The IGSF1 deficiency syndrome: characteristics of male and female patients

J Clin Endocrinol Metab. 2013 Dec;98(12):4942-52. doi: 10.1210/jc.2013-2743. Epub 2013 Oct 9.


Context: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce.

Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.

Methods: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory.

Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases.

Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged, 80 and over
  • Aging*
  • Child
  • Congenital Hypothyroidism / genetics
  • Congenital Hypothyroidism / immunology
  • Congenital Hypothyroidism / pathology
  • Congenital Hypothyroidism / physiopathology*
  • Family Health
  • Female
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / immunology
  • Genetic Diseases, X-Linked / pathology
  • Genetic Diseases, X-Linked / physiopathology*
  • Heterozygote
  • Human Growth Hormone / blood
  • Human Growth Hormone / deficiency
  • Humans
  • Immunoglobulins / deficiency*
  • Immunoglobulins / genetics
  • Infant
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Metabolic Syndrome / etiology
  • Organ Size
  • Prolactin / blood
  • Puberty, Delayed / etiology
  • Testicular Diseases / genetics
  • Testicular Diseases / immunology
  • Testicular Diseases / pathology
  • Testicular Diseases / physiopathology*
  • X Chromosome Inactivation


  • IGSF1 protein, human
  • Immunoglobulins
  • Membrane Proteins
  • Human Growth Hormone
  • Prolactin