Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the Prophet of Pit-1 gene

The Prophet of Pit-1 gene (PROP1) encodes a paired-like homeodomain protein , which is expressed early in pituitary gland development. When mutated, it is responsible for combined pituitary hormone deficiency (CPHD) in humans, as well as in Ames dwarf mice (df/df). Several independent mutations in th e homeodomain of PROP1 have been identified as causative for the human CPHD phenotype, which has been characterized, thus far, as absence or low level s of GH, PRL, TSH, LH, and FSH. Here, we report 10 CPHD cases, 9 of which w ere born to consanguineous marriages occurring in a large family living in an isolated area in the Southeast of Brazil. All affected patients present complete absence of puberty and low GH, PRL, TSH, LH, and FSH associated wi th severe hypoplasia of the pituitary gland, as seen by MRI. All 3 exons of the PROP1 genes of these patients were sequenced. The 301-302delAG framesh ift, mutation was found in both alleles of each affected case. Surprisingly , we observed ACTH/cortisol insufficiency associated with the PROP1 phenoty pe. The patients' ages varied between 8 and 67 yr, and cortisol response im pairment was identified in 5 of 6 of the older patients and in an Il-yr-old patient. Previous studies have not fully characterized patients at advance d ages, leading us to conclude that the phenotype of this PROP1 mutation in cludes late-onset adrenal insufficiency. We present an extensive clinical a nalysis of all of these patients. The presence of ACTH/cortisol deficiency in this family bearing the PROP1 301-302delAG mutation indicates the import ance of a complete endocrine characterization and of life-long monitoring o f PROP1 patients.