Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene

Background One of the causes of combined pituitary hormone deficiency (CPHD ) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and g onadotropin deficiency, but recent papers have described a concomitant alte ration of the corticotrope function. Objective: To make a detailed investigation of the hypothalamic-pituitary-a drenal axis in two sisters with PROP-1 gene mutations. Patients: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retard ation and central hypothyroidism during childhood, and showed central hypog onadism at the age of puberty. No clear clinical symptoms and signs of hypo cortisolism were present. Methods: GH, TSH, free thyroxine, total tri-iodot hyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amp lification and sequencing analysis of PROP-1 gene. Results: Both patients showed GH, PRL. LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH inje ction. Circulating concentrations of TSH were normal in basal conditions, b ut failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal a nd prolonged. The cortisol response to both tests, and to the ACTH test, wa s clearly impaired. In both sisters, the genetic analysis showed the presen ce of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results i n the synthesis of a protein with no residual functional activity. Conclusion: In addition to GH. TSH, PRL and gonadotropin deficiency, patien ts with PROP-1 gene mutations can present with late-onset central hypocorti solism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pitu itary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP- 1-deficient patients.