title: Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked Central Hypothyroidism without macroorchidism.
abstract: OBJECTIVE
  IGSF1 deficiency syndrome (IDS) is a recently described X-linked congenital central hypothyroidism disorder characterized by loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. The phenotypic spectrum and intrafamilial variability associated with IDS remain unclear due to a paucity of large, well-characterized pedigrees. Here, we present phenotypic analysis and molecular characterization of a five-generation pedigree with IGSF1 deficiency containing 10 affected males.
  
  
  METHODS
  Pituitary function was assessed in all available family members (n = 8 affected males and n = 5 carrier females). Molecular characterization of the family was performed by Sanger sequencing of PCR products amplified from the IGSF1 locus and by array comparative genomic hybridization.
  
  
  RESULTS
  A 42-kb IGSF1 deletion spanning the entire coding sequence was identified in all affected males. TSH deficiency, although subclinical in one case, was identified in all affected males (n = 8). PRL and GH deficiency were also present in 5 of 6 and 4 of 8 affected males, respectively. In contrast to previous reports, macroorchidism was not detected in any of the four affected males who were examined for this feature. Only 1 of 5 carrier females had pituitary dysfunction (TSH and GH deficiency).
  
  
  CONCLUSIONS
  Individuals with identical IGSF1 deletions can exhibit variable pituitary hormone deficiencies, of which overt TSH deficiency is the most consistent feature. We also show that macroorchidism is not obligatory in males with IDS. Mutations of IGSF1 should therefore be considered in males with isolated hypopituitarism that includes TSH deficiency.
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
authors.forename: James N
authors.initials: JN
authors.lastname: Hughes
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Aubert
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Heatlie
authors.affiliation: School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Gardner
authors.affiliation: Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.|School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Novartis Institutes of Biomedical Research, Biomarkers Division, Cambridge, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Morgan
authors.affiliation: Department of Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA.|Department of Medicine, Danbury Hospital, Danbury, CT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Belsky
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia. paul.thomas@adelaide.edu.au.|Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia. paul.thomas@adelaide.edu.au.
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Thomas
mesh_terms: D055028:Comparative Genomic Hybridization; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017384:Sequence Deletion
chemical_list: C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins