Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient

J Clin Endocrinol Metab. 2003 Jan;88(1):45-50. doi: 10.1210/jc.2002-020818.


HESX1/Hesx1 is a member of the paired-like class of homeobox genes and is essential for pituitary and forebrain development. Mice with a targeted homozygous deletion of the Hesx1 show severe central nervous system defects, absence of optic vesicles, and a very small anterior pituitary gland. This phenotype is similar to the abnormalities observed in the human disorder called septo-optic dysplasia, a syndromic form of congenital hypopituitarism. To date, four missense mutations in the human HESX1 have been described in individuals with phenotypes ranging from severe septo-optic dysplasia, relatively mild combined pituitary hormone deficiency (CPHD), to isolated GH deficiency. Here we report a Japanese patient with CPHD (GH, TSH, LH, FSH, and ACTH deficiency) due to a novel sporadic HESX1 mutation. Brain magnetic resonance imaging examination revealed hypoplastic anterior pituitary, ectopic posterior lobe, and left optic nerve hypoplasia. Molecular analysis identified the insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. This mutation changes a reading frame and introduces a premature stop codon soon after the mutation site. Therefore, this mutation would be predicted to generate a protein lacking the carboxyl-terminal homebox domain (DNA-binding domain) and cause the disease. Family analysis demonstrated that neither of the patient's parents harbored this mutation, indicating that the mutation had arisen de novo. In conclusion, a de novo heterozygous frameshift mutation in exon 2 of the HESX1 causes severe CPHD with optic nerve hypoplasia in a human.

Publication types

  • Case Reports

MeSH terms

  • Asian Continental Ancestry Group* / genetics*
  • Base Sequence / genetics
  • Basic Helix-Loop-Helix Transcription Factors
  • Child, Preschool
  • Frameshift Mutation*
  • Heterozygote*
  • Homeodomain Proteins / genetics*
  • Humans
  • Japan
  • Male
  • Metabolism, Inborn Errors / genetics
  • Optic Nerve / abnormalities*
  • Pituitary Gland / abnormalities*
  • Pituitary Hormones / deficiency*
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • HESX1 protein, human
  • Homeodomain Proteins
  • Pituitary Hormones
  • Transcription Factor HES-1
  • HES1 protein, human