title: IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.
abstract: 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.
  
  
  
  We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: S D
authors: SD
authors: Joustra
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: C A
authors: CA
authors: Heinen
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: N
authors: N
authors: Schoenmakers
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: M
authors: M
authors: Bonomi
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: B E P B
authors: BE
authors: Ballieux
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: M-O
authors: MO
authors: Turgeon
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: D J
authors: DJ
authors: Bernard
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: E
authors: E
authors: Fliers
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: A S P
authors: AS
authors: van Trotsenburg
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: M
authors: M
authors: Losekoot
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: L
authors: L
authors: Persani
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: J M
authors: JM
authors: Wit
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: N R
authors: NR
authors: Biermasz
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: A M
authors: AM
authors: Pereira
authors: Department of Pediatrics (S.D.J., J.M.W., W.O.), Department of Medicine (S.D.J., N.R.B., A.M.P.), Division of Endocrinology, Department of Clinical Chemistry and Laboratory Medicine (B.E.P.B.), and Department of Clinical Genetics (M.L.), Leiden University Medical Center, 2300 C Leiden, The Netherlands; Department of Pediatric Endocrinology (C.A.H., A.S.P.v.T.), Emma Children's Hospital, and Department of Endocrinology and Metabolism (C.A.H., E.F.), Academic Medical Center, University of Amsterdam, 1100 DE, The Netherlands; University of Cambridge Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge DB2 2OO, United Kingdom; Division of Endocrine and Metabolic Disorders (M.B.), Instituto di Ricovero e Cura a Carettere Scientifico, Instituto Auxologica Italiano, 20132 Milan, Italy; Department of Clinical Sciences and Community Health (M.B., L.P.), Università degli Studi di Milano, 20122 Milan, Italy; Department of Pharmacology and Therapeutics (M.-O.T., D.J.B.), McGill University, Montréal, Québec, Canada H9X 3V9.
authors: W
authors: W
authors: Oostdijk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy* / Q000235:genetics; D007136:Immunoglobulins / Q000172:deficiency* / Q000235:genetics; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D017410:Practice Guidelines as Topic / Q000592:standards*; D011788:Quality of Life; D013577:Syndrome; D013974:Thyroxine / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D013974:Thyroxine