An Uncommon Phenotype with Familial Central Hypogonadism Caused by a Novel PROP1 Gene Mutant Truncated in the Transactivation Domain

Context: PROP1 gene mutations are usually associated with childhood onset GH and TSH deficiencies, whereas gonadotroph deficiency is diagnosed at pubertal age. Objectives: We report a novel PROP1 mutation revealed by familial normosmic hypogonadotropic hypogonadism. We performed in vitro transactivation and DNA binding experiments to study functional consequences of this mutation. Setting: Three brothers were followed in the Department of Endocrinology of a French university hospital. Patients: These patients from a consanguineous kindred were referred for cryptorchidism and/or delayed puberty. Results: Initial investigations revealed hypogonadotropic hypogonadism. One of the patients had psychomotor retardation, intracranial hypertension, and minor renal malformations. The brothers reached normal adult height and developed GH and TSH deficiencies after age 30. A novel homozygous nonsense mutation (W194X) was found in the PROP1 gene, indicating that the protein is truncated in its transactivation domain. ...