Normal hypothalamo-pituitary development is critically dependent upon a complex genetic cascade that dictates organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Mutations in a number of transcription factors have been implicated in the aetiology of congenital hypopituitarism (CH) in mice and humans; resulting phenotypes and their inheritance may be highly variable. Mutations in genes implicated in early pituitary development may be associated with variable extra-pituitary phenotypes e.g., dominant and recessive mutations in HESX1 may be associated with septo-optic dysplasia (SOD), combined pituitary hormone deficiency (CPHD) and isolated growth hormone deficiency (IGHD). Duplications and mutations within SOX3 have recently been described in association with infundibular hypoplasia, hypopituitarism and variable mental retardation, whilst SOX2 mutations are associated with variable CH in association with learning difficulties, oesophageal atresia and anophthalmia. Recessive LHX3 mutations are associated with CH and a short stiff neck. Dominant LHX4 mutations are also associated with CH and pointed cerebellar tonsils on MRI. Recessive mutations within the pituitary-specific transcription factor Prophet of Pit1 or PROP1 are associated with CH, often with an enlarged pituitary. ACTH deficiency can evolve in a number of patients, reflecting the need for constant review of the phenotype. Dominant or recessive mutations within POU1F1 are associated with GH, variable TSH and prolactin deficiency. To conclude, genetic analysis together with functional analysis of the mutations at the protein level will in the future have a greater role to play in understanding the mechanisms leading to particular CH phenotypes and their evolution. However, there is no substitute for careful delineation of the clinical, biochemical and neuroradiological phenotype prior to undertaking genetic studies.
03 - 07 May 2008
European Society of Endocrinology