title: Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss.
abstract: BACKGROUND
  Congenital combined pituitary hormone deficiency (CPHD) is a rare heterogeneous group of conditions. CPHD-type 3 (CPHD3; MIM# 221750) is caused by recessive mutations in LHX3, a LIM-homeodomain transcription factor gene. The isoforms of LHX3 are critical for pituitary gland formation and specification of the anterior pituitary hormone-secreting cell types. They also play distinct roles in the development of neuroendocrine and auditory systems.
  
  
  METHODS
  Here, we summarize the clinical, endocrinological, radiological and molecular features of three patients from two unrelated families. Clinical evaluation revealed severe CPHD coupled with cervical vertebral malformations (rigid neck, scoliosis), mild developmental delay and moderate sensorineural hearing loss (SNHL). The patients were diagnosed with CPHD3 based on the array of hormone deficiencies and other associated syndromic symptoms, suggestive of targeted LHX3 gene sequencing. A novel missense mutation c.437G > T (p. Cys146Phe) and a novel nonsense mutation c.466C > T (p. Arg156Ter), both in homozygous forms, were found. The altered Cys146 resides in the LIM2 domain of the encoded protein and is a phylogenetically conserved residue, which mediates LHX3 transcription factor binding with a zinc cation. The p. Arg156Ter is predicted to result in a severely truncated protein, lacking the DNA binding homeodomain.
  
  
  CONCLUSIONS
  Considering genotype/phenotype correlation, we suggest that the presence of SNHL and limited neck rotation should be considered in the differential diagnosis of CPHD3 to facilitate molecular diagnosis. This report describes the first LHX3 mutations from Saudi patients and highlights the importance of combining molecular diagnosis with the clinical findings. In addition, it also expands the knowledge of LHX3-related CPHD3 phenotype and the allelic spectrum for this gene.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O.Box 3354, Riyadh, 11211, Saudi Arabia. kramzan@kfshrc.edu.sa.
authors.forename: Khushnooda
authors.initials: K
authors.lastname: Ramzan
authors.affiliation: Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Bassam
authors.initials: B
authors.lastname: Bin-Abbas
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O.Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Lolwa
authors.initials: L
authors.lastname: Al-Jomaa
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O.Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Rabab
authors.initials: R
authors.lastname: Allam
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O.Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Faiqa
authors.initials: F
authors.lastname: Imtiaz
mesh_terms: D002574:Cervical Vertebrae / Q000000981:diagnostic imaging; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D014157:Transcription Factors
keywords: Cysteine 146; Differential diagnosis; LHX3; Pituitary hormone deficiency; Sensorineural hearing loss