{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T09:48:26Z","timestamp":1779011306494,"version":"3.51.4"},"reference-count":54,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1998,11,1]]},"abstract":"<jats:p>We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 sd below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 sd, and blood pressure approximately 3 sd below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, l-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 \u00b1 2.0 ng\/mL and 0.42 \u00b1 0.13 \u03bcg\/mL, respectively; mean \u00b1 sd) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50\u2192Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and l-dopa, but they showed only minimal or no height deficit.<\/jats:p><jats:p>This syndrome represents the human homologue of the little (lit\/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.<\/jats:p>","DOI":"10.1210\/jcem.83.11.5226","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:02:29Z","timestamp":1389200549000},"page":"4065-4074","source":"Crossref","is-referenced-by-count":4,"title":["Phenotype and Genetic Analysis of a Syndrome Caused by an Inactivating Mutation in the Growth Hormone-Releasing Hormone Receptor: Dwarfism of Sindh1"],"prefix":"10.1210","volume":"83","author":[{"given":"Hiralal G.","family":"Maheshwari","sequence":"first","affiliation":[{"name":"Center for Endocrinology, Metabolism and Molecular Medicine, Departments of Medicine (H.G.M., G.B.), Chicago, Illinois 60611"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard L.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Pediatrics (B.L.S.), Chicago, Illinois 60611"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose\u0301e","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Preventive Medicine (J.D.), Northwestern University Medical School, Chicago, Illinois 60611"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Baumann","sequence":"additional","affiliation":[{"name":"Center for Endocrinology, Metabolism and Molecular Medicine, Departments of Medicine (H.G.M., G.B.), Chicago, Illinois 60611"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071620070228500_R1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/01459740.1991.9966048","article-title":"The good body: when big is better","volume":"13","author":"Cassidy","year":"1991","journal-title":"Med Anthropol."},{"key":"2020071620070228500_R2","author":"Lee","year":"1994"},{"key":"2020071620070228500_R3","first-page":"11","article-title":"Genetic basis of endocrine disease 6: molecular basis of familial growth hormone deficiency","volume":"78","author":"Phillips III","year":"1994","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/S0889-8529(05)70339-X","article-title":"Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin","volume":"25","author":"Cohen","year":"1996","journal-title":"Endocrinol Metab Clin N Am."},{"key":"2020071620070228500_R5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/ng0298-147","article-title":"Mutations in PROP1 cause familial combined pituitary hormone deficiency","volume":"18","author":"Wu","year":"1998","journal-title":"Nat Genet."},{"key":"2020071620070228500_R6","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1210\/edrv-15-3-369","article-title":"Growth hormone (GH) insensitivity due to primary GH receptor deficiency","volume":"15","author":"Rosenfeld","year":"1994","journal-title":"Endocr Rev."},{"key":"2020071620070228500_R7","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng0196-88","article-title":"Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse","volume":"12","author":"Wajnrajch","year":"1996","journal-title":"Nat Genet."},{"key":"2020071620070228500_R8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1651-2227.1997.tb18366.x","article-title":"The dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene","volume":"423","author":"Baumann","year":"1997","journal-title":"Acta Paediatr Suppl."},{"key":"2020071620070228500_R9","first-page":"432","article-title":"Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene","volume":"83","author":"Netchine","year":"1998","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R10"},{"key":"2020071620070228500_R11"},{"key":"2020071620070228500_R12","first-page":"106","article-title":"Head circumference from birth to eighteen years","volume":"41","author":"Nellhaus","year":"1968","journal-title":"Practical composite international and interracial graphs. Pediatrics."},{"key":"2020071620070228500_R13"},{"key":"2020071620070228500_R14","author":"Roche","year":"1983"},{"key":"2020071620070228500_R15","first-page":"149","article-title":"The abdomen:hip ratio","volume":"14","author":"Forbes","year":"1990","journal-title":"Normative data and observations on selected patients. Int J Obes."