3 skipping led to loss of the codons for amino acids 32-46
or 32-71, respectively, of the mature GH protein. They concluded that
the exon 3 +5A-G mutation causes IGHD II because it perturbs an ESE
required for GH splicing.

.0017
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, EX3DEL

In affected members of a Japanese family with autosomal dominant
isolated growth hormone deficiency (173100), Takahashi et al. (2002)
found a heterozygous G-to-T transversion at the first 5-prime site
nucleotide of exon 3. Analysis of the GH1 cDNA, synthesized from
lymphoblasts of the patients, revealed an abnormally short transcript as
well as a normal-sized transcript. Direct sequencing of the abnormal
transcript showed that it completely lacked exon 3. In IGHD II, several
heterozygous mutations have been reported at the donor splice site in
intron 3 of the GH1 gene or inside intron 3 (e.g., 139250.0007,
139250.0009, 139250.0010), which cause aberrant growth hormone mRNA
splicing, resulting in the deletion of exon 3. Loss of exon 3 results in
lack of amino acid residues 32 to 71 in the mature growth hormone
protein. This mutant growth hormone exerts a dominant-negative effect on
the secretion of mature normal growth hormone protein. Thus, in the
family reported by Takahashi et al. (2002), the G-to-T transversion at
the first nucleotide resulted in deletion of exon 3 and caused growth
hormone deficiency. Takahashi et al. (2002) suggested that the first
nucleotide of exon 3 is critical for the splicing of GH1 mRNA.

.0018
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS2, A-T, -2

Fofanova et al. (2003) studied mutations in 28 children from 26 families
with total IGHD living in Russia. They found 3 dominant-negative
mutations causing IGHD type II (173100): 1) an A-to-T transversion of
the second base of the 3-prime acceptor splice site of intron 2 (IVS2
-2A-T); 2) a T-to-C transition of the second base of the 5-prime donor
splice site of intron 3 (IVS3 +2T-C; 139250.0019); 3) and a G-to-A
transition of the first base of the 5-prime donor splice site of intron
3 (IVS3 +1G-A; 139250.0009). The IVS -2A-T mutation was the first
identified mutation in intron 2 of GH1. The authors concluded that the
5-prime donor splice site of intron 3 of GH1 is a mutation hotspot, and
the IVS3 +1G-A mutation can be considered to be a common molecular
defect in IGHD II in Russian patients.

.0019
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, T-C, +2

See 139250.0018 and Fofanova et al. (2003).

.0020
REMOVED FROM DATABASE
.0021
KOWARSKI SYNDROME
GH1, CYS53SER

In a Serbian patient with short stature and bioinactive growth hormone
(Kowarski syndrome; 262650) Besson et al. (2005) detected a homozygous
cys53-to-ser (C53S) mutation in the GH1 gene. The mutation arose from a
G-to-C transversion at nucleotide position 705 (G705C). The
phenotypically normal first-cousin parents were heterozygous for the
mutation. This mutation was predicted to lead to the absence of the
disulfide bridge cys53 to cys165. In GH receptor (GHR; 600946) binding
and Jak2 (147796)/Stat5 (601511) activation experiments, Besson et al.
(2005) observed that at physiologic concentrations (3-50 ng/ml), both
GHR binding and Jak2/Stat5 signaling pathway activation were
significantly reduced in the mutant GH-C53S, compared with wildtype.
Higher concentrations (400 ng/ml) were required for this mutant to
elicit responses similar to wildtype GH. Besson et al. (2005) concluded
that the absence of the disulfide bridge cys53 to cys165 affects the
binding affinity of GH for the GHR and subsequently the potency of GH to
activate the Jak2/Stat5 signaling pathway.

.0022
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, IVS3, 22-BP DEL

In a 2-year-old child and her mother with severe growth failure at
diagnosis (IGHD II; 173100) (-5.8 and -6.9 SD score, respectively),
Vivenza et al. (2006) identified a heterozygous 22-bp deletion in IVS3
of the GH1 gene, designated IVS3del+56-77, removing the putative branch
point sequence (BPS). Both patients showed 2 principal mRNA species
approximately in equal amount, i.e., a full-length species encoded by
the normal allele, and an aberrant splicing product with the skipping of
exon 3 encoded by the mutant allele. Their clinical phenotype correlated
with that observed in other IGHD II patients harboring splice site
mutations.

.0023
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, ARG183HIS

In a large kindred with dominant growth hormone deficiency (IGHD II;
173100) Gertner et al. (1998) detected a heterozygous G-to-A transition
at nucleotide 6664 in exon 5 of the GH1 gene, resulting in an
arg183-to-his substitution (R183H).

Hess et al. (2007) studied the phenotype-genotype correlation of
subjects with IGHD II caused by a R183H mutation in the GH1 gene in 34
affected members of 2 large families. Twenty-four of the 52 members from
family 1 and 10 of the 14 from family 2 carried the same mutation in a
heterozygous state. The affected subjects in family 1 were significantly
shorter (-2.6 vs -0.1 standard deviation score (SDS), p less than
0.0001) and had significantly lower IGF1 (147440) serum levels (-1.9 vs
-0.5 SDS, p less than 0.0001), compared with family members with a
normal genotype. The affected adults exhibited great variability in
their stature, ranging from -4.5 to -1.0 SD (mean -2.8 SDS), with 5
members being of normal height (greater than -2 SDS). Twelve children
were diagnosed with IGHD. Two affected children had normal peak GH
levels, although 1 of these subsequently demonstrated GH insufficiency.
The affected children from both families exhibited large variability in
their height, growth velocity, delay in bone age, age at diagnosis, peak
GH response, and IGF1 levels. Hess et al. (2007) concluded that these
detailed phenotypic analyses show the variable expressivity of patients
bearing the R183H mutation, reflecting the spectrum of GH deficiency in
affected patients, even within families, and the presence of additional
genes modifying height determination.

.0024
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, EX3, A-C, +2

In 2 independent pedigrees with IGHD II (173100), Petkovic et al. (2007)
identified a heterozygous splice enhancer mutation in exon 3, exon
3+2A-C, that encodes a glutamic acid-to-alanine change at position 32 in
the GH protein (E32A) and leads to missplicing at the mRNA level,
producing large amounts of the 17.5-kD GH isoform. Mouse pituitary cells
coexpressing both wildtype and mutant GH-E32A protein presented a
significant reduction in cell proliferation as well as GH production
after forskolin stimulation when compared with the cells expressing
wildtype GH. These results were complemented with confocal microscopy
analysis, which revealed a significant reduction of the GH-E32A-derived
isoform colocalized with secretory granules, compared with wildtype GH.
Petkovic et al. (2007) concluded that the GH-E32A mutation, which
occurred in the exon splice enhancer (ESE1), weakens recognition of exon
3 directly, and therefore increases production of the exon 3-skipped
17.5-kD GH isoform in relation to the 22-kD, wildtype GH isoform.

.0025
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
GH1, EX3, G-A, +1

In affected members of a 4-generation family segregating autosomal
dominant growth hormone deficiency (173100), Shariat et al. (2008)
identified heterozygosity for a +1G-A transition in exon 3 of the GH
gene. The change was predicted to encode a glu32-to-lys (E32K)
substitution; however, transfection studies showed that when the mutant
was expressed, there was an approximately 6-fold increase in skipping of
exon 3 compared to wildtype (39% and 6%, respectively). Functional
analysis revealed that the variant weakens the 3-prime splice site and
simultaneously disrupts a splicing enhancer located within the first 7
bases of exon 3.

*FIELD* SA
Chakravarti et al. (1984); Dayhoff (1972); Fiddes et al. (1979);
Martial et al. (1979); Paladini et al. (1979)
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77. Vnencak-Jones, C. L.; Phillips, J. A., III; Chen, E. Y.; Seeburg,
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79. Wolfrum, C.; Shih, D. Q.; Kuwajima, S.; Norris, A. W.; Kahn, C.
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*FIELD* CN
Anne M. Stumpf - reorganized: 6/1/2009
John A. Phillips, III - updated: 4/23/2009
Marla J. F. O'Neill - updated: 3/30/2009
John A. Phillips, III - updated: 9/17/2008
John A. Phillips, III - updated: 5/6/2008
Patricia A. Hartz - updated: 8/24/2007
John A. Phillips, III - updated: 5/14/2007
John A. Phillips, III - updated: 4/6/2007
Matthew B. Gross - updated: 9/8/2006
Patricia A. Hartz - updated: 9/1/2006
John A. Phillips, III - updated: 8/21/2006
John A. Phillips, III - updated: 7/24/2006
John A. Phillips, III - updated: 7/21/2006
Cassandra L. Kniffin - updated: 7/18/2006
John A. Phillips, III - updated: 4/25/2006
John A. Phillips, III - updated: 10/27/2005
John A. Phillips, III - updated: 7/14/2005
Marla J. F. O'Neill - updated: 4/12/2005
John A. Phillips, III - updated: 3/29/2005
Marla J. F. O'Neill - updated: 2/18/2005
John A. Phillips, III - updated: 10/18/2004
John A. Phillips, III - updated: 10/15/2004
John A. Phillips, III - updated: 8/20/2003
Victor A. McKusick - updated: 7/9/2003
John A. Phillips, III - updated: 6/13/2003
Victor A. McKusick - updated: 5/5/2003
John A. Phillips, III - updated: 4/8/2003
John A. Phillips, III - updated: 1/10/2003
Stylianos E. Antonarakis - updated: 9/23/2002
Victor A. McKusick - updated: 8/12/2002
John A. Phillips, III - updated: 8/7/2002
John A. Phillips, III - updated: 7/29/2002
John A. Phillips, III - updated: 6/11/2002
John A. Phillips, III - updated: 2/20/2002
John A. Phillips, III - updated: 8/9/2001
John A. Phillips, III - updated: 5/10/2001
John A. Phillips, III - updated: 11/13/2000
Armand Bottani - updated: 3/14/2000
John A. Phillips, III - updated: 3/6/2000
John A. Phillips, III - updated: 3/3/2000
Victor A. McKusick - updated: 2/24/2000
John A. Phillips, III - updated: 2/23/2000
Victor A. McKusick - updated: 12/7/1999
John A. Phillips, III - updated: 11/9/1999
John A. Phillips, III - reorganized: 11/9/1999
John A. Phillips, III - updated: 10/7/1999
John A. Phillips, III - updated: 10/1/1999
John A. Phillips, III - updated: 2/9/1999
John A. Phillips, III - updated: 1/7/1999
Victor A. McKusick - updated: 9/17/1998
John A. Phillips, III - updated: 5/12/1998
John A. Phillips, III - updated: 3/17/1998
John A. Phillips, III - updated: 12/25/1997
Victor A. McKusick - updated: 9/30/1997
Victor A. McKusick - updated: 6/23/1997
Victor A. McKusick - updated: 6/12/1997
John A. Phillips, III - updated: 5/29/1997
John A. Phillips, III - updated: 4/29/1997
John A. Phillips, III - updated: 4/8/1997
John A. Phillips, III - updated: 4/4/1997

