Balkan Journal of Medical Genetics

FAMILIAL NON-AUTOIMMUNE HYPERTHYROIDISM IN FAMILY MEMBERS ACROSS FOUR GENERATIONS DUE TO A NOVEL DISEASE-CAUSING VARIANT IN THE THYROTROPIN RECEPTOR GENE
Malej A, Avbelj Stefanija M, Bratanič N, Trebušak Podkrajšek K,
*Corresponding Author: Associate Professor Katarina Trebušak Podkrajšek, Ph.D., Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Slovenia. Tel: +386- 1-543-7669. Fax: +386-1-543-7641. E-mail: katarina.trebusakpodkrajsek@mf.uni-lj.si
page: 87

DISCUSSION

We present the first multi-generation Slovenian family with FNAH due to a novel TSHR disease-causing variant. All affected subjects presented with low severity of hyperthyroid symptoms. Nevertheless, members of the second generation who were the initial patients in the family clinically diagnosed with non-autoimmune hyperthyroidism, had cardiac complications. For this generation, it is not clear exactly when hyperthyroidism started as they did not complain of specific hyperthyroid symptoms. Moreover, they all presented with a specific appearance, namely scrawny build, aquiline nose, staring eyes, and long, thin fingers. In later generations when hyperthyroidism was detected in childhood, family members typically had advanced stature compared to their chronological age. Subjects III-6 and III-9 underwent an early thyroidectomy at ages 25 and 18 years, respectively. Subject III-6 had thyroidectomy due to tracheal compression of the large goiter 3 years after ceasing to take methimazol. Subject III-9 had a thyroidectomy following the relapse of thyrotoxicosis 6 months after cessation of methimazol therapy. As is typical for FNAH [5], the hyperthyroidism in affected family members could not be persistently controlled with antithyroid drugs and required a thyroidectemy and/or application of I-131. The exception was patient IV-2 with the TSHR family variant. When diagnosed, a small goiter without overt clinical signs of hyperthyroidism was observed. Elevated thyroid hormone levels and suppressed TSH were detected, while TSHR antibodies were determined several times, but were never detected. The treatment with antithyroid drugs was started several years later and he is currently euthyrotic. During followup, elevated TPO and TG antibody levels were detected. Nevertheless, the presence of the TPO or TG antibodies is common in the general population and was previously also reported in a limited number of FNAH patients [17]. In addition, the patient’s mother is receiving therapy for autoimmune hypothyroidism (Figure 1). The novel TSHR variant p.Met453Val detected in affected family members was predicted to be pathogenic, predominantly because it was not present in the general population. In silico tools predicted it to be pathogenic and it was located in the mutational hot-spot of the gene in the exon 10. Amino acid position 453 in the TSHR protein is highly conserved across species. Two different changes at the same amino acid position have so far been reported, namely, amino acid change of methionine to threonine (p.Met453Thr; c.1358T>C) [18,19] and amino and acid change of methionine to arginine (p.Met453Arg; c.1358 T>G) [20]. Variant p.Met453Thr was reported in two Caucasian patients with CNAH that started in early childhood, one with severe neonatal hyperthyroidism [18] and the other with thyrotoxicosis [19]. Additionally, it was reported in a Thai family with three affected patients with different ages of onset [21]. Mutant TSHR carrying p.Met453 Thr had a 5-times activity increase in constitutive activity compared to the wild-type that was measured with basal cAMP activity and TSHR cell surface expression [22]. Additionally, the mutant TSHR carrying p.Met453Thr had enhanced constitutive internalization, but no recycling was observed [23]. Variant p.Met453Arg was reported in the Japanese family with non-autoimmune hyperthyroidism that was not severe and onset varying between childhood to adulthood [20]. The mutant TSHR carrying the p.Met 453Arg variant caused constitutive activation of the receptor [20]. These two disease-causing variants resulted in the change of the same amino acid as reported here and were functionally evaluated. Therefore, we can reliably claim the reported novel variant p.Met453Val to also be causative for non-autoimmune hypethyroidism. Excess of thyroid hormones affects hemodynamic changes, and consequently, predisposes patients to heart failure as reviewed by Osuna et al. [24]. Furthermore, the mortality risk of patients with heart failure is significantly higher in patients with abnormal thyroid function [25]. Therefore, it is of utmost importance to diagnose and appropriately treat hyperthyroidism to prevent late cardiovascular complications in adults. This is significantly easier in inherited forms of hyperthyroidism in families where the familial disease-causing variant was identified. This was the case in the younger generations of the reported family where early cardiovascular complications were less frequent. Therefore, besides expanding the mutational spectrum of the activating TSHR variants in FNAH, our experience with this multi-generation family confirms the need for early diagnosis and appropriate treatment of FNAH. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by funding from the Slovenian Research Agency [research core funding P3-0343 and P1-0170].

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