},{"key":"2020071620070228500_R16"},{"key":"2020071620070228500_R17"},{"key":"2020071620070228500_R18","author":"Tanner","year":"1983"},{"key":"2020071620070228500_R19","first-page":"1312","article-title":"Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women","volume":"78","author":"Chapman","year":"1994","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R20","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/0026-0495(89)90108-X","article-title":"Regulation of plasma growth hormone-binding proteins in health and disease","volume":"38","author":"Baumann","year":"1989","journal-title":"Metabolism."},{"key":"2020071620070228500_R21","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.1073\/pnas.81.11.3443","article-title":"Strategies for multilocus linkage analysis in humans","volume":"81","author":"Lathrop","year":"1984","journal-title":"Proc Natl Acad Sci USA."},{"key":"2020071620070228500_R22","first-page":"252","article-title":"Faster sequential genetic linkage computations","volume":"53","author":"Cottingham Jr","year":"1993","journal-title":"Am J Hum Genet."},{"key":"2020071620070228500_R23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1159\/000154222","article-title":"Avoiding recomputation in linkage analysis","volume":"44","author":"Schaffer","year":"1994","journal-title":"Hum Hered."},{"key":"2020071620070228500_R24","author":"Dufour","year":"1995"},{"key":"2020071620070228500_R25","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1056\/NEJM198006263022601","article-title":"X-linked hypogammaglobulinemia and isolated growth hormone deficiency","volume":"302","author":"Fleisher","year":"1980","journal-title":"N Engl J Med."},{"key":"2020071620070228500_R26","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/ng0492-56","article-title":"Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene","volume":"1","author":"Tatsumi","year":"1992","journal-title":"Nat Genet."},{"key":"2020071620070228500_R27","first-page":"1734","article-title":"Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone","volume":"6","author":"Mayo","year":"1992","journal-title":"Mol Endocrinol."},{"key":"2020071620070228500_R28","first-page":"77","article-title":"Molecular cloning and expression of a human anterior pituitary receptor for growth hormone-releasing hormone","volume":"7","author":"Gaylinn","year":"1993","journal-title":"Mol Endocrinol."},{"key":"2020071620070228500_R29","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/BF02825444","article-title":"Growth parameters of Pakistani children","volume":"58","author":"Akram","year":"1991","journal-title":"Indian J Pediatr."},{"key":"2020071620070228500_R30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1006\/geno.1994.1045","article-title":"Assignment of the human growth hormone-releasing hormone receptor gene (GHRHR) to 7p14 by in situ hybridization","volume":"19","author":"Gaylinn","year":"1994","journal-title":"Genomics."},{"key":"2020071620070228500_R31","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1006\/geno.1994.1185","article-title":"Mapping the human growth hormone-releasing hormone receptor (GHRHR) gene to the short arm of chromosome 7 (7p13\u2013p21) near the epidermal growth factor receptor (EGFR) gene","volume":"20","author":"Vamvakopoulos","year":"1994","journal-title":"Genomics."},{"key":"2020071620070228500_R32","first-page":"1348","article-title":"Prevalence of glucose intolerance in Asian Indians","volume":"15","author":"Ramachandran","year":"1992","journal-title":"Urban-rural difference and significance of upper body adiposity. Diabetes Care."},{"key":"2020071620070228500_R33","first-page":"87","article-title":"Inherited ateliotic dwarfism in mice","volume":"67","author":"Eicher","year":"1976","journal-title":"Characteristics of the mutation, little, on chromosome 6. J Hered."},{"key":"2020071620070228500_R34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/ng0793-227","article-title":"GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function","volume":"4","author":"Godfrey","year":"1993","journal-title":"Nat Genet."},{"key":"2020071620070228500_R35","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/364208a0","article-title":"Molecular basis of the little mouse phenotype and implications for cell type-specific growth","volume":"364","author":"Lin","year":"1993","journal-title":"Nature."},{"key":"2020071620070228500_R36","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/0742-8413(91)90200-D","article-title":"Retarded cerebral growth of hormone-deficient mice","volume":"98","author":"Noguchi","year":"1991","journal-title":"Comp Biochem Physiol [C]:"},{"key":"2020071620070228500_R37"},{"key":"2020071620070228500_R38","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1126\/science.273.5277.974","article-title":"A receptor in pituitary and hypothalamus that functions in growth hormone release","volume":"273","author":"Howard","year":"1996","journal-title":"Science."