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A Novel Mutation in The LHX3 Gene is Responsible for Combined Pituitary Hormone Deficiency, Hearing Impairment, and Vertebral Malformations

ABSTRACT

Context: The 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 years) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis and congenital hearing impairment. Three of the patients also have mild autistic-like behaviour.

Design: As 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 seventeenth century. Anatomical abnormalities in the occipito–atlanto–axial 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 phenotypic consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. Additionally the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.

FOOTNOTES

(J Clin Endocrinol Metab, published January 6, 2009, 10.1210/jc.2008-0325)

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