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

*FIELD* ED
carol: 03/26/2013
joanna: 8/25/2010
terry: 4/30/2010
carol: 12/24/2009
alopez: 6/5/2009
alopez: 6/2/2009
alopez: 6/1/2009
alopez: 5/8/2009
alopez: 4/23/2009
carol: 3/31/2009
terry: 3/30/2009
alopez: 9/17/2008
carol: 5/6/2008
mgross: 8/29/2007
terry: 8/24/2007
alopez: 5/14/2007
carol: 5/14/2007
carol: 4/6/2007
carol: 10/31/2006
terry: 10/18/2006
mgross: 9/8/2006
mgross: 9/7/2006
terry: 9/1/2006
alopez: 8/21/2006
alopez: 7/24/2006
alopez: 7/21/2006
carol: 7/21/2006
ckniffin: 7/18/2006
carol: 5/23/2006
ckniffin: 5/12/2006
alopez: 4/25/2006
alopez: 1/6/2006
alopez: 10/27/2005
terry: 8/3/2005
alopez: 7/14/2005
tkritzer: 4/12/2005
alopez: 3/29/2005
wwang: 2/22/2005
terry: 2/18/2005
alopez: 10/18/2004
alopez: 10/15/2004
joanna: 3/17/2004
alopez: 8/20/2003
terry: 7/28/2003
carol: 7/18/2003
cwells: 7/17/2003
terry: 7/9/2003
alopez: 6/13/2003
tkritzer: 5/6/2003
tkritzer: 5/5/2003
tkritzer: 4/22/2003
tkritzer: 4/21/2003
terry: 4/8/2003
alopez: 1/10/2003
mgross: 9/23/2002
tkritzer: 8/15/2002
tkritzer: 8/14/2002
terry: 8/12/2002
cwells: 8/7/2002
alopez: 7/31/2002
tkritzer: 7/29/2002
alopez: 6/11/2002
alopez: 2/20/2002
alopez: 8/9/2001
mgross: 5/11/2001
terry: 5/10/2001
alopez: 3/26/2001
alopez: 3/23/2001
terry: 11/13/2000
carol: 10/16/2000
mgross: 10/12/2000
terry: 10/2/2000
carol: 3/14/2000
terry: 3/14/2000
mgross: 3/6/2000
mgross: 3/3/2000
terry: 2/24/2000
mgross: 2/23/2000
carol: 2/22/2000
mcapotos: 2/21/2000
yemi: 2/18/2000
carol: 12/7/1999
terry: 12/7/1999
mgross: 11/24/1999
carol: 11/9/1999
mgross: 10/7/1999
mgross: 10/1/1999
alopez: 2/10/1999
mgross: 2/9/1999
alopez: 1/7/1999
carol: 9/21/1998
terry: 9/17/1998
dkim: 9/11/1998
terry: 5/29/1998
alopez: 5/12/1998
psherman: 3/17/1998
alopez: 1/23/1998
mark: 1/5/1998
terry: 12/3/1997
alopez: 10/30/1997
alopez: 10/28/1997
dholmes: 10/1/1997
terry: 9/30/1997
dholmes: 9/29/1997
jenny: 9/9/1997
terry: 7/10/1997
terry: 7/7/1997
joanna: 7/7/1997
terry: 7/7/1997
mark: 7/3/1997
jenny: 6/23/1997
terry: 6/19/1997
mark: 6/12/1997
terry: 6/10/1997
jenny: 6/5/1997
jenny: 5/29/1997
jenny: 5/14/1997
jenny: 4/29/1997
jenny: 4/8/1997
jenny: 4/4/1997
mark: 1/3/1997
carol: 10/7/1996
joanna: 4/19/1996
mark: 3/3/1996
terry: 2/28/1996
carol: 10/10/1994
davew: 8/5/1994
pfoster: 4/22/1994
warfield: 4/21/1994
carol: 8/16/1993
carol: 10/8/1992

MIM 173100
*RECORD*
*FIELD* NO
173100
*FIELD* TI
#173100 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II; IGHD2
;;IGHD II;;
GROWTH HORMONE DEFICIENCY, ISOLATED, AUTOSOMAL DOMINANT;;
read morePITUITARY DWARFISM DUE TO ISOLATED GROWTH HORMONE DEFICIENCY, AUTOSOMAL
DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder in some instances is due to dominant-negative mutations in the
gene for growth hormone (GH1; 139250).

See entry 262400 for a summary of the different types of IGHD.

CLINICAL FEATURES

Phillips and Cogan (1994) referred to the autosomal dominant form of
isolated growth hormone deficiency as IGHD II. They pointed out that the
clinical severity varies considerably between kindreds and that affected
patients respond well to GH treatment without the development of
antibodies.

Merimee et al. (1969) and Tyson (1971) observed a family with affected
persons in 4 generations. Dominant inheritance seems possible in the
case of those patients who have isolated growth hormone deficiency but
do not have insulinopenia as is found in most such cases. Unlike type I
isolated growth hormone deficiency (see 262400), a recessive, insulin
responses to glucose and to arginine are usually greater than normal.

Tani et al. (1987) described 5 cases of isolated growth hormone
deficiency in 3 successive generations. The 3 patients who were so
studied had no abnormality of their growth hormone genes on Southern
blot analysis. CT scans showed empty sella. Growth hormone was
detectable in the plasma by radioimmunoassay but levels were clearly
lower than in normal children, and significant increases were not
obtained with the insulin tolerance test or with the arginine-TRH-LHRH
triple loading test. Repeated injections of growth hormone releasing
factor (GHRF; 139190) had no effect.

In a high proportion of patients with isolated growth hormone deficiency
and multiple pituitary hormone deficiency, characteristic radiologic
findings include (1) a small or absent anterior pituitary gland, (2) a
small or truncated infundibulum, and (3) an ectopic posterior pituitary
hyperintensity located at the base of the hypothalamus or inferior end
of the truncated pituitary stalk. These findings have been attributed to
a developmental defect, trauma, or ischemia at birth. Hamilton et al.
(1998) described isolated growth deficiency in mother and son with
characteristic findings on magnetic resonance imaging. The son also had
a Chiari type I malformation and medial deviation of the carotid
arteries secondary to a narrow skull base. Testing failed to identify a
mutation in either the PIT1 gene (173110) or the growth hormone gene
cluster. The authors interpreted the case as one of autosomal dominant
defect in early development, lending support to the hypothesis that
dysgenesis, rather than birth trauma, may cause a small anterior
pituitary and ectopic posterior pituitary.

INHERITANCE

Numerous reports support autosomal dominant inheritance of a form of
isolated growth hormone deficiency. Persons who appear to have had
isolated growth hormone deficiency have been observed in successive
generations. Selle (1920) is said (Warkany et al., 1961) to have
described a kindred in which 'primordial dwarfism' was transmitted
through 3 generations, 10 persons being affected. Multigeneration
kindreds were included in the review of Rischbieth and Barrington
(1912).

Dominant inheritance is a possible explanation for the findings in a
family in which 2 midget parents with demonstrated isolated growth
hormone deficiency have 3 offspring, 2 dwarfed and 1 of normal stature
(Rimoin et al., 1966). The father's condition may have been the result
of new dominant mutation and he may have transmitted the condition to
the 2 affected offspring.

Sheikholislam and Stempfel (1972) reported isolated GH deficiency in a
man and 3 daughters and a son. Three other children were unaffected.
Pedigree patterns consistent with dominant inheritance were reported
also by Butenandt and Knorr (1970) and by Sadeghi-Nejad and Senior
(1974). (The latter report concerned association with Rieger syndrome
(180500).)

Poskitt and Rayner (1974) described 2 families, each with a father and
son affected by isolated GH deficiency.

Rona and Tanner (1977) described an affected parent and 2 children with
no known consanguinity.

Van Gelderen and van der Hoog (1981) reported isolated GH deficiency in
2 girls and their mother. Two maternal uncles, 135 cm tall, and the
maternal grandmother were presumably affected also. The mother's height
was 133 cm.

CYTOGENETICS

Schober et al. (1995) described growth hormone deficiency and empty
sella in a 6-year-old girl with 18p monosomy. Good response to growth
hormone treatment was observed. A rudimentary pituitary stalk was
considered to underlie the hormone deficiency. The association of growth
hormone deficiency and pituitary hypoplasia in 18p monosomy was also
found by Artman et al. (1992). In addition to short stature, the
craniofacial features of 18p monosomy may resemble those of Turner
syndrome: round face, hypertelorism, flattened nasal bridge, and wide
mouth with small upper lip. Various degrees of mental retardation have
been observed.

MOLECULAR GENETICS

In affected members of a Turkish family segregating IGHD II, Phillips
and Cogan (1994) identified a splice site mutation in the GH1 gene
(IVS3+6T-C; 139250.0007).

Mullis et al. (2005) studied a total of 57 subjects with IGHD II
belonging to 19 families with different splice site as well as missense
mutations within the GH1 gene. The subjects presenting with the splice
site mutation within the first 2 bp of intervening sequence 3
(139250.0009) leading to a skipping of exon 3 were more likely to
present in the follow-up with other pituitary hormone deficiencies. In
addition, although the patients with missense mutations had been
reported to be less affected, a number of patients presenting with a
missense GH form showed some pituitary hormone impairment. The
development of multiple hormonal deficiencies is not age-dependent, and
there is a clear variability in onset, severity, and progression, even
within the same families. Mullis et al. (2005) concluded that the
message of clinical importance from these studies is that the pituitary
endocrine status of all such patients should continue to be monitored
closely over the years because further hormonal deficiencies may evolve
with time.

