title: Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Tatsi
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.forename: Antonis
authors.initials: A
authors.lastname: Voutetakis
authors.forename: Eleni
authors.initials: E
authors.lastname: Valavani
authors.forename: Maria-Alexandra
authors.initials: MA
authors.lastname: Magiakou
authors.forename: Christina
authors.initials: C
authors.lastname: Kanaka-Gantenbein
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Catherine
authors.initials: C
authors.lastname: Dacou-Voutetakis
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010900:Pituitary Diseases / Q000235:genetics* / Q000473:pathology; D010902:Pituitary Gland / Q000002:abnormalities* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics; D013577:Syndrome; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000097607:Homeobox Protein SIX3; C509239:SHH protein, human; C097504:TGIF1 protein, human