All cases of familial thyrotoxicosis with absence of evidence of autoimmunity and all children with persistent isolated neonatal hyperthyroidism should be evaluated for familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) or persistent sporadic non-autoimmune hyperthyroidism (PSNAH). First, all index patients should be analysed for the presence/absence of a thyroid-stimulating hormone (TSH) receptor (TSHR) germline mutation, and if they display a TSHR germline mutation, all other family members including asymptomatic and euthyroid family members should also be analysed. A functional characterization of all new TSHR mutations is necessary. Appropriate ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences, especially in children. Therefore, in children the diagnosis of FNAH or PSNAH needs to be established as early as possible in the presence of the clinical hallmarks of the disease.

Keywords:
Non-autoimmune hyperthyroidism, TSHR, Germline mutations, Guidelines
1.
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al: Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.
2.
Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schunemann HJ: Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 suppl):123S–131S.
3.
Fuhrer D, Warner J, Sequeira M, Paschke R, Gregory J, Ludgate M: Novel TSHR germline mutation (Met463Val) masquerading as Graves’ disease in a large Welsh kindred with hyperthyroidism. Thyroid 2000;10:1035–1041.
4.
Vaidya B, Campbell V, Tripp JH, Spyer G, Hattersley AT, Ellard S: Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Clin Endocrinol (Oxf) 2004;60:711–718.
5.
Nwosu BU, Gourgiotis L, Gershengorn MC, Neumann S: A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidism. Thyroid 2006;16:505–512.
6.
Horton GL, Scazziga B: Hereditary hyperthyroidism with diffuse non autoimmune hyperactivity due to autonomy of function and growth. Ann Endocrinol (Paris) 1987;48:92.
7.
Tonacchera M, Van Sande J, Cetani F, Swillens S, Schvartz C, Winiszewski P, et al: Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab 1996;81:547–554.
8.
Schwab KO, Gerlich M, Broecker M, Sohlemann P, Derwahl M, Lohse MJ: Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism. J Pediatr 1997;131:899–904.
9.
Fuhrer D, Wonerow P, Willgerodt H, Paschke R: Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 1997;82:4234–4238.
10.
Khoo DH, Parma J, Rajasoorya C, Ho SC, Vassart G: A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J Clin Endocrinol Metab 1999;84:1459–1462.
11.
Alberti L, Proverbio MC, Costagliola S, Weber G, Beck-Peccoz P, Chiumello G, et al: A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism. Eur J Endocrinol 2001;145:249–254.
12.
Arturi F, Chiefari E, Tumino S, Russo D, Squatrito S, Chazenbalk G, et al: Similarities and differences in the phenotype of members of an Italian family with hereditary non-autoimmune hyperthyroidism associated with an activating TSH receptor germline mutation. J Endocrinol Invest 2002;25:696–701.
13.
Claus M, Maier J, Paschke R, Kujat C, Stumvoll M, Fuhrer D: Novel thyrotropin receptor germline mutation (Ile568Val) in a Saxonian family with hereditary nonautoimmune hyperthyroidism. Thyroid 2005;15:1089–1094.
14.
Karges B, Krause G, Homoki J, Debatin KM, de Roux N, Karges W: TSH receptor mutation V509A causes familial hyperthyroidism by release of interhelical constraints between transmembrane helices TMH3 and TMH5. J Endocrinol 2005;186:377–385.
15.
Nishihara E, Nagayama Y, Amino N, Hishinuma A, Takano T, Yoshida H, et al: A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism. Endocr J 2007;54:927–934.
16.
Liu Z, Sun Y, Dong Q, He M, Cheng CH, Fan F: A novel TSHR gene mutation (Ile691Phe) in a Chinese family causing autosomal dominant non-autoimmune hyperthyroidism. J Hum Genet 2008;53:475–478.
17.
Fukata S, Hishinuma A, Nakatake H, Tajiri J: A Japanese family with familial nonautoimmune hyperthyroidism with a novel mutation (Asn406Ser) in extracellular domain of thyrotropin receptor. Clin Endocrinol (Oxf) 2012;77:329–330.
18.
Winkler F, Kleinau G, Tarnow P, Rediger A, Grohmann L, Gaetjens I, et al: A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6. J Clin Endocrinol Metab 2010;95:3605–3610.