Shariat et al. (2008) studied a 4-generation family with IGHD II and
identified a heterozygous missense mutation in the GH1 gene (EX3+1G-A;
139250.0025) in affected individuals. Functional analysis of this
variant as well as G-T and G-C changes at the first nucleotide of exon 3
illustrated the multiple mechanisms by which changes in sequence can
cause disease: splice site mutations, splicing enhancer function,
messenger RNA decay, missense mutations, and nonsense mutations. The
authors noted that for IGHD II, only exon skipping leads to production
of the dominant-negative isoform, with increasing skipping correlating
with increasing disease severity.

*FIELD* SA
Gertner et al. (1978); Merimee (1972)
*FIELD* RF
1. Artman, H. G.; Morris, C. A.; Stock, A. D.: 18p- syndrome and
hypopituitarism. J. Med. Genet. 29: 671-672, 1992.

2. Butenandt, O.; Knorr, D.: Familiaerer Hypopituitarismus. Mschr.
Kinderheilk. 118: 470-473, 1970.

3. Gertner, J. M.; Genel, M.; Arulanantham, K.; Crawford, J. D.:
Dominant inheritance of isolated growth hormone deficiency transmitted
through an individual of normal stature. (Abstract) Pediat. Res. 12:
451, 1978.

4. Hamilton, J.; Chitayat, D.; Blaser, S.; Cohen, L. E.; Phillips,
J. A., III; Daneman, D.: Familial growth hormone deficiency associated
with MRI abnormalities. Am. J. Med. Genet. 80: 128-132, 1998.

5. Merimee, T. J.: Studies in HGH-deficient dwarfs: the type II anomaly. Johns
Hopkins Med. J. 131: 165-171, 1972.

6. Merimee, T. J.; Hall, J. G.; Rimoin, D. L.; McKusick, V. A.: A
metabolic and hormonal basis for classifying ateliotic dwarfs. Lancet 293:
963-965, 1969. Note: Originally Volume I.

7. Mullis, P. E.; Robinson, I. C. A. F.; Salemi, S.; Eble, A.; Besson,
A.; Vuissoz, J.-M.; Deladoey, J.; Simon, D.; Czernichow, P.; Binder,
G.: Isolated autosomal dominant growth hormone deficiency: an evolving
pituitary deficit? A multicenter follow-up study. J. Clin. Endocr.
Metab. 90: 2089-2096, 2005.

8. Phillips, J. A., III; Cogan, J. D.: Genetic basis of endocrine
disease 6: molecular basis of familial human growth hormone deficiency. J.
Clin. Endocr. 78: 11-16, 1994.

9. Poskitt, E. M. E.; Rayner, P. H. W.: Isolated growth hormone deficiency:
two families with autosomal dominant inheritance. Arch. Dis. Child. 49:
55-59, 1974.

10. Rimoin, D. L.; Merimee, T. J.; McKusick, V. A.: Growth hormone
deficiency in man: an isolated recessively inherited defect. Science 152:
1635-1637, 1966.

11. Rischbieth, H.; Barrington, A.: Dwarfism.In: Pearson, K.: Treasury
of Human Inheritance. Vol. 1, Part 7 London: Dulau and Co. (pub.)
Sec. 15A: 1912. P. 355 only.

12. Rona, R. J.; Tanner, J. M.: Aetiology of idiopathic growth hormone
deficiency in England and Wales. Arch. Dis. Child. 52: 197-208,
1977.

13. Sadeghi-Nejad, A.; Senior, B.: Autosomal dominant transmission
of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's
syndrome). J. Pediat. 85: 644-648, 1974.

14. Schober, E.; Scheibenreiter, S.; Frisch, H.: 18p monosomy with
GH-deficiency and empty sella: good response to GH-treatment. Clin.
Genet. 47: 254-256, 1995.

15. Selle, G.: Ueber Vererbung des echten Zwergwuchses. Inaug.
Dissert.: Univ. of Jena (pub.) 1920.

16. Shariat, N.; Holladay, C. D.; Cleary, R. K.; Phillips, J. A.,
III; Patton, J. G.: Isolated growth hormone deficiency type II caused
by a point mutation that alters both splice site strength and splicing
enhancer function. Clin. Genet. 74: 539-545, 2008.

17. Sheikholislam, B. M.; Stempfel, R. S., Jr.: Hereditary isolated
somatotropin deficiency: effects of human growth hormone administration. Pediatrics 49:
362-374, 1972.

18. Tani, N.; Kaneko, K.; Momotsu, T.; Takasawa, T.; Ito, S.; Shibata,
A.; Miki, T.; Tateishi, H.; Kumahara, Y.: A family case with autosomal-dominantly
inherited pituitary dwarfism. Tohoku J. Exp. Med. 152: 319-324,
1987.

19. Tyson, J. E. A.: Isolated growth hormone deficiency, type I (sexual
ateleiosis, type I). Birth Defects Orig. Art. Ser. VII(6): 251-252,
1971.

20. van Gelderen, H. H.; van der Hoog, C. E.: Familial isolated growth
hormone deficiency. Clin. Genet. 20: 173-175, 1981.

21. Warkany, J.; Monroe, B. B.; Sutherland, B. S.: Intrauterine growth
retardation. Am. J. Dis. Child. 102: 249-279, 1961.

*FIELD* CS

Growth:
Dwarfism

Endocrine:
Isolated growth hormone deficiency

Lab:
Insulin responses to glucose and to arginine usually greater than
normal;
No insulinopenia

Inheritance:
Autosomal dominant form

*FIELD* CN
Marla J. F. O'Neill - updated: 3/30/2009
John A. Phillips, III - updated: 7/21/2006
Victor A. McKusick - updated: 12/4/1998
John A. Phillips, III - updated: 3/5/1996

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

*FIELD* ED
alopez: 06/05/2009
alopez: 6/2/2009
carol: 3/31/2009
terry: 3/30/2009
terry: 2/6/2009
alopez: 7/21/2006
carol: 11/9/1999
carol: 12/9/1998
terry: 12/4/1998
dkim: 9/11/1998
alopez: 6/2/1997
jenny: 4/1/1997
mark: 2/25/1997
terry: 2/24/1997
carol: 10/7/1996
joanna: 4/19/1996
joanna: 3/5/1996
mark: 7/12/1995
mimadm: 1/14/1995
pfoster: 4/5/1994
warfield: 3/29/1994
carol: 3/24/1994
supermim: 3/16/1992

MIM 262400
*RECORD*
*FIELD* NO
262400
*FIELD* TI
#262400 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IA; IGHD1A
;;IGHD IA;;
GROWTH HORMONE DEFICIENCY, ISOLATED, AUTOSOMAL RECESSIVE;;
read moreILLIG-TYPE GROWTH HORMONE DEFICIENCY;;
PRIMORDIAL DWARFISM;;
SEXUAL ATELEIOTIC DWARFISM;;
PITUITARY DWARFISM I
*FIELD* TX
A number sign (#) is used with this entry because isolated growth
hormone deficiency (IGHD) type IA is caused by mutation in the growth
hormone gene (GH1; 139250).

INHERITANCE

Phillips and Cogan (1994) reported 4 forms of IGHD. IGHD IA and IB
(612781) are both inherited in an autosomal recessive manner. Both IGHD
IA and IB can be caused by mutations in the GH1 gene; IGHD IB can also
be caused by mutation in the GHRHR gene (139191). In IGHD IA, deletions,
frameshifts, and nonsense mutations lead to absent GH with severe
dwarfism; patients often develop anti-GH antibodies when given exogenous
growth hormone. In IGHD IB caused by mutant GH1, splice site mutations
are responsible for low but detectable levels of GH. Dwarfism is less
severe than in IGHD IA, and patients usually respond well to exogenous
GH. IGHD II (173100) has an autosomal dominant mode of inheritance and
is caused by splice site or missense mutations in the GH1 gene that have
dominant-negative effects. The clinical severity of IGHD II is variable
between kindreds. Patients usually respond well to exogenous GH. IGHD
III (307200) is an X-linked disorder that is often associated with
hypogammaglobulinemia, suggesting a contiguous gene syndrome. Mutations
in the BTK gene (300300) have been implicated in this disorder.

CLINICAL FEATURES

Proportionate short stature, accompanied by a decreased growth velocity,
is the most important clinical finding to support the diagnosis of
growth hormone deficiency (GHD) (Phillips, 1995; Rimoin and Phillips,
1997). Delayed bone maturation and the absence of bone dysplasias and
chronic diseases are additional criteria. Adequate function of the GH
pathway is needed throughout childhood to maintain normal growth. While
most newborns with GHD have normal lengths and weights, those with
complete absence of GH due to GH gene deletions can have birth lengths
that are shorter than expected for their birth weights. The low linear
growth of infants with congenital GHD becomes progressively retarded
with age and some may have micropenis or fasting hypoglycemia. In those
with IGHD, skeletal maturation is usually delayed in proportion to
height retardation. Other frequent findings include truncal obesity, a
facial appearance that is younger than that expected for their
chronologic age, delayed secondary dentition, and a high-pitched voice.
Puberty may be delayed until the late teens, but normal fertility
usually occurs. The skin of adults with GHD appears fine and wrinkled,
similar to that seen in premature aging. Concomitant or combined
deficiencies of other pituitary hormones (luteinizing hormone (LH,
152780); follicle-stimulating hormone (FSH, 136530); thyroid-stimulating
hormone (TSH, 188540); and/or ACTH, 202200) in addition to GH is called
combined pituitary hormone deficiency (CPHD; see 173110 and 601538) or
panhypopituitary dwarfism. The combination of GH and these additional
hormone deficiencies often causes more severe retardation of growth and
skeletal maturation and spontaneous puberty may not occur.

Mullis (2007) stated that IGHD IA was first described by Illig (1970) in
3 Swiss children with unusually severe growth impairment and apparent
deficiency of growth hormone.

Illig and Prader (1972) observed a possibly distinct form of IGHD. All
features are more severe than in the majority of cases and there may be
an exaggerated tendency to develop antibodies to administered growth
hormone, which vitiates therapy. The patients may be somewhat short at
birth, dwarfism is more extreme than in other cases, hypoglycemia is a
conspicuous feature, and the facial features ('baby doll facies') are
exaggerated. It may be that the cases of the more usual hGH deficiency
have some growth hormone whereas these have none.

