This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kriström, B. Articles by Escher, S. A. Search for Related Content PubMed PubMed Citation Articles by Kriström, B. Articles by Escher, S. A. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology

A Novel Mutation in the LIM Homeobox 3 Gene Is Responsible for Combined Pituitary Hormone Deficiency, Hearing Impairment, and Vertebral Malformations

Departments of Clinical Science, Pediatrics (B.K.), of Radiation Sciences, Diagnostic Radiology (A.-M.Z., A.R.), of Orthopaedics (H.J.), of Otolaryngology (P.S.), and of Molecular Biology (S.A.E.), Umeå University, SE-901 85 Umeå, Sweden

Address all correspondence and requests for reprints to: B. Kriström, Department of Clinical Science, Pediatrics, Umeå University, SE–901 85 Umeå, Sweden. E-mail: berit.kristrom{at}pediatri.umu.se.

Context: The LIM homeobox 3 (LHX3) LIM-homeodomain transcription factor gene, found in both man and mouse, is required for development of the pituitary and motor neurons, and is also expressed in the auditory system.

Objective: The objective of this study was to determine the cause of, and further explore, the phenotype in six patients (aged 6 months to 22 yr) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis, and congenital hearing impairment. Three of the patients also have mild autistic-like behavior.

Design: Because patients with CPHD and restricted neck rotation have previously been shown to have mutations in the LHX3 gene, a candidate gene approach was applied, and the gene was sequenced. Neck anatomy was explored by computed tomography and magnetic resonance imaging, including three-dimensional reformatting.

Results: A novel, recessive, splice-acceptor site mutation was found. The predicted protein encoded by the mutated gene lacks the homeodomain and carboxyl terminus of the normal, functional protein. Genealogical studies revealed a common gene source for all six families dating back to the 17th century. Anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression of the dens axis were found in all patients assessed.

Conclusions: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypical consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. In addition, the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.