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Sporadic Heterozygous Frameshift Mutation of HESX1 Causing Pituitary and Optic Nerve Hypoplasia and Combined Pituitary Hormone Deficiency in a Japanese Patient

Department of Pediatrics, Hokkaido University School of Medicine (T.T., K.O., K.S., S.A., J.N., K.F.), Sapporo 060-0835, Japan; Department of Neonatology, Sapporo City Hospital (T.H., T.N.), Sapporo 060-0011, Japan; and Department of Pediatrics, Asahikawa Medical College (J.N., K.F.), Asahikawa 078-8510, Japan

Address all correspondence and requests for reprints to: Kenji Fujieda, M.D., Ph.D., Department of Pediatrics, Asahikawa Medical College, 2-1-1-1 Midorigaoka, Higashi, Asahikawa 078-8510, Japan. E-mail: ken-fuji{at}asahikawa-med.ac.jp.

Abstract

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.

Footnotes

Abbreviations: CPHD, Combined pituitary hormone deficiency; MRI, magnetic resonance imaging; SOD, septo-optic dysplasia.

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