19.
Duprez L, Parma J, Van Sande J, Allgeier A, Leclere J, Schvartz C, et al: Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994;7:396–401.
20.
Lee YS, Poh L, Loke KY: An activating mutation of the thyrotropin receptor gene in hereditary non-autoimmune hyperthyroidism. J Pediatr Endocrinol Metab 2002;15:211–215.
21.
Gozu HI, Lublinghoff J, Bircan R, Paschke R: Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol 2010;322:125–134.
22.
Kopp P, van Sande J, Parma J, Duprez L, Gerber H, Joss E, et al: Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995;332:150–154.
23.
Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R: Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 1997;82:3879–3884.
24.
Kopp P, Jameson JL, Roe TF: Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene. Thyroid 1997;7:765–770.
25.
Esapa CT, Duprez L, Ludgate M, Mustafa MS, Kendall-Taylor P, Vassart G, et al: A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis. Thyroid 1999;9:1005–1010.
26.
Tonacchera M, Agretti P, Rosellini V, Ceccarini G, Perri A, Zampolli M, et al: Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene. Thyroid 2000;10:859–863.
27.
Biebermann H, Winkler F, Handke D, Gruters A, Krude H, Kleinau G: Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation. Thyroid Res 2011;4(suppl 1):S8.
28.
Watkins MG, Dejkhamron P, Huo J, Vazquez DM, Menon RK: Persistent neonatal thyrotoxicosis in a neonate secondary to a rare thyroid-stimulating hormone receptor activating mutation: case report and literature review. Endocr Pract 2008;14:479–483.
29.
Bertalan R, Sallai A, Solyom J, Lotz G, Szabo I, Kovacs B, et al: Hyperthyroidism caused by a germline activating mutation of the thyrotropin receptor gene: difficulties in diagnosis and therapy. Thyroid 2010;20:327–332.
30.
Lueblinghoff J, Mueller S, Sontheimer J, Paschke R: Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism. J Endocrinol Invest 2010;33:228–233.
31.
Hebrant A, van Staveren WC, Maenhaut C, Dumont JE, Leclere J: Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. Eur J Endocrinol 2011;164:1–9.
32.
Thomas JS, Leclere J, Hartemann P, Duheille J, Orgiazzi J, Petersen M, et al: Familial hyperthyroidism without evidence of autoimmunity. Acta Endocrinol (Copenh) 1982;100:512–518.
33.
Biebermann H, Schoneberg T, Hess C, Germak J, Gudermann T, Gruters A: The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 2001;86:4429–4433.
34.
Supornsilchai V, Sahakitrungruang T, Wongjitrat N, Wacharasindhu S, Suphapeetiporn K, Shotelersuk V: Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene. Clin Endocrinol (Oxf) 2009;70:623–628.
35.
Ferrara AM, Capalbo D, Rossi G, Capuano S, Del Prete G, Esposito V, et al: A new case of familial nonautoimmune hyperthyroidism caused by the M463V mutation in the TSH receptor with anticipation of the disease across generations: a possible role of iodine supplementation. Thyroid 2007;17:677–680.
36.
Akcurin S, Turkkahraman D, Tysoe C, Ellard S, De Leener A, Vassart G, et al: A family with a novel TSH receptor activating germline mutation (p.Ala485Val). Eur J Pediatr 2008;167:1231–1237.
37.
Pohlenz J, Pfarr N, Kruger S, Hesse V: Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R). Acta Paediatr 2006;95:1685–1687.
38.
Nishihara E, Chen CR, Higashiyama T, Mizutori-Sasai Y, Ito M, Kubota S, et al: Subclinical nonautoimmune hyperthyroidism in a family segregates with a thyrotropin receptor mutation with weakly increased constitutive activity. Thyroid 2010;20:1307–1314.
39.
Ringkananont U, Van Durme J, Montanelli L, Ugrasbul F, Yu YM, Weiss RE, et al: Repulsive separation of the cytoplasmic ends of transmembrane helices 3 and 6 is linked to receptor activation in a novel thyrotropin receptor mutant (M626I). Mol Endocrinol 2006;20:893–903.
40.
