A significant proportion of cases of GH deficiency (5-30%) may be due to genetic causes. At least four Mendelian types of isolated GH deficiency (IGHD) have been delineated based on the mode of inheritance and the degree of GH deficiency: IGHD type IA, autosomal recessive with absent endogenous GH; type IB, autosomal recessive with diminished GH; type II, autosomal dominant with diminished GH; and type III, X-linked with diminished GH. Most patients with IGHD type IA have heterogeneous deletions, ranging in size from 6.7 kb to 45 kb, that encompass the entire gene encoding for pituitary GH, GH-1. Nonsense, frameshift and splice GH-1 mutations that predict a complete lack of bioactive GH synthesis in homozygotes have also been reported in association with IGHD IA. Additionally, some cases of IGHD type II have dominant negative mutations in one allele of the GH-1 gene. Panhypopituitary Dwarfism (PD), a condition characterized by deficiency of at least other pituitary trophic hormone in addition to GH deficiency, can have autosomal and X-Linked modes of inheritance. Interestingly, both recessive and dominant mutations at the gene encoding for the pituitary transcription factor Pit-1 have been found in a specific subtype of PD that combines GH, prolactin and TSH deficiencies. In contrast, the loci and mutations responsible for the other Mendelian forms of IGHD and PD remain unknown. Linkage studies using genetic markers have excluded the GH locus on chromosome 17 in similar to 50% of the cases and the GH-releasing hormone (GHRH) locus on chromosome 20 in all the studied families (types IB and II) in whom the mutation cannot be traced to defects in these genes. Furthermore, several uncharacterized loci on the X chromosome must be required for normal GH secretion. In summary, genetic studies have provided a better understanding of the mechanism of GH deficiency as well as new tools for specific diagnosis of several forms of IGHD and PD. However, isolation and evaluation of other genes involved in GH secretion is still necessary. Several possible candidate genes have been recently cloned and characterized, including genes encoding the human GHRH receptor, the pituitary adenylate cyclase activating polypeptide (PACAP) and the PACAP receptor. Analysis of these genes in IGHD and PD families may clarify the molecular basis of the defect and also provide new insights into the complex regulation of GH.
