Endocrine Abstracts

Recent advances in our knowledge of pituitary development, acquired mainly from animal models, have enhanced our understanding of the aetiology of isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). A number of developmental genes known to be important for organ commitment and cell differentiation and proliferation (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in CPHD with or without other syndromic features. Phenotypes associated with these genetic mutations and the inheritance may be highly variable.

Dominant and recessive mutations within HESX1 are associated with septo-optic dysplasia, CPHD and IGHD. LHX3 mutations are recessively inherited and associated with CPHD in patients with a short neck. LHX4 mutations are dominantly inherited and associated with CPHD and cerebellar abnormalities. Mutations within the transcription factor PIT1 (POU1F1) are associated with dominant or recessive inheritance of GH, prolactin and TSH deficiency, whilst mutations in the paired-like homeobox gene PROP1 are associated with recessive GH, prolactin, TSH and gonadotrophin deficiencies, with a variable pituitary mass that can then involute. Cortisol deficiency may evolve in some patients. More recently, a polyalanine expansion within SOX3, a member of the SOX family of transcription factors, has been associated with IGHD and mental retardation.

Mutations within these developmental genes account for a small proportion of cases of IGHD and CPHD, suggesting the role of other as yet unidentified genetic and environmental factors. However, functional analyses of these mutations reveal valuable insights into the function of the proteins and into the complex genetic cascade underlying pituitary development. Hence, genetic testing will in the future have a greater role to play in understanding the mechanisms leading to particular hypopituitary phenotypes, and also in predicting the evolution of these disorders. There is nevertheless no substitute for careful delineation of the phenotype prior to undertaking genetic studies.