Isolated Growth Hormone Deficiency, Type Ib

A number sign (#) is used with this entry because isolated growth hormone deficiency type IB (IGHD1B) is caused by homozygous or compound heterozygous mutation in the GH1 (139250) gene on chromosome 17q23.

Description

IGHD type IB is an autosomal recessive disorder characterized by low but detectable levels of GH, short stature (more than 2 SD below the mean for age and sex), delayed bone age, and a good response to rhGH treatment without antibody formation (summary by Alatzoglou et al., 2014).

For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400.

Clinical Features

Cogan et al. (1993) reported members of a consanguineous Saudi Arabian family with typical features of IGHD1B.

Abdul-Latif et al. (2000) identified an extended, highly inbred Bedouin kindred with isolated growth hormone deficiency that clinically fulfilled the criteria for type IB.

Molecular Genetics

In affected members of a consanguineous Saudi Arabian family with IGHD1B, Cogan et al. (1993) identified homozygosity for a donor splice site mutation in intron 4 in the GH1 gene (IVS4+1G-C; 139250.0005), which segregated with the phenotype in the family. In a different consanguineous Saudi Arabian family with IGHD1B, Phillips and Cogan (1994) identified homozygosity for a different substitution at the same donor splice site of intron 4 (IVS4+1G-T; 139250.0005) in the GH1 gene.

In affected members of a highly consanguineous Bedouin kindred with IGHD1B, Abdul-Latif et al. (2000) identified homozygosity for a mutation at the fifth base of intron 4 in the GH1 gene, 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.

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.