},{"key":"2020071620070228500_R39","doi-asserted-by":"crossref","first-page":"6854","DOI":"10.1073\/pnas.83.18.6854","article-title":"Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro","volume":"83","author":"Billestrup","year":"1986","journal-title":"Proc Natl Acad Sci USA."},{"key":"2020071620070228500_R40","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/364208a0","article-title":"Molecular basis of the little mouse phenotype and implications for cell type-specific growth","volume":"364","author":"Lin","year":"1993","journal-title":"Nature."},{"key":"2020071620070228500_R41","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/306084a0","article-title":"Transcriptional regulation of growth hormone gene expression by growth hormone releasing factor","volume":"306","author":"Barinaga","year":"1983","journal-title":"Nature."},{"key":"2020071620070228500_R42","first-page":"4396","article-title":"Nocturnal growth hormone (GH) secretion is eliminated by infusion of GH-releasing hormone antagonist","volume":"81","author":"Ocampo-Lim","year":"1996","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/joe.0.1060001","article-title":"Effects of a fragment of human growth hormone-releasing factor in normal and Little mice","volume":"106","author":"Clark","year":"1985","journal-title":"J Endocrinol."},{"key":"2020071620070228500_R44","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1210\/endo-113-5-1669","article-title":"Etiology of growth hormone deficiency in Little, Ames, and Snell dwarf mice","volume":"113","author":"Cheng","year":"1983","journal-title":"Endocrinology."},{"key":"2020071620070228500_R45","first-page":"55","article-title":"Growth and growth hormone","volume":"278","author":"Goodman","year":"1968","journal-title":"II. A comparison of isolated growth-hormone deficiency and multiple pituitary-hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med."},{"key":"2020071620070228500_R46","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1542\/peds.59.4.628","article-title":"Head circumference in children with short stature secondary to primary hypothyroidism","volume":"59","author":"Burt","year":"1977","journal-title":"Pediatrics."},{"key":"2020071620070228500_R47","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1365-2265.1979.tb02094.x","article-title":"Effect of human growth hormone therapy on head circumference in children with hypopituitarism","volume":"10","author":"Laron","year":"1979","journal-title":"Clin Endocrinol (Oxf)."},{"key":"2020071620070228500_R48","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1210\/endo.136.9.7649123","article-title":"Differential gene expression of growth hormone (GH)-releasing hormone (GRH) and GRH receptor in various rat tissues","volume":"136","author":"Matsubara","year":"1995","journal-title":"Endocrinology."},{"key":"2020071620070228500_R49","first-page":"281","article-title":"Growth hormone releasing hormone-like messenger ribonucleic acid and immunoreactive peptide are present in human testis and placenta","volume":"75","author":"Berry","year":"1992","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R50","first-page":"1097","article-title":"Expression of the growth hormone releasing hormone gene and its peptide product in the rat ovary","volume":"130","author":"Bagnato","year":"1992","journal-title":"Endocrinology."},{"key":"2020071620070228500_R51","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1210\/endo.137.5.8612561","article-title":"A novel peptide from the growth hormone releasing hormone gene stimulates Sertoli cell activity","volume":"137","author":"Breyer","year":"1996","journal-title":"Endocrinology."},{"key":"2020071620070228500_R52","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/0002-9378(70)90534-X","article-title":"Obstetric and gynecologic considerations of dwarfism","volume":"108","author":"Tyson","year":"1970","journal-title":"Am J Obstet Gynecol."},{"key":"2020071620070228500_R53","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1210\/jcem-70-4-975","article-title":"Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone","volume":"70","author":"Bowers","year":"1990","journal-title":"J Clin Endocrinol Metab."},{"key":"2020071620070228500_R54"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/83\/11\/4065\/9231962\/jcem4065.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/83\/11\/4065\/9231962\/jcem4065.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T23:47:04Z","timestamp":1647906424000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/83\/11\/4065\/2865761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,11,1]]},"references-count":54,"journal-issue":{"issue":"11","published-print":{"date-parts":[[1998,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jcem.83.11.5226","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,11,1]]}}}