In recent years a number of specific transcription factors required for the normal development of the anterior pituitary have been identified and studied. It is not surprising that mutations in the genes encoding these proteins can lead to abnormal development of the cells that secrete the hormones of the anterior pituitary and therefore result in isolated, or more commonly, combined, hormonal deficiencies. Some of the best understood of these factors are listed in Table1.
Table1. Pituitary Transcription Factors in Hormone Deficiency
Pit1 is a POU (an acronym for three related transcription factors) domain class 1 transcription factor, which is also known as POU1F1. The protein is found only in the pituitary gland and although it was first identified by its binding to regulatory sites in the growth hormone gene promoter, it is now recognized to also bind to the regulatory region of the genes for the GHRH receptor, PRL, and the TSHβ subunit. Patients with Pit1 disorders are usually diagnosed when the failure to grow normally, due to GH deficiency, becomes apparent.
Prop1 (Prophet of Pit1) precedes and induces the expression of POU1F1. In mice it is expressed exclusively in the embryonic pituitary, where it is implicated in the differentiation of POU1F1-dependent somatotrophs, lactotrophs and thyrotrophs. The mechanisms for its effects on the gonadotropins and ACTH are not clear and are clinically more variable than those of the other hormones.
Lhx3 and Lhx4 (LIM-homeobox-3 and -4) have many structural features in common but impact different patterns of cell lineages in the developing pituitary. Thus their clinical presentations differ. Patients with Lhx-3 mutations invariably present with combined hypopituitarism with deficiency of GH, TSH, gonadotropins, and PRL. There can occasionally be impaired corticotroph function. Individuals with heterozygous mutations in the gene for Lhx-4 present with a highly variable pituitary hormone deficiency phenotype. All patients demonstrate GH deficiency, and most also have a deficit in TSH secretion, whereas the gonadotroph and adrenal axes are sometimes affected, but sometimes normal.
Mutations in Tbx19 (TPIT) have been noted in patients with early onset isolated ACTH deficiency. Severe hypoglycemia, jaundice, and neonatal death often result from such defects. Tbx19 is required for normal development and differentiation of both corticotrophs and melanotrophs and is required for the activation of POMC expression.