Moe (1968) reported brother and sister with hypoglycemia and presumed
isolated somatotropin deficiency. The father had diabetes insipidus.

From Israel, Laron et al. (1985) reported 4 cases of isolated growth
hormone deficiency in which studies with a cDNA probe for chorionic
somatomammotropin (150200) showed homozygosity for deletion of the
growth hormone gene (the hGH-N gene). Yet, in all 4 cases, there was
good growth response to human pituitary hormone. One family originated
from Iraq, 2 from Yemen, and 1 from Iran. The reason for the discrepancy
with the findings in patients from Switzerland, Argentina, and Japan
studied by Phillips et al. (1981) and others was not clear. A
heterogeneous response to growth hormone therapy, in terms of
development of anti-human growth hormone antibodies, was documented by
Matsuda et al. (1987) in their study of 4 Japanese patients with
autosomal recessive growth hormone deficiency.

Pena-Almazan et al. (2001) evaluated 46 infants with congenital GHD
followed in a single regional medical center. All were born full-term
and had peak GH of less than 10 microg/liter after provocative
stimulation. Length standard deviation score at birth was normal but
subsequently showed deceleration, at 6 months and 12 months of age,
before GH treatment. The majority were delivered vaginally (83%), and
delivery was uncomplicated in 61%. Perinatal morbidities were found in
72% of infants and included jaundice in 17, hypoglycemia with or without
seizure in 14, and hypoxemia in 5. Multiple pituitary hormone
deficiencies were found in 85% of the subjects. Organic lesions were
documented in all 22 subjects who had magnetic resonance imaging and in
4 of 11 subjects who had computed tomography scan. In patients studied,
GHD did not adversely affect fetal growth but is essential for normal
linear growth during early infancy. The authors concluded that
congenital developmental abnormalities in the hypothalamic-pituitary
region are the most common cause of GHD and are best diagnosed by an MRI
study.

Mullis (2007) reviewed the classification of IGHD. He noted that the
development of anti-GH antibodies is an inconsistent finding in IGHD IA
patients despite having identical molecular defects (homozygosity for
GH1 gene deletions).

Hernandez et al. (2007) reviewed the clinical, biochemical, and
molecular features described for individuals with IGHD.

CLINICAL MANAGEMENT

- Growth Hormone Replacement Therapy

The advent of transgenic technology provided the methods for production
of pharmaceuticals by isolation of the proteins of interest from the
blood of transgenic animals. The mammary gland has been investigated as
a bioreactor since milk is easily collected from lactating animals and
protein production can reach as high as 1 kg per day in cattle and 200 g
per day in goats. Mammary-specific promoters have been used in
transgenic animals to limit transgene expression to the mammary gland.
Archer et al. (1994) used gene therapy techniques to target a foreign
gene to a single organ. They directly infused replication-defective
retroviruses encoding the human growth hormone gene into the mammary
gland of goats via the teat canal during a period of hormone-induced
mammogenesis. This resulted in the secretion of human GH into the milk
when lactation commenced on day 14 of the regime.

The treatment of GH deficiency is replacement using exogenous,
biosynthetic GH. Factors important in the clinical response include the
etiology and severity of deficiency, age of onset, and duration of
replacement, as well as the sex of the affected individual. Blethen et
al. (1997) determined near-adult heights (AH) in 121 children (72 males
and 49 females) with GHD who were prepubertal when they began treatment
with recombinant DNA-derived preparations of human GH. AH as an SD score
was -0.7 +/- 1.2 (mean +/- SD), and was significantly greater than the
pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score
(-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the
start of puberty (-1.9 +/- 1.3). Statistically significant variables
were duration of treatment with GH, sex (males were taller than females,
as expected for the normal population), age (younger children had a
greater AH), height at the start of GH, and growth rate during first
year of GH. Bone age delay (chronologic age minus bone age) had a
negative impact on the AH SD score. Blethen et al. (1997) concluded that
early diagnosis of GHD and continuous treatment with larger doses of GH
to near AH should improve the outcome in children with short stature due
to GHD.

Cassorla et al. (1997) studied the effect of delaying epiphyseal fusion
on the growth of GH-deficient children. Patients treated with GH and a
luteinizing hormone-releasing hormone (LHRH; 152760) analog had
suppression of their pituitary-gonadal axis and a marked delay in bone
age progression. After 3 years of treatment, Cassorla et al. (1997)
observed a greater gain in height prediction in these patients than in
patients treated with GH and placebo. The authors concluded that
delaying epiphyseal fusion with an LHRH analog in pubertal GH-deficient
children treated with GH increases height prediction and may increase
final height compared to treatment with GH alone.

Rappaport et al. (1997) assessed the efficacy of GH therapy in GHD
children treated before the age of 3 years. Their 5-year height gain was
negatively correlated with the height SD score at the start of
treatment; the first-year height gain was the most predictive parameter.
There was no significant influence of intrauterine growth retardation,
body mass index and age at the start of treatment, or parental target
height. Rappaport et al. (1997) concluded that the rapid and almost
complete return to normal height obtained in the study supported GH
treatment in early diagnosed GH-deficient children. They considered the
GH dosage used to be the minimum to obtain satisfactory catch-up growth.
In addition, the dosage allowed growth at a rate normal for age in
patients diagnosed before growth retardation.

De Boer and van der Veen (1997) advocated retesting all patients with
childhood-onset GHD once they have reached their final height. This
retesting identifies patients who have so-called transient GHD and who
are therefore not at risk to develop the adult GHD syndrome, as well as
those patients most likely to develop the adult GHD syndrome if GH
treatment is stopped at final height and who could benefit from
continued GH treatment in adulthood.

Tobiume et al. (1997) found that serum bone alkaline phosphatase (B-ALP)
levels are a useful marker for bone formation in GH-deficient children
undergoing GH therapy, and that B-ALP appeared to be a useful marker for
predicting growth responses to long-term GH therapy.

Cuneo et al. (1998) reported the results of an Australian multicenter,
randomized, double-blind, placebo-controlled trial of the effects of
recombinant human GH treatment in adults with GH deficiency. Patients
were randomly assigned to receive either GH or placebo. GH treatment in
adults with GH deficiency produced the following results: prominent
increases in serum IGF1 (147440) at the doses employed, in some cases to
supraphysiologic levels; modest decreases in total and low density
lipoprotein cholesterol, together with substantial reductions in
total-body and truncal fat mass consistent with an improved
cardiovascular risk profile; substantial increases in lean tissue mass;
and modest improvements in perceived quality of life. The excessive IGF1
response and side-effect profile suggested that lower doses of GH may be
required for prolonged GH treatment in adults with severe GH deficiency.

Maghnie et al. (1999) reevaluated GH secretion after completion of GH
treatment at a mean age of 19.2 +/- 3.2 years in 35 young adults with
childhood-onset GHD. A high proportion of children with IGHD and normal
or small pituitary showed normalization of GH secretion at the
completion of GH treatment, whereas GHD was permanent in all patients
with pituitary hypoplasia, pituitary stalk agenesis, and posterior
pituitary ectopia. IGF1 and IGFBP3 (146732) determinations shortly after
GH withdrawal had limited value in the diagnosis of childhood-onset GHD
associated with congenital hypothalamic pituitary abnormalities, but
became accurate after 6 to 12 months. The authors concluded that
patients with GHD and congenital hypothalamic pituitary abnormalities do
not require further investigation of GH secretion, whereas patients with
IGHD and normal or small pituitary gland should be retested well before
the attainment of adult height.

It had been suggested that GH treatment may increase the risk of
developing leukemia, in part because Fanconi anemia (227650), which is
associated with an increased risk of leukemia, is also associated with
GH deficiency and can present as short stature without skeletal or
hematologic abnormalities in childhood. Nishi et al. (1999) collected
data from more than 32,000 patients from the Foundation for Growth
Science in Japan, which had monitored the safety and efficacy of GH
treatment in GH-deficient patients since 1975. New leukemia was observed
in 14 patients, and myelodysplastic syndrome (MDS; see 600049) in 1
patient. Leukemia developed in 9 of these patients during GH treatment
and in 6 after the cessation of GH treatment. Six patients had known
risk factors for leukemia, such as Fanconi anemia and previous radiation
or chemotherapy. The incidence of leukemia of patient-years of GH
therapy and patient-years of risk in GH-treated patients without risk
factors was 3.0 per 100,000 and 3.9 per 100,000, respectively, a figure
similar to the incidence in the general population aged zero to 15
years. The authors concluded that the incidence of leukemia in
GH-treated patients without risk factors is not greater than that in the
general population aged zero to 15 years, and a possible increased
occurrence of leukemia with GH treatment appears to be limited to
patients with risk factors.

Guyda (1999) comprehensively reviewed the treatment protocols for
children with GHD as well as the administration of GH for other non-GHD
conditions in childhood and adolescence. Protocols for idiopathic short
stature (ISS), intrauterine growth retardation, chronic renal failure,
and genetic disorders such as Turner syndrome were included. Information
on the current worldwide distribution of GH use in almost 100,000
children was included, along with the long-term response and final
heights attained in different disorders. Information on the psychosocial
outcomes was also included.

In humans, hypopituitarism and GHD are believed to constitute risk
factors for cardiovascular disease and, therefore, early death. However,
patients with a PROP1 (601538) gene mutation, presenting with a combined
pituitary-derived hormonal deficiency (262600), can survive to a very
advanced age, apparently longer than normal individuals in the same
population. Besson et al. (2003) analyzed the impact of untreated GHD on
life span. Hereditary dwarfism was recognized in 11 subjects. Genetic
analysis revealed an underlying deletion spanning 6.7 kb of genomic DNA
encompassing the GH1 gene that caused isolated GHD. These patients were
never treated for their hormonal deficiency and thus provided a unique
opportunity to compare their life span and cause of death directly with
those of their unaffected brothers and sisters as well as with the
normal population. Although the cause of death did not vary between the
2 groups, median life span in the GH-deficient group was significantly
shorter than that of unaffected brothers and sisters (males, 56 vs 75
years, P less than 0.0001; females, 46 vs 80 years, P less than 0.0001).
The authors concluded that GH treatment in adult patients suffering from
either childhood- or adult-onset GHD is crucially important.

