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 transcription factor PROP1 (Prophet of Pit1). We have scanned for PROP1 mutations 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. Assessment of GH, TSH, gonadotropin, and PRL levels in homozygous affected individuals indicated impaired production of these hormones by the AP. Interestingly, two of the affected subjects also displayed cortisol deficiency, which was progressive in one of these patients. This phenotypic feature is not normally 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 and support a role for PROP1 in the maintenance and/or differentiation of all five hormone-secreting cell types. From a clinical perspective, these data indicate that the presence of an impaired pituitary-adrenal axis in CPHD patients does not exclude the possibility of an underlying PROP1 gene defect.