Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes

J Clin Endocrinol Metab. 2013 Apr;98(4):E779-84. doi: 10.1210/jc.2012-3982. Epub 2013 Mar 8.


Context: Holoprosencephaly (HPE) is a developmental defect characterized by wide phenotypic variability, ranging from minor midline malformations (eg, single central incisor) to severe deformities. In 10-15% of HPE patients, mutations in specific genes have been identified (eg, SHH, TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a distinct abnormality of unknown pathogenesis, whereas isolated pituitary hypoplasia (IPH) has been linked to various developmental genes.

Objective: Three of our patients with PSIS had a single central incisor, a malformation encountered in some HPE cases. Based on this observation, we initiated a search for mutations in HPE-associated genes in 30 patients with PSIS or IPH.

Design and participants: The entire coding region of the TGIF, SHH, and SIX3 genes was sequenced in patients with combined pituitary hormone deficiency associated with either PSIS or IPH and in healthy controls.

Results: Two novel mutations in the HPE-related genes were detected (ie, c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH gene) in 2 of our patients. The overall incidence of HPE-related gene mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No molecular defect in the SIX3 gene was detected in our cohort.

Conclusions: The data suggest that HPE-related gene mutations are implicated in the etiology of isolated pituitary defects (PSIS or IPH). Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE spectrum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Cohort Studies
  • Eye Proteins / genetics
  • Female
  • Hedgehog Proteins / genetics
  • Holoprosencephaly / genetics*
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Mutation* / physiology
  • Nerve Tissue Proteins / genetics
  • Pedigree
  • Pituitary Diseases / genetics*
  • Pituitary Diseases / pathology
  • Pituitary Gland / abnormalities*
  • Pituitary Gland / pathology
  • Repressor Proteins / genetics
  • Syndrome


  • Eye Proteins
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Repressor Proteins
  • SHH protein, human
  • Sine oculis homeobox homolog 3 protein
  • TGIF1 protein, human