Autosomal recessive deficiency of combined pituitary hormones (except ACTH) in a consanguineous Brazilian kindred

Abstract

Familial hypopituitarism represents a clinically and genetically heterogeneous disorder. In a subset of these families, defects in Pit-I, a transcription factor essential for proper pituitary development have been identified as underlying molecular cause. These patients present extreme short stature, GH, PRL and TSH deficiency but intact ACTH, LH and FSH secretion. The pituitary is usually hypoplastic. In this report we describe a consanguineous family (the parents are first cousins) with thirteen siblings. Of the ten living siblings, four (two males and two females) have panhypopituitarism with severe growth failure. They had evidence of growth hormone, prolactin and gonadotropin deficiencies and developed central hypothyroidism late in life. ACTH secretion was normal. Bone age was retarded and dual-photon bone densitometry indicated severe osteoporosis. Combined provocative tests for pituitary hormones indicated blunted responses for GH, LH, FSH and a modest rise in serum PRL and TSH. A clonidine-test failed to induce pituitary GH response. A corticotropin-releasing factor (CRF) provocative test was conducted after 6 months without the use of prednisone with a normal ACTH response after CRF in the affected sibling. Plasma IGF-I and IGF-BP3 were below normal levels. Serum E2 (females) and serum testosterone (males) levels were very low. MRI evaluation of the pituitary indicated pituitary aplasia in all subjects. The phenotype described in this kindred is different from families reported with Pit-1 mutations. However, it resembles previously published kindreds with similar clinical and biochemical findings. The relative preservation of ACTH suggests a genetic defect early in pituitary gland development.

Clinical Characteristics, Etiologies and Pathophysiology of Patients with Severe Short Stature with Severe GH Deficiency: Questionnaire Study on the Data Registered with the Foundation for Growth Science, Japan

“…In this survey, therefore, CPHD and abnormality of pituitary (and stalk) might arise from some perinatal insult [11]. However, we must take into consideration the possibility of PROP-1 and Pit-1 gene mutations, which show CPHD, since such patients infrequently show hypoplastic pituitary [11][12][13][14].…”

A novel POU1F1 pathogenic variant: Two familial case reports with phenotype expansion

“…Severe osteoporosis was previously reported in a family with CPHD due to POU1F1 variants. 2 Whole-exome-sequencing did not identify a separate genetic cause for osteoporosis. Furthermore, regular monitoring of cortisol and ACTH did not show evidence of corticosteroid excess with treatment.…”