PROP1 mutations cause progressive failure of anterior pituitary function including adrenal insufficiency

Abstract

Mutations in the PROP1 gene are the most common genetic defects in patients with combined pituitary insufficiency. The phenotype of these patients is typically characterized by deficiency of GH, TSH, Prl, and gonadotropins. There is, however, much controversy about the time of onset and the extent of pituitary insufficiency in this disorder. In particular it is unclear, whether adrenal failure is a typical feature of this condition. In this study we conducted a longitudinal analysis of 9 patients with PROP1 mutations covering 15.7±3.4yrs. Patients, aged 5 to 39yrs initially presented with growth failure (-3.7±0.3 height SDS) at a mean age of 4.9±0.8yrs. The first endocrine defects diagnosed in all patients were GH and TSH deficiency, and substitution was instituted at 6.1±1.1 and 6.8±1.2yrs, accordingly. All patients also required sex hormone substitution at 15.0±0.7yrs since they failed to enter puberty. Interestingly, repeated functional testing of the anterior pituitary axes revealed a increasingly progressive decline with age. Pair wise intra-individual analysis of sequential stimulation tests several years apart confirmed the decrease in stimulated peak levels of GH (1.2±0.2 vs. 0.3±0.1, P=0.062), TSH (3.7±0.5 vs. 1.0±0.3, P=0.0039), Prl (473.0±115.7 vs. 152.4±35.1, P=0.062) and cortisol (647.2±114.9 vs. 313.2±38.3, P=0.0078). Also, all of our patients gradually developed at least partial adrenal insufficiency with a decline of the function of the HPA axis as confirmed by significantly decreasing basal cortisol levels and stimulated peak cortisol levels with age. They presented with symptoms of adrenal failure later in their clinical course and eventually required substitution with hydrocortisone at 14.1±6.6yrs. In conclusion, adrenal insufficiency appears to be a common feature of this genetic defect that has important clinical relevance already in childhood and adolescence. We also provide evidence that the entire anterior pituitary insufficiency is progressive, eventually encompassing all anterior pituitary axes including the HPA axis.