Growth Hormone Deficiency, Isolated Partial

A number sign (#) is used with this entry because of evidence that isolated partial growth hormone (GH; 139350) deficiency (GHDP) is caused by heterozygous, compound heterozygous, or homozygous mutation in the growth hormone secretagogue receptor gene (GHSR; 601898) on chromosome 3q26.

Molecular Genetics

Pantel et al. (2006) screened for mutations in the GHSR gene in 41 probands with idiopathic short stature and 51 probands with isolated growth hormone deficiency and identified the same mutation (A204E; 601898.0001) in 2 probands of unrelated Moroccan families. No mutations in the GH1 (139250) or GHRHR (139191) genes were identified in the probands. In family 1, which was consanguineous, the proband was homozygous for the mutation; 2 affected sibs and the affected parents were all heterozygous for the mutation, as was an unaffected sib whose height was in the low range of normal (-1.1 SD below the mean). In family 2, the proband and her affected father were both heterozygous for the mutation, as were 2 unaffected sibs, 1 of normal height and the other in the low range of normal (-1.2 SD below the mean), consistent with incomplete penetrance and variable expressivity. Pantel et al. (2006) noted that 2 of the affected children had a phenotype compatible with idiopathic short stature, whereas the other 2 had isolated growth hormone deficiency confirmed by testing. The mutation was not found in 100 Moroccan controls. Functional studies showed that the mutation results in decreased cell surface expression of the receptor and selectively impairs the constitutive activity of GHSR, while preserving its ability to respond to ghrelin. The authors suggested autosomal dominant inheritance of growth failure in these families.

In a 17.4-year-old male proband with short stature and endocrine analysis consistent with partial IGHD, Pantel et al. (2009) analyzed 3 candidate genes, GH1, GHRHR, and GHSR, and identified compound heterozygosity for a nonsense and a missense mutation in the GHSR gene (W2X, 601898.0002 and R237W, 601898.0003). The proband initially presented at 5 years of age with episodic abdominal pain, vomiting, hypoglycemia, and ketosis in the context of postnatal growth delay. He had markedly low levels of IGF1 (147440) and a low GH response to provocative tests without other pituitary hormone deficiency. His pituitary gland was subnormal in size by MRI. He responded to treatment with GH and had delayed puberty starting at 15 years of age; unexplained recurrent episodes of abdominal pain, vomiting, and ketosis continued while on GH therapy, but without hypoglycemia. His unaffected mother and an unaffected brother were heterozygous for the missense mutation; his father, who had normal stature but was reported to have had delayed puberty, was heterozygous for the nonsense mutation. His mother had a first cousin who had very short stature (adult height, 138 cm). In vitro expression experiments showed that the R237W mutation would result in a partial loss of constitutive activity of the receptor, whereas both its ability to respond to ghrelin and its cell surface expression are preserved.