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Novel presentation of the c.1856A > G (p.Asp619Gly) TSHR gene-activating variant: relapsing hyperthyroidism in three subsequent generations manifesting in early childhood and an in vitro functional study

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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.

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Data availability

Maximum care was taken to thoroughly describe the methodology and provide all relevant data to enable reproduction of our observations. All data generated or analyzed during this study are included in this published article or its Supplementary Material file.

Code availability

Not applicable.

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Acknowledgements

We acknowledge the family for giving us permission to publish their case.

Funding

This work was partially supported by the Project for the Conceptual Development of Research Organization, Motol University Hospital (Ministry of Health, Czech Republic; 00064203) and Operational Programme Research and Development for Innovation (Ministry of Education, Youth and Sports, Czech Republic, co-financed by the EU; CZ.1.05/4.1.00/16.0337). Mutation analyses were further supported by the Ministry of Health of the Czech Republic (grant NU20-03–00285). The funding bodies had no impact on the study design, analyses, or data interpretation.

Author information

Authors and Affiliations

  1. Vera Vavrova Laboratory/VIAL, Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Martin Bezdicka & Ondrej Soucek

  2. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

    Petra Kleiblova & Marianna Borecka

  3. Private Paediatric Endocrinology Practice, Carlsbad, Czech Republic

    Jiri Soucek

  4. Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Marianna Borecka

  5. Department of Pediatrics, Third Faculty of Medicine, Charles University and Kralovske Vinohrady University Hospital, Prague, Czech Republic

    Eva El-Lababidi

  6. Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Daniel Smrz & Michal Rataj

  7. Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Zdenek Sumnik, Jana Malikova & Ondrej Soucek

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  1. Martin Bezdicka
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Contributions

Martin Bezdicka performed the functional study and drafted the Supplementary file. P.K. and Mariana Borecka performed the molecular genetics analyses of the participants. J.S. revealed hyperthyroidism in the boy and treated him until referral to the university center. D.S. and M.R. performed the flow cytometry. E.E. and Z.S. reviewed the case and gave important clinical hints and suggestions. J.M. supervised the site-directed mutagenesis and transformation procedures. O.S. treated the patient in the referral center, designed the study, and drafted the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Ondrej Soucek.

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Ethical approval

This research was performed according to the appropriate ethical guidelines and the Declaration of Helsinki.

Consent to participate and for publication

The patient as well as his parents gave written informed consent to have their case published, including the pictures kindly provided by the family.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Bezdicka, M., Kleiblova, P., Soucek, J. et al. Novel presentation of the c.1856A > G (p.Asp619Gly) TSHR gene-activating variant: relapsing hyperthyroidism in three subsequent generations manifesting in early childhood and an in vitro functional study. Hormones 20, 803–812 (2021). https://doi.org/10.1007/s42000-021-00299-x

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