Context. Mutations in transcription factors result in combined pituitary hormone deficiency (CPHD)

Objective. A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and to provide a useful framework for clinician to determine the genetic etiology and recurrence risks for individuals and families.

Design. 195 CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1.

Patients. Patients selected had two pituitary hormone deficiencies or at least one deficiency with intracerebral malformations.

Results: Total prevalence of mutations was 13.3% and, 52.4% in 20 patients with familial CPHD history. No mutation of HESX1 was observed in 16 patients harboring septo-optic dysplasia. A mutation of LHX4 gene, previously reported, was found in 1 familial case from 39 patients bearing pituitary stalk interruption syndrome (PSIS). In 109 patients without extrapituitary abnormalities, 20 had PROP1 mutations, including 8 patients with a family history of CPHD. Among 20 patients without PSIS, no LHX3 gene defect was found, even with a neck rotation deficit. One POU1F1 gene defect was found in one patient presenting the rare postpubertal association of thyrotroph (TSHD) and somatotroph (GHD) deficits.

Conclusions. Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GHD and TSHD post pubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.