BACKGROUND: Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants in the thyroid-stimulating hormone receptor (TSHR) gene. The c.1856A > G (p.Asp619Gly) pathogenic variant has been described in cases of toxic adenoma but never before, to our knowledge, in a case of familial non-autoimmune hyperthyroidism. PATIENT FINDINGS: A 3-year-old boy was admitted for acute gastroenteritis presenting with goiter and tall stature. Laboratory findings revealed peripheral hyperthyroidism and negativity for thyroid autoantibodies. Antithyroid drug treatment was effective, but relapses occurred shortly after attempts to decrease the drug dose. As the boy's father and paternal grandmother also experienced relapsing hyperthyroidism manifesting in early childhood, genetic testing of TSHR was indicated. The c.1856A > G (p.Asp619Gly) pathogenic variant was found in all three affected family members. Functional in vitro characterization of the variant verified that it enhances constitutional activation of the receptor, leading to increased production of cyclic adenosine monophosphate. Total thyroidectomy was indicated in the boy due to an unsatisfactory prognosis. Due to persistent positive thyroglobulin serum concentration, a diagnostic radioiodine scan was performed approximately 2 years later. Residual thyroid tissue was revealed; therefore, radioiodine ablative therapy was performed. Despite adequate thyroxine substitution over a long period of follow-up, TSH remained suppressed. CONCLUSIONS: Unlike Graves' disease, familial non-autoimmune hyperthyroidism cases present with antithyroid drug-dependence. Not ultrasound but positive thyroglobulin serum concentration indicated residual thyroid tissue. Early detection of residual thyroid tissue and radioiodine ablation prevented the subject from experiencing relapsing hyperthyroidism and undergoing unnecessary repeated surgery. Life-long hormone substitution should be adjusted to free thyroxine rather than TSH serum concentrations.

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics 3rd Faculty of Medicine Charles University and Kralovske Vinohrady University Hospital Prague Czech Republic

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Private Paediatric Endocrinology Practice Carlsbad Czech Republic

Vera Vavrova Laboratory VIAL Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

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Hanley P, Lord K, Bauer AJ (2016) Thyroid disorders in children and adolescents: a review. JAMA Pediatr 170:1008–1019. https://doi.org/10.1001/jamapediatrics.2016.0486 PubMed DOI

Lavard L, Ranlov I, Perrild H, Andersen O, Jacobsen BB (1994) Incidence of juvenile thyrotoxicosis in Denmark, 1982–1988. A nationwide study Eur J Endocrinol 130:565–568. https://doi.org/10.1530/eje.0.1300565 PubMed DOI

Paschke R, Niedziela M, Vaidya B, Persani L, Rapoport B, Leclere J (2012) 2012 European thyroid association guidelines for the management of familial and persistent sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations. Eur Thyroid J 1:142–147. https://doi.org/10.1159/000342982 PubMed DOI PMC

Kleinau G, Neumann S, Gruters A, Krude H, Biebermann H (2013) Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 34:691–724. https://doi.org/10.1210/er.2012-1072 PubMed DOI PMC

Stephenson A, Lau L, Eszlinger M, Paschke R (2020) The thyrotropin receptor mutation database update. Thyroid 30:931–935. https://doi.org/10.1089/thy.2019.0807 PubMed DOI

Ferraz C, Paschke R (2017) Inheritable and sporadic non-autoimmune hyperthyroidism. Best Pract Res Clin Endocrinol Metab 31:265–275. https://doi.org/10.1016/j.beem.2017.04.005 PubMed DOI

Delange F, Benker G, Caron P, Eber O, Ott W, Peter F, Podoba J, Simescu M, Szybinsky Z et al (1997) Thyroid volume and urinary iodine in European schoolchildren standardization of values for assessment of iodine deficiency. Eur J Endocrinol 136:180–187. https://doi.org/10.1530/eje.0.1360180 PubMed DOI

Zimmermann MB, Hess SY, Molinari L, De Benoist B, Delange F, Braverman LE, Fujieda K, Ito Y, Jooste PL et al (2004) New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a World Health Organization/Nutrition for Health and Development Iodine Deficiency Study Group Report. Am J Clin Nutr 79:231–237. https://doi.org/10.1093/ajcn/79.2.231 PubMed DOI

