IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management
Open accessAbstract
Context: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. Objective: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. Methods: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. Results: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. Conclusion: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.
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IGSF1 is the most frequently implicated gene in congenital central hypothyroidism.
“Recent data indicate IGSF1 as the most frequently implicated gene in congenital CeH [32].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [32]
The Abstract identifies congenital central hypothyroidism as a feature of IGSF1 deficiency, and the Discussion’s Genetic evaluation section recommends testing for IGSF1 mutations in patients with central hypothyroidism of unknown cause. Neither passage establishes that IGSF1 is the most frequently implicated gene relative to other genes. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIGSF1 is the most frequently implicated gene in congenital central CH.
“Recent data indicate IGSF1 as the most frequently implicated gene in congenital central CH (235).”
In IGSF1 syndrome, central CH is associated with abnormal testicular growth leading to adult macro-orchidism (+2.0 SD), a tendency toward pubertal delay, low prolactin, and rarely reversible growth hormone deficiency.
“In this syndrome, central CH is associated with abnormal testicular growth leading to adult macro-orchidism (+2.0 standard deviation score), a tendency toward pubertal delay, low prolactin, and, rarely, reversible growth hormone deficiency (234,235).”
IGSF1 mutations are the molecular cause of an X-linked syndrome including mild-to-moderate central CH.
“Immunoglobulin superfamily member 1 gene (IGSF1) mutations are the molecular cause of a recently described X-linked syndrome, including mild-to-moderate central CH.”
Some female carriers of IGSF1 mutations can manifest central CH.
“Some female carriers can also manifest central CH.”
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- Authors
- Joustra, S. D., Heinen, C. A., Schoenmakers, N., Bonomi, M., Ballieux, B. E. P. B., Turgeon, M.-O., Bernard, D. J., Fliers, E., van Trotsenburg, A. S. P., Losekoot, M., Persani, L., Wit, J. M., Biermasz, N. R., Pereira, A. M., Oostdijk, W., & on behalf of the IGSF1 Clinical Care Group
- Affiliations
- Leiden University (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Cambridge (GB)
- University of Milan (IT)
- McGill University (CA)
- Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), 1100 DE, The Netherlands
- Leiden University Medical Center (NL)
- Department of Pediatrics (S.D.J., J.M.W., W.O.), 2300 C Leiden, The Netherlands
- Corresponding author
- Biermasz, N. R.
- Oostdijk, W.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-04-01
- Volume
- 101
- Issue
- 4
- Pages
- 1627-1636
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4880178
- OpenAlex
- W2261702141
- Cited by
- 91
- References
- 47
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 6 · 2020: 6 · 2019: 14 · 2018: 14 · 2017: 7 · 2016: 3 · 2015: 1
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (100585, 100585/Z/12/Z)
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- Universiteit Leiden
- Leids Universitair Medisch Centrum
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- central hypothyroidism, macroorchidism, delayed puberty, prolactin deficiency, adrenal insufficiency, levothyroxine, dehydroepiandrosterone, waist circumference, metabolic parameters, clinical management guidelines
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Female, Humans, Hypothyroidism, Immunoglobulins, Infant, Male, Membrane Proteins, Middle Aged, Neuropsychological Tests, Quality of Life, Syndrome, Thyroxine, Practice Guidelines as Topic, Genetic Diseases, X-Linked, Young Adult
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