Background: The last 15 years have witnessed an explosion in our knowledge of hypothalamo-pituitary development, acquired mainly from naturally-occurring and transgenic animal models. A complex genetic cascade dictates organ commitment, cell differentiation and cell proliferation within the anterior pituitary. Mutations in genes encoding both signalling molecules and transcription factors have been implicated in the aetiology of hypopituitarism, with or without other syndromic features, in mice and humans. These include HESX1, LHX3, LHX4, PROP1, POU1F1 and, more recently, SOX3 and SOX2. Phenotypes associated with mutations in genes encoding these factors and their inheritance may be highly variable.

Phenotypic profile: Mutations in genes implicated in early pituitary development may be associated with extrapituitary phenotypes, which in turn may be highly variable. For example, dominant and recessive mutations in HESX1 may be associated with septo-optic dysplasia, combined pituitary hormone deficiency (CPHD) and isolated growth hormone (GH) deficiency. Duplications and polyalanine expansions within the transcription factor SOX3 have recently been described in association with infundibular hypoplasia, hypopituitarism and variable mental retardation, whilst mutations in SOX2 are associated with variable hypopituitarism in association with learning difficulties, oesophageal atresia and anophthalmia. Mutations within the LIM domain gene LHX3 are associated with a recessive phenotype characterised by deficiencies in GH, thyroid-stimulating hormone (TSH), luteinising hormone (LH) and follicle-stimulating hormone (FSH) with sparing of the corticotrophs, in association with a short stiff neck with limited rotation. A single mutation has been described within the LHX4 gene, and is dominantly inherited and associated with GH, TSH and adrenocorticotrophic hormone (ACTH) deficiency. The mutation is associated with a hypoplastic anterior pituitary, an undescended posterior pituitary and pointed cerebellar tonsils. PROP1 and POU1F: Recessive mutations within the pituitary-specific transcription factor Prophet of Pit1, or PROP1, are associated with CPHD (GH, prolactin [PRL] and TSH deficiency with additional LH and FSH deficiency). An enlarged sella turcica with appearances suggestive of a pituitary tumour is occasionally observed in association with PROP1 mutations. ACTH deficiency can evolve in a number of patients, reflecting the need for constant review of the phenotype. Mutations within POU1F1 are associated with GH, TSH and PRL deficiencies, with the TSH deficiency being highly variable. Magnetic resonance imaging reveals either a normal or hypoplastic anterior pituitary. Mutations may be either dominantly or recessively inherited, and the R271W mutation, which is believed to act as a dominant negative mutation, represents a mutational 'hot spot'.

Conclusions: In the future, genetic analysis together with functional analysis of the mutations at the protein level will have a greater role to play in understanding the mechanisms leading to particular hypopituitary phenotypes and in predicting the evolution of these disorders. However, there is no substitute for careful delineation of the clinical, biochemical and neuroradiological phenotype prior to undertaking genetic studies.