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

• Published in: Endocrinology (Philadelphia) 2009-02, Vol.150 (2), p.1069-1069
• Main Authors: Kriström, Berit, Zdunek, Anna-Maija, Rydh, Anders, Jonsson, Håkan, Sehlin, Petra, Escher, Stefan A
• Format: Article
• Language: English
• Subjects: Abnormalities; Auditory system; Autism; Combined pituitary hormone deficiency; Computed tomography; Dens; Hearing; Hearing loss; Homeobox; Impairment; Lhx3 protein; Magnetic resonance imaging; Motor neurons; Mutation; Neck; Phenotypes; Pituitary; Pituitary hormones; Proteins; Rotation; Scoliosis; Vertebrae
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.150.2.9998

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.