Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked Central Hypothyroidism without macroorchidism

James N. Hughes, Matthew Aubert, Jessica Heatlie, Alison Gardner, Jozef Gecz, Thomas Morgan, Joseph Belsky, Paul Q. Thomas

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


Objectives: 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. Patients and 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). Conclusion: 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.

Original languageEnglish
Pages (from-to)609-615
Number of pages7
JournalClinical Endocrinology
Issue number4
Publication statusPublished or Issued - 1 Oct 2016
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this