Hartman et al. (2008) investigated if improvements in aerobic exercise
capacity in adults with GHD treated with GH are related to changes in
physical activity or the GH dosing regimen. They found that GH
replacement therapy in GH-deficient adults improved maximal oxygen
consumption similarly with both individualized dosing and fixed body
weight-based regimens, without any influence of physical activity.

- Growth Hormone-Releasing Peptides

GH-releasing peptides (GHRPs) are small synthetic peptides that are
relatively specific stimulators of GH secretion (Mericq et al., 1998).
GHRPs have no structural similarity to GHRH (139190); they bind to
entirely different receptors and exhibit a strong synergy with GHRH in
the release of GH. Chapman et al. (1997) found that oral administration
of the GHRP6 mimetic MK-677 at both 10 and 50 mg/day increased serum
IGF1 and 24-hour mean GH concentrations in 9 severely GH-deficient men
aged 17 to 34 years who had been treated for GH deficiency with GH
during childhood. In 6 prepubertal children with GHD and growth failure,
Mericq et al. (1998) found that repeated administration of GHRP2 was
able to produce a rise in nocturnal GH that was sustained after several
months of treatment, although the effect of each injection of GHRP2 on
GH secretion was relatively brief. Serum levels of IGF1 and IGFBP3 did
not increase. Mericq et al. (1998) concluded that GHRP2 is well
tolerated and able to stimulate GH secretion, and that formulations or
routes of administration that allow for a longer duration of action
would likely be needed to use GHRP2 in therapy.

- Cardiovascular Effects of Growth Hormone Therapy

To determine the effects of recombinant human GH replacement therapy on
cardiac mass and function, Shulman et al. (2003) analyzed comprehensive
echocardiograms of 10 children with classical GH deficiency before and
during the first year of therapy and correlated the findings with linear
growth response. They concluded that cardiac growth impeded by GH
deficiency can be improved by GH replacement therapy. While body size
and cardiac mass both increased during the first year of treatment,
there was an increase in left ventricular mass normalized for changes in
body size, implying a quantitatively more significant effect of GH
replacement therapy on the heart.

Colao et al. (2005) investigated the risk of early atherosclerosis in
adolescents with GHD during GH replacement and withdrawal. Among 23
adolescents diagnosed with GHD during childhood, 8 were found to be
non-GHD at retesting 1 to 3 months after cessation of GH replacement
therapy. Intima-medial thickness (IMT) at the common carotid arteries
was similar in GHD subjects and in controls, but was higher in patients
determined to be non-GHD. In GHD adolescents, 6 months of GH treatment
withdrawal and 6 months of GH treatment reinstitution modified IGF1
levels, lipid profile, and insulin resistance but not IMT or systolic
and diastolic peak velocities at the common carotid arteries. Colao et
al. (2005) concluded that increased IMT in the adult GHD population
begins later in life or after a longer period of GH deprivation than
that studied, and that adolescents with idiopathic GHD should be
retested for GHD after completion of growth, as continued GH replacement
in non-GHD subjects could negatively affect endothelial properties.

Pinto et al. (1997) investigated the pathogenesis of pituitary stalk
interruption syndrome (PSIS), the identification of which by magnetic
resonance imaging (MRI) is a clinical marker of permanent GHD. Pinto et
al. (1997) classified 51 patients, 27 of them males, with GHD and PSIS
according to whether the GHD was isolated (group 1; 16 cases) or
associated with other anterior pituitary abnormalities (group 2; 35
cases). The 2 groups had similar characteristics: frequencies of
perinatal abnormalities, ages at occurrence of first signs and at
diagnosis, height, GH peak response to stimuli other than growth
hormone-releasing hormone (GHRH; 139190). However, associated
malformations were less frequent in group 1 (12%) than in group 2 (54%;
P less than 0.01); hypoglycemia occurred in 25% of group 1 and 70% of
group 2 (P less than 0.01); and the GH peak response to GHRH was less
than 10 micro g/L in 0% of group 1 (4 cases evaluated) and 57% of group
2 (21 cases; P less than 0.05). Thirty-one cases (61%; 25 from group 2)
had features suggesting an antenatal origin: familial recurrence (4
cases), microphallus (10 boys), and/or associated malformations (50%; 21
cases). Twenty-seven cases (53%; 22 from group 2) had features
suggesting a hypothalamic origin. Pinto et al. (1997) concluded that
most patients with GHD associated with multiple anterior pituitary
abnormalities and PSIS have features suggesting an antenatal origin, and
that the GH, GHRH receptor (139191), and PIT1 (173110) genes do not seem
to be implicated in PSIS.

DIAGNOSIS

While short stature, delayed growth velocity, and delayed skeletal
maturation are all seen with GH deficiency, none of these symptoms or
signs is specific for GH deficiency. Therefore, patients should be
evaluated for other, alternative systemic diseases before provocative
tests to document GH deficiency are done. Provocative tests for GH
deficiency include post-exercise, L-DOPA, insulin tolerance, arginine,
insulin-arginine, clonidine, glucagon, and propranolol protocols.
Inadequate GH peak responses (usually less than 7-10 ng/ml) differ from
protocol to protocol. Importantly, additional testing for concomitant
deficiencies of LH, FSH, TSH, and/or ACTH should be done to provide a
complete diagnosis and thus enable planning of optimal treatment
(Phillips, 1995; Rimoin and Phillips, 1997).

Rosenfeld (1997) suggested the following as guidelines for diagnosing
GHD: severe growth retardation with height more than 3 standard
deviations (SD) below the mean for age in the absence of an alternative
explanation; moderate growth retardation with height 2 to 3 SD below the
mean for age, plus growth deceleration with height velocity less than
25th percentile for age, in the absence of an alternative explanation;
severe growth deceleration with height velocity less than 5th percentile
for age, in the absence of an alternative explanation; a predisposing
condition (e.g., cranial irradiation) plus growth deceleration; or other
evidence of pituitary dysfunction (e.g., other pituitary deficiencies,
neonatal hypoglycemia, microphallus). However, even in the appropriate
clinical setting, the diagnosis of GHD remains problematic, largely
because of the difficulty in measuring physiologic GH secretion. GH
stimulation tests are widely used in the diagnosis of GHD, although they
are associated with a high false positive rate.

Tillmann et al. (1997) compared alternative tests of the GH axis such as
urinary GH excretion, serum IGF1, and IGFBP3 levels to GH stimulation
tests in identifying children defined clinically as GH deficient. The
best sensitivity for a single GH test was 85% at a peak GH cutoff level
of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The
sensitivities of IGF1, IGFBP3, and urinary GH, using a cutoff of -2 SD
score, were poor at 34%, 22%, and 25%, respectively. The authors devised
a scoring system based on the positive predictive value of each test,
incorporating data from the urinary GH, IGF1, and IGFBP3 levels. A
specificity of 94% could be achieved with a score of 10 or more, with a
maximum of 17, and a sensitivity of 32%. The latter could not be
improved above 81% with a score of 5 points or more and a specificity of
69%. A high score was highly indicative of GHD, but was achieved by few
patients. A normal IGFBP3 level, however, did not exclude GHD,
particularly in patients with radiation-induced GHD and those in
puberty. A GH test with a peak level more than 10 ng/mL was the most
useful single investigation to exclude a diagnosis of GHD.

Mahajan and Lightman (2000) evaluated the GH-releasing effect of a
combination of the hypothalamic secretagogue GHRH with a small dose of
the synthetic peptide GHRP2 to diagnose GHD. They compared the GH
response to ITT and GHRH/GHRP in a group of 36 adults (22 males and 14
females, aged 18 to 59 years) with hypothalamic/pituitary disease and in
30 healthy volunteers (15 males and 15 females, aged 22 to 66 years).
The GHRH/GHRP test produced a measurable GH secretory response in
normal, hypopituitary, and GH-deficient patients. The test had no
detected side effects. Using the ITT as the 'gold standard' with a GH
response of 9 mU/L as the cut-off to define GHD, they compared the
clinical efficacy of these 2 tests. Choosing an arbitrary cut-off of 17
mU/L to define GHD in the GHRH/GHRP test, this new test proved to have
78.6% sensitivity and 100% specificity even when only the 30-minute
datum point was used.

By magnetic resonance imaging (MRI), Chen et al. (1999) studied
GH-deficient children showing ectopic posterior pituitary hyperintense
signal (EPP). Patients were classified into 2 groups according to the
presence (group 1; 14 patients) or absence (group 2; 11 patients) of
pituitary stalk visibility after gadolinium injection. Most (12 of 14)
patients in group 1 had isolated GH deficiency, whereas all but 1
patient in group 2 had multiple anterior pituitary hormone deficiency.
The prevalence of a normally sized adenohypophysis was higher in group 1
than in group 2 (50% vs 9%; P less than 0.05). The authors concluded
that in cases of GH deficiency associated with EPP, patients with no
visible pituitary stalk on MRI after gadolinium injection present a more
severe form of the disease in childhood that is associated with multiple
anterior pituitary hormone deficiency, whereas visibility of the
pituitary stalk is related to isolated GH deficiency.

Osorio et al. (2002) stated that the pathogenesis of pituitary stalk
interruption and ectopic posterior lobe, frequently observed on MRI in
patients with GHD, was controversial. They performed pituitary
stimulation tests and MRI, and studied the GH1, GHRHR, and PROP1
(601538) genes, in 76 patients with IGHD or combined pituitary hormone
deficiency (CPHD). Compared with the 62 patients without mutations, 14
patients with mutations had higher frequencies of consanguinity (P less
than 0.001) and familial cases (P less than 0.05) and lower frequency of
breech delivery or hypoxemia at birth (P less than 0.005). On MRI, all
patients with mutations had an intact stalk, whereas it was interrupted
or thin in 74% without mutations (P less than 0.001). The posterior
pituitary lobe was in normal position in 92% of patients with mutations
versus 13% without mutations (P less than 0.001). Among patients with
combined pituitary hormone deficiency, hormonal deficiencies were of
pituitary origin in all with PROP1 and PIT1 mutations and suggestive of
hypothalamic origin in 81% without mutations. GH1, GHRHR (139191), and
PROP1 mutations were associated with consanguineous parents, intact
pituitary stalk, normal posterior lobe, and pituitary origin of hormonal
deficiencies. Osorio et al. (2002) concluded that pituitary MRI and
hormonal response to stimulation tests are useful in selection of
patients and candidate genes to elucidate the etiologic diagnosis of
GHD.

