Martin Bezdicka1, Petra Kleiblova2, Jiri Soucek3, Marianna Borecka2,4, Eva El-Lababidi5, Daniel Smrz6, Michal Rataj6, Zdenek Sumnik7, Jana Malikova7, Ondrej Soucek8,9. 1. Vera Vavrova Laboratory/VIAL, Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 2. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. 3. Private Paediatric Endocrinology Practice, Carlsbad, Czech Republic. 4. Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic. 5. Department of Pediatrics, Third Faculty of Medicine, Charles University and Kralovske Vinohrady University Hospital, Prague, Czech Republic. 6. Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 7. Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 8. Vera Vavrova Laboratory/VIAL, Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. Ondrej.Soucek@lfmotol.cuni.cz. 9. Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. Ondrej.Soucek@lfmotol.cuni.cz.
Abstract
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.
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.
Authors: F Delange; G Benker; P Caron; O Eber; W Ott; F Peter; J Podoba; M Simescu; Z Szybinsky; F Vertongen; P Vitti; W Wiersinga; V Zamrazil Journal: Eur J Endocrinol Date: 1997-02 Impact factor: 6.664
Authors: Michael B Zimmermann; Sonja Y Hess; Luciano Molinari; Bruno De Benoist; François Delange; Lewis E Braverman; Kenji Fujieda; Yoshiya Ito; Pieter L Jooste; Khairya Moosa; Elizabeth N Pearce; Eduardo A Pretell; Yoshimasa Shishiba Journal: Am J Clin Nutr Date: 2004-02 Impact factor: 7.045