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IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

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Joustra, SD 
Heinen, CA 
Schoenmakers, Nadia  ORCID logo
Bonomi, M 
Ballieux, BEPB 


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.



Adolescent, Adult, Aged, Aged, 80 and over, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Female, Genetic Diseases, X-Linked, Humans, Hypothyroidism, Immunoglobulins, Infant, Male, Membrane Proteins, Middle Aged, Neuropsychological Tests, Practice Guidelines as Topic, Quality of Life, Syndrome, Thyroxine, Young Adult

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J Clin Endocrinol Metab

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The Endocrine Society
Wellcome Trust (100585/Z/12/Z)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)
The authors acknowledge the efforts of P. Beck-Peccoz, I. Campi, K. Chatterjee, E.P. van der Kleij – Corssmit, S.E. Hannema, and L. Klieverik for conceptualization of the study. We furthermore thank S. Dyack, E.F. Gevers, M.M. van Haelst, C. Noordam, M. Pekelharing-Berghuis, J. Smit, A. Vandersteen, and A.H. van der Vlugt for sharing patient data, and dr. M.C. Kruit for neuroradiological analysis of cerebral imaging. DJB was supported by operating grant MOP-133557 from the Canadian Institutes for Health Research, MOT by a graduate research award from the Natural Sciences and Engineering Research Council of Canada, and NS by the Wellcome Trust (100585/Z/12/Z) and the National Institute for Health Research Biomedical Research Centre Cambridge, United Kingdom.