Based on a study of the GH-IGF axis in a large, genetically homogeneous
population with a homozygous donor splice site mutation in intron 1 of
the GHRHR gene (139191.0002), Aguiar-Oliveira et al. (1999) recommended
that diagnostic tests used in the investigation of GHD should be
tailored to the age of the individual. In particular, measurement of
IGF1 in the ternary complex may prove useful in the diagnosis of GHD in
children and older adults, whereas free ALS may be more relevant to
younger adults.

The biochemical diagnosis of GH deficiency has traditionally been based
on provocative tests using a variety of GH stimulation agents. Estrogen
administration increases GH responsiveness to provocative stimuli. It
had been proposed that estrogen priming might reduce the percentage of
false-positive GH deficiency diagnosis in prepubertal and early pubertal
subjects. To evaluate the effect of estrogen administration on GH
stimulation tests in both short normal and GHD patients and to compare
the diagnostic efficiency of this approach with that of serum levels of
IGF1 and IGFBP3, Martinez et al. (2000) studied the effect of estradiol
on the GH-IGF axis in 15 prepubertal children with GH deficiency and 44
prepubertal or early pubertal children with idiopathic short stature.
All received a daily dose of micronized estradiol or placebo for 3 days
before a sequential arginine-clonidine test. The authors concluded that
GH stimulation tests after estradiol priming had the highest diagnostic
efficiency. They also suggested that the effect of estrogen priming on
GH stimulated levels, by reducing the number of false nonresponders,
might be useful to better discriminate between normal and abnormal GH
status in children with idiopathic short stature.

MOLECULAR GENETICS

For an extensive discussion of the molecular genetics of IGHD type 1A
and a listing of allelic variants in the GH1 gene, see 139250.

Dattani (2005) reviewed the genetic causes and phenotypic features of
IGHD and combined pituitary hormone deficiency (see 613038). The author
noted that hormone abnormalities may evolve over time, necessitating
frequent reevaluation, and that determining the genotype can aid in
management, e.g., because it is well established that the enlarged
anterior pituitary associated with PROP1 mutations will undergo
spontaneous involution, invasive procedures can be avoided.

HISTORY

Hastings Gilford (1904) called dwarfs with normal body proportions
ateleiotic ('not arrived at perfection'). He distinguished sexual and
asexual types and referred to patients with the former type as 'Tom
Thumb dwarfs.' The 2 types correspond to what are referred to here as
pituitary dwarfism I and III (262600), respectively. The first type has
an isolated deficiency of growth hormone, whereas the second has
deficiency of all anterior pituitary hormones. The existence of an
isolated growth hormone deficiency in recessively inherited sexual
ateleiosis was demonstrated by Rimoin et al. (1966). (Merimee et al.
(1975) reported autopsy studies in the original case on the basis of
which Rimoin et al. (1966) delineated autosomal recessive isolated
growth hormone deficiency.) Families of this type have been reported by
McKusick (1955), von Verschuer and Conradi (1938), Dzierzynski (1938)
and others.

Leisti et al. (1973) found growth hormone deficiency in a male with
deletion of the short arm of chromosome 18. The association may be
coincidence or may indicate that a locus controlling growth hormone
synthesis is on the deleted segment (see 146390).

On the basis of a study of 140 cases of idiopathic growth hormone
deficiency, Rona and Tanner (1977) favored a multifactorial hypothesis.
They pointed to a high male-female ratio and a high frequency of breech
delivery. They felt that birth trauma may be a significant factor.
McKusick (1972) noted the association of osteogenesis imperfecta (see
166200) in 2 cases from his own experience. Birth trauma affecting the
pituitary gland or hypothalamus may be particularly likely to happen
when the baby has OI. He suggested the presence of a small deletion as
an alternative explanation, since the genes encoding growth hormone and
the alpha-1 chain of type I collagen (COL1A1; 120150) are closely linked
on chromosome 17.

Potential for gene therapy in the type of growth hormone deficiency
shown by Phillips et al. (1981) to have deletion of the growth hormone
gene was reported by Palmiter et al. (1982). They fused to the
structural gene for rat growth hormone a DNA fragment containing the
promoter of the mouse metallothionein-I gene. The fused gene was then
injected into the pronuclei of fertilized mouse eggs. Of 21 mice that
developed from those eggs, 7 could be shown by Southern blot analysis to
be carrying the fusion gene and 6 of the 7 grew appreciably larger than
their littermates. In addition to correcting genetic diseases, the
method has promise for accelerating animal growth and forming valuable
gene products such as antihemophilic globulin (F8; 300841), where the
protein requires special covalent modifications, such as proteolytic
cleavage, glycosylation or gamma-carboxylation for activity or
stability. The designation hpGRF-40 refers to a peptide with major
growth factor-releasing function derived from pancreatic tumors causing
acromegaly. It seemed likely that peptide(s) of similar or identical
sequence are released from the hypothalamus to control the synthesis and
secretion of pituitary growth hormone.

*FIELD* SA
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children. J. Clin. Endocr. Metab. 83: 2355-2360, 1998.

31. Merimee, T. J.; Ostrow, P.; Aisner, S. C.: Clinical and pathological
studies in a growth hormone-deficient dwarf. Johns Hopkins Med. J. 136:
150-154, 1975.

32. Moe, P. J.: Hypopituitary dwarfism. The importance of early therapy. Acta
Paediat. Scand. 57: 300-304, 1968.

33. Mullis, P. E.: Genetics of growth hormone deficiency. Endocr.
Metab. Clin. N. Am. 36: 17-36, 2007.

34. Mullis, P. E.; Akinci, A.; Kanaka, C.; Eble, A.; Brook, C. G.
D.: Prevalence of human growth hormone-1 gene deletions among patients
with isolated growth hormone deficiency from different populations. Pediat.
Res. 31: 532-534, 1992.

35. Nishi, Y.; Tanaka, T.; Takano, K.; Fujieda, K.; Igarashi, Y.;
Hanew, K.; Hirano, T.; Yokoya, S; Tachibana, K.; Saito, T.; Watanabe,
S.: Recent status in the occurrence of leukemia in growth hormone-treated
patients in Japan. J. Clin. Endocr. Metab. 84: 1961-1965, 1999.

36. Osorio, M. G. F.; Marui, S.; Jorge, A. A. L.; Latronico, A. C.;
Lo, L. S. S.; Leite, C. C.; Estefan, V.; Mendonca, B. B.; Arnhold,
I. J. P.: Pituitary magnetic resonance imaging and function in patients
with growth hormone deficiency with and without mutations in GHRH-R,
GH-1, or PROP-1 genes. J. Clin. Endocr. Metab. 87: 5076-5084, 2002.

37. Palmiter, R. D.; Brinster, R. L.; Hammer, R. E.; Trumbauer, M.
E.; Rosenfeld, M. G.; Birnberg, N. C.; Evans, R. M.: Dramatic growth
of mice that develop from eggs microinjected with metallothionein-growth
hormone fusion genes. Nature 300: 611-615, 1982.

38. Pena-Almazan, S.; Buchlis, J.; Miller, S.; Shine, B.; Macgillivray,
M.: Linear growth characteristics of congenitally GH-deficient infants
from birth to one year of age. J. Clin. Endocr. Metab. 86: 5691-5694,
2001.

39. Phillips, J. A., III: Inherited defects in growth hormone synthesis
and action.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle,
D. (eds.): The Metabolic and Molecular Bases of Inherited Disease.
Vol. II. New York: McGraw-Hill (7th ed.): 1995. Pp. 3023-3044.

40. Phillips, J. A., III; Cogan, J. D.: Genetic basis of endocrine
disease 6: molecular basis of familial human growth hormone deficiency. J.
Clin. Endocr. Metab. 78: 11-16, 1994.

41. Phillips, J. A., III; Hjelle, B. L.; Seeburg, P. H.; Zachmann,
M.: Molecular basis for familial isolated growth hormone deficiency. Proc.
Nat. Acad. Sci. 78: 6372-6375, 1981.

42. Pinto, G.; Netchine, I.; Sobrier, M. L.; Brunelle, F.; Souberbielle,
J. C.; Brauner, R.: Pituitary stalk interruption syndrome: a clinical-biologica
l-genetic assessment of its pathogenesis. J. Clin. Endocr. Metab. 82:
3450-3454, 1997.

43. Rappaport, R.; Mugnier, E.; Limoni, C.; Crosnier, H.; Czernichow,
P.; Leger, J.; Limal, J.-M.; Rochiccioli, P.; Soskin, S.; Brauner,
R.; Pinto, G.; Pawels, C.; and 27 others: A 5-year prospective
study of growth hormone (GH)-deficient children treated with GH before
the age of 3 years. J. Clin. Endocr. Metab. 82: 452-456, 1997.

44. Rimoin, D. L.; Merimee, T. J.; McKusick, V. A.: Growth-hormone
deficiency in man: an isolated, recessively inherited defect. Science 152:
1635-1637, 1966.

45. Rimoin, D. L.; Phillips, J. A., III: Genetic disorders of the
pituitary gland.In: Rimoin, D. L.; Connor, J. M.; Pyeritz, R. E. (eds.)
: Principles and Practice of Medical Genetics. Vol. I. New York:
Churchill Livingstone (3rd ed.): 1997. Pp. 1331-1364.

46. Rona, R. J.; Tanner, J. M.: Aetiology of idiopathic growth hormone
deficiency in England and Wales. Arch. Dis. Child. 52: 197-208,
1977.

47. Rosenfeld, R. G: Editorial: is growth hormone deficiency a viable
diagnosis? J. Clin. Endocr. Metab. 82: 349-351, 1997.

48. Seip, M.; Van der Hagen, C. B.; Trygstad, O.: Hereditary pituitary
dwarfism with spontaneous dwarfism. Arch. Dis. Child. 43: 47-52,
1968.

