Symptomatic Heterozygotes and Prenatal Diagnoses in a Nonconsanguineous Family with Syndromic Combined Pituitary Hormone Deficiency Resulting from Two Novel LHX3 Mutations

Context: Only 11 mutations have been reported in the transcription factor LHX3, known to be important for the development of the pituitary and motor neurons. All patients were homozygous, with various syndromic forms of combined pituitary hormone deficiency (CPHD), hampering to allocate, in these consanguineous patients, the respective contribution of LHX3 and additional genes to each symptom. Objective: The aim of the study was to report the family history and the molecular basis of a nonconsanguineous patient with syndromic CPHD. Patient: The patient, who presented at birth with respiratory distress, had a syndromic CPHD, including severe scoliosis, and normal intelligence. His father and paternal grandmother displayed limited head rotation. Results: Two new LHX3 defects were identified. The paternally inherited c.252-3C>G mutation, which disrupts an acceptor splice site, would lead to severely truncated proteins containing a single LIM domain, resembling LIM-only proteins. Coexpression studies revealed the dominant-negative effect of this LIM-only protein over the wild-type LHX3. The maternally inherited p.Cys118Tyr mutation results in partial loss of transcriptional activity and synergy with POU1F1. Given the severity of the patient's phenotype, two prenatal diagnoses were performed: the first led to pregnancy interruption, the second to the birth of a healthy boy. Conclusions: This study of the first nonconsanguineous patient with LHX3 mutations demonstrates the pleiotropic roles of LHX3 during development and its full involvement in the complex disease phenotype. Isolated limitation of head rotation may exist in heterozygous carriers and would result from a dominant-negative effect. These data allowed the first prenatal diagnoses of this severe condition to be performed. (J Clin Endocrinol Metab 97: E503-E509, 2012)