Genetics of IGHD and CPHD

M T Dattani

Paediatric Endocrinology, Institute of Child Health/Great Ormond Street Children’s Hospital, London

Endocrine Nurses Training Course 10-12 September 2003
St Aidan's College, University of Durham, Windmill Hill, Durham DH1 3LJ

Recent advances in molecular biology have enhanced our understanding of the aetiology of growth hormone deficiency. A number of developmental genes (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in combined pituitary hormone deficiency (CPHD) with or without other syndromic features.

Phenotypes associated with mutations within these genes as well as the inheritance may be highly variable. For example, mutations within HESX1 are associated with septo-optic dysplasia, CPHD and isolated growth hormone deficiency (IGHD). LHX3 mutations are recessively inherited and associated with CPHD in patients with a short neck with limited rotation. LHX4 mutations are dominantly inherited and associated with CPHD in association with cerebellar abnormalities. Mutations within the transcription factor PIT1 or 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. Patients with PROP1 deficiency manifest a variable pituitary mass that can then involute, with possible evolution of cortisol deficiency in some patients. The pituitary mass can be mistaken for a tumour, and lead to unnecessary interventional procedures. Additionally, the GHRH receptor gene and the GH-1 gene have been implicated in isolated growth hormone deficiency.

Novel mechanisms for the various phenotypes are now emerging eg. dominant-negative GHD due to splice site mutations within the GH-1 gene. Mutations within the genes described in this review account for a small proportion of cases of IGHD and CPHD, suggesting the role of other as yet unidentified genetic and environmental factors. Hence, genetic testing will in the future have a greater role to play in understanding the mechanisms leading to particular GHD phenotypes, and also in predicting the evolution of these disorders. However, there is no substitute for careful delineation of the phenotype prior to undertaking genetic studies.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society