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

JOUSTRA, S.D.; HEINEN C.A.; SCHOENMAKERS N.; BONOMI, M.; BALLIEUX B.E.; TURGEON M.O.; BERNARD D.J.; FLIERS E.; VAN TROTSENBURG A.S.; LOSEKOOT M.; PERSANI L.; WIT J.M.; BIERMASZ N.R.; PEREIRA A.M.; OOSTDIJK W.; AISENBERG J.; VAN DEN AKKER E.L.; BERGADÁ, I; BOCCA G.; BRASLAVSKY D; CALLEWAERT B.; CUMMINGS E.A.; CUPPEN M.P.; DATTANI M.; DOMENE H M; VAN DER HEYDEN J.C.; VAN HULLE S.; JACOBS M.A.; LINKS T.P.; LUNSHOF L.; MUL D.; NEIJENS F.S.; PEDRO H.F.; SALERNO M.; DE SCHEPPER J.; VOORHOEVE P.G.; ZIDELL A.S.; VAN DER ZWAAG P.A.; ZWAVELING-SOONAWALA N.

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Lugar: Chevy Chase; Año: 2016

0021-972X

Mutations in the immunoglobulin superfamily,member1 (IGSF1) gene cause the X-linkedIGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosteronerise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GHdeficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1mutations.Objective: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to dateand formulate recommendations for clinical management.Methods: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34adults) and 56 female IGSF1 mutation carriers (3 children, 53 adults) from 30 unrelated familiesaccording to a standardized clinical protocol. At evaluation, boys were treated with levothyroxinein 89%, adult males in 44%, and females in 5% of cases.Results: Additional symptoms in male patients included small thyroid gland volume (74%), highbirth weight (25%), and large head circumference (20%). In general, the timing of pubertal testiculargrowth was normal or even premature, in contrast to a late rise in testosterone levels. Lateadrenarche was observed in patients with prolactin deficiency, and adult DHEA concentrationswere decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, althoughcortisol concentrations were normal later on. Waist circumference of male patients was increasedin 60%, but blood lipids were normal. Female carriers showed low FT4 and low-normal FT4 in 18%and60%,respectively, delayedageatmenarchein31%,mild prolactin deficiency in22%,increasedwaist circumference in 57%, and a negative correlation between FT4 concentrations and metabolicparameters.Conclusion: IGSF1 deficiency represents the mostcommongenetic cause of central hypothyroidismand is associated with multiple other characteristics. Based on these results, we provide recommendationsfor mutational analysis, endocrine work-up, and long-term care.