title: A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Clinical Science, Pediatrics, Umeå University, Umeå, Sweden. berit.kristrom@pediatri.umu.se
authors.forename: Berit
authors.initials: B
authors.lastname: Kriström
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Zdunek
authors.forename: Anders
authors.initials: A
authors.lastname: Rydh
authors.forename: Håkan
authors.initials: H
authors.lastname: Jonsson
authors.forename: Petra
authors.initials: P
authors.lastname: Sehlin
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Escher
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006311:Hearing Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D060850:LIM-Homeodomain Proteins; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010907:Pituitary Hormones / Q000172:deficiency* / Q000235:genetics; D012600:Scoliosis / Q000235:genetics; D017384:Sequence Deletion; D013116:Spinal Cord / Q000002:abnormalities*; D014157:Transcription Factors
chemical_list: D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D010907:Pituitary Hormones; D014157:Transcription Factors