Jaeschke H, Eszlinger M, Lueblinghoff J, Coslovsky R, Paschke R: Prolonged inappropriate TSH suppression during hypothyroidism after thyroid ablation in a patient with nonautoimmune familial hyperthyroidism. Horm Metab Res 2011;43:500–504.
41.
de Roux N, Polak M, Couet J, Leger J, Czernichow P, Milgrom E, et al: A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab 1996;81:2023–2026.
42.
Elgadi A, Arvidsson CG, Janson A, Marcus C, Costagliola S, Norgren S: Autosomal-dominant non-autoimmune hyperthyroidism presenting with neuromuscular symptoms. Acta Paediatr 2005;94:1145–1148.
43.
Nishihara E, Fukata S, Hishinuma A, Kudo T, Ohye H, Ito M, et al: Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient. Endocr J 2006;53:735–740.
44.
Bircan R, Miehle K, Mladenova G, Ivanova R, Sarafova A, Borissova AM, et al: Multiple relapses of hyperthyroidism after thyroid surgeries in a patient with long term follow-up of sporadic non-autoimmune hyperthyroidism. Exp Clin Endocrinol Diabetes 2008;116:341–346.
45.
Borgel K, Pohlenz J, Koch HG, Bramswig JH: Long-term carbimazole treatment of neonatal nonautoimmune hyperthyroidism due to a new activating TSH receptor gene mutation (Ala428Val). Horm Res 2005;64:203–208.
46.
Chester J, Rotenstein D, Ringkananont U, Steuer G, Carlin B, Stewart L, et al: Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene. J Pediatr Endocrinol Metab 2008;21:479–486.
47.
Lavard L, Sehested A, Brock Jacobsen B, Muller J, Perrild H, Feldt-Rasmussen U, et al: Long-term follow-up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr). Horm Res 1999;51:43–46.
48.
Fuhrer D, Mix M, Wonerow P, Richter I, Willgerodt H, Paschke R: Variable phenotype associated with Ser505Asn-activating thyrotropin-receptor germline mutation. Thyroid 1999;9:757–761.
49.
Aycan Z, Agladioglu SY, Ceylaner S, Cetinkaya S, Bas VN, Kendirici HN: Sporadic nonautoimmune neonatal hyperthyroidism due to A623V germline mutation in the thyrotropin receptor gene. J Clin Res Pediatr Endocrinol 2010;2:168–172.
50.
Paschke R, Ludgate M: The thyrotropin receptor in thyroid diseases. N Engl J Med 1997;337:1675–1681.
51.
Kopp P: The TSH receptor and its role in thyroid disease. Cell Mol Life Sci 2001;58:1301–1322.
52.
Lueblinghoff J, Eszlinger M, Jaeschke H, Mueller S, Bircan R, Gozu H, et al: Shared sporadic and somatic thyrotropin receptor mutations display more active in vitro activities than familial thyrotropin receptor mutations. Thyroid 2011;21:221–229.
53.
Mueller S, Jaeschke H, Paschke R: Current standards, variations, and pitfalls for the determination of constitutive TSHR activity in vitro. Methods Enzymol 2010;485:421–436.
54.
Mueller S, Gozu HI, Bircan R, Jaeschke H, Eszlinger M, Lueblinghoff J, et al: Cases of borderline in vitro constitutive thyrotropin receptor activity: how to decide whether a thyrotropin receptor mutation is constitutively active or not? Thyroid 2009;19:765–773.
55.
Jaeschke H, Mueller S, Eszlinger M, Paschke R: Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas. Clin Endocrinol (Oxf) 2010;73:815–820.
56.
Gozu HI, Mueller S, Bircan R, Krohn K, Ekinci G, Yavuzer D, et al: A new silent germline mutation of the TSH receptor: coexpression in a hyperthyroid family member with a second activating somatic mutation. Thyroid 2008;18:499–508.
57.
Schaarschmidt J, Paschke S, Özerden M, Jäschke H, Huth S, Eszlinger M, Meller J, Paschke R: Late manifestation of subclinical hyperthyroidism after goitrogenesis in an index patient with a N670S TSH receptor germline mutation masquerading as TSH receptor antibody negative Graves’ disease. Horm Metab Res 2012, E-pub ahead of print.
© 2012 European Thyroid Association Published by S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.