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IGSF1 deficiency: lessons from an extensive case series and recommendations for clinical management

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Abstract
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 T-4 (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.
Keywords
CONGENITAL CENTRAL HYPOTHYROIDISM, BETA-SUBUNIT GENE, THYROTROPIN-RELEASING-HORMONE, DEHYDROEPIANDROSTERONE-SULFATE, PROLACTIN PRL, THYROID SIZE, MUTATIONS, RECEPTOR, CHILDREN, ADOLESCENTS

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Citation

Please use this url to cite or link to this publication:

Chicago
Joustra, SD, CA Heinen, N Schoenmakers, M Bonomi, BEBP Ballieux, M-O Turgeon, DJ Bernard, et al. 2016. “IGSF1 Deficiency: Lessons from an Extensive Case Series and Recommendations for Clinical Management.” Journal of Clinical Endocrinology & Metabolism 101 (4): 1627–1636.
APA
Joustra, S., Heinen, C., Schoenmakers, N., Bonomi, M., Ballieux, B., Turgeon, M.-O., Bernard, D., et al. (2016). IGSF1 deficiency: lessons from an extensive case series and recommendations for clinical management. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 101(4), 1627–1636.
Vancouver
1.
Joustra S, Heinen C, Schoenmakers N, Bonomi M, Ballieux B, Turgeon M-O, et al. IGSF1 deficiency: lessons from an extensive case series and recommendations for clinical management. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM. 2016;101(4):1627–36.
MLA
Joustra, SD, CA Heinen, N Schoenmakers, et al. “IGSF1 Deficiency: Lessons from an Extensive Case Series and Recommendations for Clinical Management.” JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 101.4 (2016): 1627–1636. Print.
@article{7195254,
  abstract     = {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 T-4 (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.},
  author       = {Joustra, SD and Heinen, CA and Schoenmakers, N and Bonomi, M and Ballieux, BEBP and Turgeon, M-O and Bernard, DJ and Fliers, E and van Trotsenburg, ASP and Losekoot, M and Persani, L and Wit, JM and Biermasz, NR and Pereira, AM and Oostdijk, W and Aisenberg, J and van den Akker, ELT and Bergad{\'a}, I and Bocca, G and Braslavsky, D and Callewaert, Bert and Cummings, EA and Cuppen, MPJM and Dattani, M and Domen{\'e}, HM and van der Heyden, JC and Van Hulle, Severine and Jacobs, MAM and Links, TP and Lunshof, L and Mul, D and Neijens, FS and Pedro, HF and Salerno, M and De Schepper, Jean and Voorhoeve, PG and Zidell, AS and van der Zwaag, PA and Zwaveling-Soonawala, N},
  issn         = {0021-972X},
  journal      = {JOURNAL OF CLINICAL ENDOCRINOLOGY \& METABOLISM},
  keyword      = {CONGENITAL CENTRAL HYPOTHYROIDISM,BETA-SUBUNIT GENE,THYROTROPIN-RELEASING-HORMONE,DEHYDROEPIANDROSTERONE-SULFATE,PROLACTIN PRL,THYROID SIZE,MUTATIONS,RECEPTOR,CHILDREN,ADOLESCENTS},
  language     = {eng},
  number       = {4},
  pages        = {1627--1636},
  title        = {IGSF1 deficiency: lessons from an extensive case series and recommendations for clinical management},
  url          = {http://dx.doi.org/10.1210/jc.2015-3880},
  volume       = {101},
  year         = {2016},
}

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