Adrenocorticotropin deficiency in combined pituitary hormone deficiency patients homozygous for a novel PROP1 deletion

Incomplete differentiation of the anterior pituitary (AP) hormone-secreting cells can result in combined pituitary hormone deficiency (CPHD), in which patients display deficiencies in GH and at least one other AP hormone. The majority of familial CPHD cases are due to mutations in the pituitary tran scription factor PROP1 (Prophet of Pit1). We have scanned for PROP1 mutatio ns in a large consanguineous Indian CPHD pedigree and identified a novel 13 -bp deletion in exon 2 that is predicted to generate a null allele. Assessm ent of GH, TSH, gonadotropin, and PRL levels in homozygous affected individ uals indicated impaired production of these hormones by the AP. Interesting ly, two of the affected subjects also displayed cortisol deficiency, which was progressive in one of these patients. This phenotypic feature is not no rmally associated with CPHD resulting from PROP1 mutation. These data show that PROP1 mutations can result in panhypopituitarism, the most severe form of AP deficiency, in which the production of all hormones is compromised a nd support a role for PROP1 in the maintenance and/or differentiation of al l five hormone-secreting cell types. From a clinical perspective, these dat a indicate that the presence of an impaired pituitary-adrenal ards in CPHD patients does not exclude the possibility of an underlying PROP1 gene defec t.