49. Shulman, D. I.; Root, A. W.; Diamond, F. B.; Bercu, B. B.; Martinez,
R.; Boucek, R. J., Jr.: Effects of one year of recombinant human
growth hormone (GH) therapy on cardiac mass and function in children
with classical GH deficiency. J. Clin. Endocr. Metab. 88: 4095-4099,
2003.

50. Tillmann, V.; Buckler, J. M. H.; Kibirige, M. S.; Price, D. A.;
Shalet, S. M.; Wales, J. K. H.; Addison, M. G.; Gill, M. S.; Whatmore,
A. J.; Clayton, P. E.: Biochemical tests in the diagnosis of childhood
growth hormone deficiency. J. Clin. Endocr. Metab. 82: 531-535,
1997.

51. Tobiume, H.; Kanzaki, S.; Hida, S.; Ono, T.; Moriwake, T.; Yamauchi,
S.; Tanaka, H.; Seino, Y.: Serum bone alkaline phosphatase isoenzyme
levels in normal children and children with growth hormone (GH) deficiency:
a potential marker for bone formation and response to GH therapy. J.
Clin. Endocr. Metab. 82: 2056-2061, 1997.

52. Von Verschuer, O. F.; Conradi, L.: Eine Sippe mit rezessiv erblichem
primordialem Zwergwuchs. Z. Menschl. Vererb. Konstitutionsl. 22:
261-267, 1938.

53. Zachmann, M.; Fernandez, F.; Tassinari, D.; Thakker, R.; Prader,
A.: Anthropometric measurements in patients with growth hormone deficiency
before treatment with human growth hormone. Europ. J. Pediat. 133:
277-282, 1980.

*FIELD* CS

Growth:
Sexual ateleiotic dwarfism

Metabolic:
Hypoglycemia

Facies:
Puppet (baby doll) facies

Immunol:
Antibodies to administered growth hormone

Lab:
Isolated growth hormone deficiency

Inheritance:
Autosomal recessive

*FIELD* CN
John A. Phillips, III - updated: 1/7/2011
Marla J. F. O'Neill - updated: 11/23/2009
Anne M. Stumpf - reorganized: 6/1/2009
Victor A. McKusick - updated: 2/24/2000

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

*FIELD* ED
carol: 04/07/2011
alopez: 1/7/2011
carol: 1/8/2010
wwang: 12/4/2009
terry: 11/23/2009
alopez: 6/2/2009
alopez: 6/1/2009
terry: 3/24/2009
terry: 8/26/2008
carol: 3/14/2007
alopez: 2/25/2000
terry: 2/24/2000
carol: 11/9/1999
alopez: 2/10/1999
davew: 8/15/1994
mimadm: 4/18/1994
carol: 3/24/1994
warfield: 3/9/1994
carol: 8/16/1993
carol: 10/5/1992

MIM 262650
*RECORD*
*FIELD* NO
262650
*FIELD* TI
#262650 KOWARSKI SYNDROME
;;BIODEFECTIVE GROWTH HORMONE;;
PITUITARY DWARFISM WITH NORMAL IMMUNOREACTIVE GROWTH HORMONE AND LOW
read moreSOMATOMEDIN
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Kowarski syndrome is caused by mutation in the growth hormone gene (GH1;
139250) on chromosome 17q. Mutation in the GH1 gene also causes several
types of isolated growth hormone deficiency (IGHD); see 262400 for a
summary.

DESCRIPTION

Kowarski syndrome, or short stature associated with bioinactive growth
hormone, is characterized clinically by normal or slightly increased GH
secretion, pathologically low IGF1 (147440) levels, and normal catch-up
growth on GH replacement therapy (Besson et al., 2005).

CLINICAL FEATURES

Kowarski et al. (1978) studied 2 unrelated 3-year-old boys with growth
retardation and delayed bone ages, and with normal immunoreactive growth
hormone after stimulation but low levels of somatomedin. Unlike the
result in patients with Laron dwarfism (262500), exogenous human growth
hormone induced normal levels of somatomedin and a significant increase
in growth rate. The family data provided no clue to the genetics. The
authors suggested that the phenotype may be caused by secretion of a
biologically inactive but immunoreactive growth hormone molecule.

Valenta et al. (1985) described a similar case; furthermore, they
confirmed a structural abnormality of the growth hormone molecule: 60 to
90% of circulating growth hormone was in the form of tetramers and
dimers (normal, 14 to 39% in plasma) and the patients' growth hormone
polymers were abnormally resistant to conversion into monomers by urea.

Chen (1988) suggested that a biologically ineffective mutant GH molecule
may be the basis of 'pituitary dwarfism' in some cases.

MOLECULAR GENETICS

Takahashi et al. (1996) reported the case of a boy with short stature
who was heterozygous for a mutation in the GH1 gene (139250.0008). In
this child, growth hormone not only could not activate the GH receptor
(GHR; 600946) but also inhibited the action of wildtype GH because of
its greater affinity for GHR and GH-binding protein (GHBP; see 600946)
that is derived from the extracellular domain of the GHR. Thus, a
dominant-negative effect was observed.

In a girl with short stature, Takahashi et al. (1997) demonstrated a
biologically inactive growth hormone resulting from a heterozygous
mutation in the GH1 gene (139250.0013). At age 3 years, the girl's
height was 3.6 standard deviations below the mean for age and sex. Bone
age was delayed by 1.5 years. She had a prominent forehead and a
hypoplastic nasal bridge with normal body proportions. She showed lack
of growth hormone action despite high immunoassayable GH levels in serum
and marked catch-up growth to exogenous GH administration. Results of
other studies were compatible with the production of a bioinactive GH,
which prevented dimerization of the growth hormone receptor, a crucial
step in GH signal transduction.

Besson et al. (2005) described a Serbian patient with Kowarski syndrome
who was homozygous for a mutation in the GH1 gene that disrupted the
first disulfide bridge in growth hormone (139250.0021). The parents were
each heterozygous for the mutation and were of normal stature.

*FIELD* SA
Bright et al. (1983)
*FIELD* RF
1. Besson, A.; Salemi, S.; Deladoey, J.; Vuissoz, J.-M.; Eble, A.;
Bidlingmaier, M.; Burgi, S.; Honegger, U.; Fluck, C.; Mullis, P. E.
: Short stature caused by a biologically inactive mutant growth hormone
(GH-C53S). J. Clin. Endocr. Metab. 90: 2493-2499, 2005.

2. Bright, G. M.; Rogol, A. D.; Johanson, A. J.; Blizzard, R. M.:
Short stature associated with normal growth hormone and decreased
somatomedin-C concentrations: response to exogenous growth hormone. Pediatrics 71:
576-580, 1983.

3. Chen, E.: Personal Communication. San Francisco, Calif. 10/25/1988.

4. Kowarski, A. A.; Schneider, J. J.; Ben-Galim, E.; Weldon, V. V.;
Daughaday, W. H.: Growth failure with normal serum RIA-GH and low
somatomedin activity: somatomedin restoration and growth acceleration
after exogenous GH. J. Clin. Endocr. 47: 461-464, 1978.

5. Takahashi, Y.; Kaji, H.; Okimura, Y.; Goji, K.; Abe, H.; Chihara,
K.: Short stature caused by a mutant growth hormone. New Eng. J.
Med. 334: 432-436, 1996. Note: Erratum: New Eng. J. Med. 334: 1207
only, 1996.

6. Takahashi, Y.; Shirono, H.; Arisaka, O.; Takahashi, K.; Yagi, T.;
Koga, J.; Kaji, H.; Okimura, Y.; Abe, H.; Tanaka, T.; Chihara, K.
: Biologically inactive growth hormone caused by an amino acid substitution. J.
Clin. Invest. 100: 1159-1165, 1997.

7. Valenta, L. J.; Sigel, M. B.; Lesniak, M. A.; Elias, A. N.; Lewis,
U. J.; Friesen, H. G.; Kershnar, A. K.: Pituitary dwarfism in a patient
with circulating abnormal growth hormone polymers. New Eng. J. Med. 312:
214-217, 1985.

*FIELD* CS

Growth:
Growth retardation

Endocrine:
Pituitary dwarfism

Radiology:
Delayed bone age

Lab:
Normal immunoreactive growth hormone after stimulation;
Low somatomedin;
Exogenous human growth hormone responsive;
Structural abnormality of growth hormone molecule

Inheritance:
Autosomal recessive

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

*FIELD* ED
alopez: 06/01/2009
carol: 3/26/2008
alopez: 11/3/1999
terry: 9/29/1997
mimadm: 3/12/1994
supermim: 3/17/1992
carol: 10/18/1991
supermim: 3/20/1990
supermim: 2/8/1990
carol: 2/5/1990

MIM 612781
*RECORD*
*FIELD* NO
612781
*FIELD* TI
#612781 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IB; IGHD1B
;;IGHD IB;;
DWARFISM OF SINDH
read more*FIELD* TX
A number sign (#) is used with this entry because isolated growth
hormone deficiency (IGHD) type IB can be caused by mutation in the GH1
(139250) or GHRHR (139191) gene.

DESCRIPTION

Patients with IGHD type IB are characterized by low but detectable
levels of GH, short stature, significantly retarded bone age, and a
positive response and immunologic tolerance to GH therapy.

See entry 262400 for a summary of the different types of IGHD.

CLINICAL FEATURES

Wajnrajch et al. (1996) described 2 first cousins, a boy and a girl,
from a consanguineous Indian Moslem kindred with the typical phenotype
of severe growth hormone deficiency (isolated growth hormone deficiency
IB). The 3.5-year-old girl and her 16-year-old cousin had shown poor
growth since infancy and both were extremely short. They were
prepubertal with frontal bossing and predominantly truncal obesity. Both
failed to produce growth hormone in response to standard provocative
tests and to repetitive stimulation with growth hormone-releasing
hormone (GHRH; 139190). They responded to administration of growth
hormone (GH; 139250).

