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Impaired Adrenocorticotropin-Adrenal Axis in Combined Pituitary Hormone Deficiency Caused by a Two-Base Pair Deletion (301–302delAG) in the Prophet of Pit-1 Gene¹

Department of Reproductive Medicine (F.P., V.V.V., P.L.M.), University of California, San Diego, La Jolla, California 92093-0674; Endocrine Genetics Unit, Department of Medicine, and LIM-25 (S.P.A.T., C.F., D.M.L., C.Y.H.), University of São Paulo, School of Medicine, 02146–903, São Paulo, Brazil; and Department of Pediatrics (J.D.C.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2578

Address correspondence and requests for reprints to: Flavia Pernasetti, Department of Reproductive Medicine. 0674, 9500 Gilman Drive, La Jolla, California 92093. E-mail: fpernase{at}ucsd.edu

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 the homeodomain of PROP1 have been identified as causative for the human CPHD phenotype, which has been characterized, thus far, as absence or low levels of GH, PRL, TSH, LH, and FSH. Here, we report 10 CPHD cases, 9 of which were 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 with 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 frameshift mutation was found in both alleles of each affected case. Surprisingly, we observed ACTH/cortisol insufficiency associated with the PROP1 phenotype. The patients’ ages varied between 8 and 67 yr, and cortisol response impairment was identified in 5 of 6 of the older patients and in an 11-yr-old patient. Previous studies have not fully characterized patients at advanced ages, leading us to conclude that the phenotype of this PROP1 mutation includes late-onset adrenal insufficiency. We present an extensive clinical analysis of all of these patients. The presence of ACTH/cortisol deficiency in this family bearing the PROP1 301–302delAG mutation indicates the importance of a complete endocrine characterization and of life-long monitoring of PROP1 patients.

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