Tanner JM, Goldstein H, Whitehouse RH (1970) Standards for children’s height at ages 2–9 years allowing for heights of parents. Arch Dis Child 45:755–762. https://doi.org/10.1136/adc.45.244.755 PubMed DOI PMC

Barstow C, Rerucha C (2015) Evaluation of short and tall stature in children. Am Fam Physician 92:43–50 PubMed

Wong FC, Au EY, Ip RW, Yau HC, Lit LC (2018) False-positive TSH receptor antibody results in an infant with activating TSHR mutation. Endocr J 65:793–794. https://doi.org/10.1507/endocrj.EJ18-0161 PubMed DOI

Giuliani C, Saji M, Bucci I, Napolitano G (2016) Bioassays for TSH receptor autoantibodies from FRTL-5 cells to TSH receptor-LH/CG Receptor chimeras the contribution of Leonard D Kohn. Front Endocrinol (Lausanne) 7:103. https://doi.org/10.3389/fendo.2016.00103 DOI PMC

Nwosu BU, Gourgiotis L, Gershengorn MC, Neumann S (2006) A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidism. Thyroid 16:505–512. https://doi.org/10.1089/thy.2006.16.505 PubMed DOI

Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling M, Lundell G, Torring O (2008) TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs surgery or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol 158:69–75. https://doi.org/10.1530/EJE-07-0450 PubMed DOI

Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G (1993) Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365:649–651. https://doi.org/10.1038/365649a0 PubMed DOI

Kleinau G, Worth CL, Kreuchwig A, Biebermann H, Marcinkowski P, Scheerer P, Krause G (2017) Structural-functional features of the thyrotropin receptor: a class a G-protein-coupled receptor at work. Front Endocrinol (Lausanne) 8:86. https://doi.org/10.3389/fendo.2017.00086 DOI

Nishihara E, Nagayama Y, Amino N, Hishinuma A, Takano T, Yoshida H, Kubota S, Fukata S, Kuma K et al (2007) A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism. Endocr J 54:927–934. https://doi.org/10.1507/endocrj.k07-088 PubMed DOI

Claeysen S, Govaerts C, Lefort A, Van Sande J, Costagliola S, Pardo L, Vassart G (2002) A conserved Asn in TM7 of the thyrotropin receptor is a common requirement for activation by both mutations and its natural agonist. FEBS Lett 517:195–200. https://doi.org/10.1016/s0014-5793(02)02620-0 PubMed DOI

Huth S, Jaeschke H, Schaarschmidt J, Paschke R (2014) Controversial constitutive TSHR activity patients, physiology, and in vitro characterization. Horm Metab Res 46:453–461. https://doi.org/10.1055/s-0034-1375651 PubMed DOI

Nishihara E, Tsugawa M, Ozaki Y, Nagayama Y, Fukata S, Hirokawa M, Ito M, Nishikawa M, Nakamura H et al (2018) Long-term follow-up of a patient with sporadic nonautoimmune hyperthyroidism due to a thyrotropin-receptor mutation (D619G). AACE Clin Case Rep 4:e84–e89. https://doi.org/10.4158/EP171919 DOI

Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Pearce SH (2018) 2018 European thyroid association guideline for the management of graves’ hyperthyroidism. Eur Thyroid J 7:167–186. https://doi.org/10.1159/000490384 PubMed DOI PMC

Andersen SL, Olsen J, Laurberg P (2016) Antithyroid drug side effects in the population and in pregnancy. J Clin Endocrinol Metab 101:1606–1614. https://doi.org/10.1210/jc.2015-4274 PubMed DOI

Jaeschke H, Eszlinger M, Lueblinghoff J, Coslovsky R, Paschke R (2011) Prolonged inappropriate TSH suppression during hypothyroidism after thyroid ablation in a patient with nonautoimmune familial hyperthyroidism. Horm Metab Res 43:500–504. https://doi.org/10.1055/s-0031-1277184 PubMed DOI

Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM (1998) Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 39:1551–1554 PubMed