Salvatori et al. (1999) reported members of a large extended pedigree
with familial dwarfism from Itabaianinha, a rural county in the state of
Sergipe, located in northeastern Brazil. Inhabitants of this region are
thought to be of Portuguese descent. They have a high frequency of
consanguineous marriages. The diagnosis of dwarfism was based on early
growth failure, proportionate short stature, and radiologic evidence of
delayed bone age. Affected subjects were very short and attained an
adult stature that ranged between 105 and 135 cm. In addition, patients
had high-pitched voices and increased abdominal fat accumulation. Except
for a somewhat delayed onset of puberty, which did not affect their
fertility, they did not manifest any signs or symptoms that suggest
deficiency of other pituitary hormones. Ten patients were treated with
recombinant human growth hormone for 1 year, and each showed a brisk
increase in growth velocity without reduced responsiveness over time.

Menezes Oliveira et al. (2006) studied the consequences of lifetime
isolated GHD (IGHD) on the metabolic and cardiovascular status of adult
members of a large Brazilian kindred (Itabaianinha cohort) with severe
IGHD due to a homozygous mutation in the GHRHR gene (139191.0002). GHD
subjects had increased abdominal obesity, higher total and low density
lipoprotein cholesterol, and higher C-reactive protein (123260) than
controls. They did not have an increase in carotid wall thickness, and
there was no evidence of premature atherosclerosis as evaluated by
exercise echocardiography. The authors concluded that in this
homogeneous cohort, untreated severe IGHD is not associated with
evidence of premature atherosclerosis despite unfavorable cardiovascular
risk profile.

CLINICAL MANAGEMENT

Gondo et al. (2001) compared the pituitary hormone response to GHRP2, a
potent growth hormone secretagogue, in 11 individuals with isolated GH
deficiency (GHD) due to a homozygous mutation of the GHRHR gene
(139191.0002) and in 8 normal unrelated controls. Basal serum GH levels
were lower in the GHD group compared with controls. After GHRP2
administration, there was a 4.5-fold increase in serum GH relative to
baseline values in the GHD group, which was significantly less than the
79-fold increase in the control group. The authors concluded that an
intact GHRH signaling system is not an absolute requirement for GHRP2
action on GH secretion and that GHRP2 has a GHRH-independent effect on
pituitary somatotroph cells.

Walenkamp et al. (2008) described the evolution of growth and skeletal
age of a brother and sister of Moroccan descent with a homozygous GHRHR
mutation who presented at the ages of 16 and 14.9 years of age,
respectively. Heights were -5.1 and -7.3 SD, and pubertal stages were
advanced. Combined GH and GNRH analog (GNRHa) treatment resulted in a
height gain of 24 and 28.2 cm, respectively, compared with the initial
predicted adult height by the method of Bayley and Pinneau. Adult height
was within the population range and well within the target range. The
authors concluded that, in cases of isolated GH deficiency caused by a
GHRHR mutation, combined treatment of GH and GNRHa can be very effective
in increasing final height, even at an advanced bone age and pubertal
stage.

MOLECULAR GENETICS

In at least 2 members of a consanguineous family with profound growth
hormone deficiency, Wajnrajch et al. (1996) demonstrated a nonsense
mutation in the human GHRHR gene (139191.0001). The phenotype in this
Indian Moslem kindred was comparable to that in the 'little' mouse,
which carries a mutation in the growth hormone-releasing factor receptor
(Ghrfr). The authors pointed out that other members of the G
protein-coupled receptor superfamily are subject to mutations that can
cause an increase in ligand-mediated signaling or constitutive receptor
activation and resulted in hyperfunction of target cells. Endocrine
disorders resulting from such activating mutations include familial male
precocious puberty (176410) caused by mutation in the LH receptor
(152790), Jansen metaphyseal dysplasia with hypercalcemia (156400)
caused by mutation in the PTH receptor (168468), and hyperparathyroidism
caused by mutation in the calcium-sensing receptor (145980.0004).
Wajnrajch et al. (1996) suggested that analogous mutations in the GHRHR
gene should be sought in patients with excessive production of growth
hormone causing gigantism or acromegaly.

Leiberman et al. (2000) demonstrated that heterozygosity for a splice
site mutation causing autosomal recessive growth hormone deficiency in
an inbred Bedouin kindred (139250.0015) was associated with short
stature in carriers who were found normal on pharmacologic stimulation
for GH release.

Aguiar-Oliveira et al. (1999) measured IGF1, IGF2 (147470), IGF-binding
protein-1 (IGFBP1; 146730), IGFBP2 (146731), IGFBP3, and acid labile
subunit (ALS; 601489) in 27 subjects with GHD (aged 5 to 82 years) from
an extended kindred in Northeast Brazil with the intron 1 splice site
GHRHR mutation (139191.0002) and in 55 indigenous controls (aged 5 to 80
years). All components of the IGF axis, measured and theoretical, showed
complete separation between GHD and control subjects, except IGFBP1 and
IGFBP2 concentrations, which did not differ. The most profound effects
of GHD were on total IGF1, IGF1 in the ternary complex, and ALS. The
proportion of IGF1 associated with IGFBP3 remained constant throughout
life, but was significantly lower in GHD due to an increase in
IGF1/IGFBP2 complexes. As diagnostic tests, IGF1 in the ternary complex
and total IGF1 provided the greatest separation between GHD and controls
in childhood. The authors concluded that severe GHD not only reduces the
amounts of IGFs, IGFBP3, and ALS, but also modifies the distribution of
the IGFs bound to each IGFBP.

HISTORY

Rimoin (1979) had knowledge of 3 autopsies in cases of isolated growth
hormone deficiency. All had eosinophilic cells with granules containing
immunoreactive hormone. Thus, the defect in these cases was conjectured
to reside in 'hypothalamic releasing factor.' Borges et al. (1983) and
Grossman et al. (1983) showed that some patients with isolated
idiopathic growth hormone deficiency responded to administration of
hpGRF-40. Thus, the basic defect in some such patients (Phillips type
IB) was thought to reside in the hypothalamus.

*FIELD* RF
1. Aguiar-Oliveira, M. H.; Gill, M. S.; de A. Barretto, E. S.; Alcantara,
M. R. S.; Miraki-Moud, F.; Menezes, C. A.; Souza, A. H. O.; Martinelli,
C. E.; Pereira, F. A.; Salvatori, R.; Levine, M. A.; Shalet, S. M.;
Camacho-Hubner, C.; Clayton, P. E.: Effect of severe growth hormone
(GH) deficiency due to a mutation in the GH-releasing hormone receptor
on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary
complex formation throughout life. J. Clin. Endocr. Metab. 84: 4118-4126,
1999.

2. Borges, J. L. C.; Blizzard, R. M.; Gelato, M.; Furlanetto, R.;
Rogol, A. D.; Evans, W. S.; Vance, M. L.; Kaiser, D. L.; MacLeod,
R. M.; Merriam, G. R.; Loriaux, D. L.; Spiess, J.; Rivier, J.; Vale,
W.; Thorner, M. O.: Effects of human pancreatic tumour growth hormone
releasing factor on growth hormone and somatomedin C levels in patients
with idiopathic growth hormone deficiency. Lancet 322: 119-124,
1983. Note: Originally Volume II.

3. Gondo, R. G.; Aguiar-Oliveira, M. H.; Hayashida, C. Y.; Toledo,
S. P. A.; Abelin, N.; Levine, M. A.; Bowers, C. Y.; Souza, A. H. O.;
Pereira, R. M. C.; Santos, N. L.; Salvatori, R.: Growth hormone-releasing
peptide-2 stimulates GH secretion in GH-deficient patients with mutated
GH-releasing hormone receptor. J. Clin. Endocr. Metab. 86: 3279-3283,
2001.

4. Grossman, A.; Savage, M. O.; Wass, J. A. H.; Lytras, N.; Suerias-Diaz,
J.; Coy, D. H.; Besser, G. M.: Growth-hormone-releasing factor in
growth hormone deficiency: demonstration of a hypothalamic defect
in growth hormone release. Lancet 322: 137-138, 1983. Note: Originally
Volume II.

5. Leiberman, E.; Pesler, D.; Parvari, R.; Elbedour, K.; Abdul-Latif,
H.; Brown, M. R.; Parks, J. S.; Carmi, R.: Short stature in carriers
of recessive mutation causing familial isolated growth hormone deficiency. Am.
J. Med. Genet. 90: 188-192, 2000.

6. Menezes Oliveira, J. L.; Marques-Santos, C.; Barreto-Filho, J.
A.; Ximenes Filho, R.; de Oliveira Britto, A. V.; Souza, A. H.; Prado,
C. M.; Pereira Oliveira, C. R.; Pereira, R. M.; Ribeiro Vicente, T.
A.; Farias, C. T.; Aguiar-Oliveira, M. H.; Salvatori, R.: Lack of
evidence of premature atherosclerosis in untreated severe isolated
growth hormone (GH) deficiency due to a GH-releasing hormone receptor
mutation. J. Clin. Endocr. Metab. 91: 2093-2099, 2006.

7. Rimoin, D. L.: Personal Communication. Torrance, Calif. 7/27/1979.

8. Salvatori, R.; Hayashida, C. Y.; Aguiar-Oliveira, M. H.; Phillips,
J. A., III; Souza, A. H. O.; Gondo, R. G.; Toledo, S. P. A.; Conceicao,
M. M.; Prince, M.; Maheshwari, H. G.; Baumann, G.; Levine, M. A.:
Familial dwarfism due to a novel mutation of the growth hormone-releasing
hormone receptor gene. J. Clin. Endocr. Metab. 84: 917-923, 1999.

9. Wajnrajch, M. P.; Gertner, J. M.; Harbison, M. D.; Chua, S. C.,
Jr.; Leibel, R. L.: Nonsense mutation in the human growth hormone-releasing
hormone receptor causes growth failure analogous to the little (lit)
mouse. Nature Genet. 12: 88-90, 1996.

10. Walenkamp, M. J. E.; Pereira, A. M.; Oosdijk, W.; Stokvis-Brantsma,
W. H.; Pfaeffle, R. W.; Blankenstein, O.; Wit, J. M.: Height gain
with combined growth hormone and gonadotropin-releasing hormone analog
therapy in two pubertal siblings with a growth hormone-releasing hormone
receptor mutation. J. Clin. Endocr. Metab. 93: 204-207, 2008.

*FIELD* CN
John A. Phillips, III - updated: 6/5/2009

*FIELD* CD
Anne M. Stumpf: 5/12/2009

*FIELD* ED
terry: 11/02/2010
alopez: 6/5/2009
alopez: 6/1/2009