<abstract xmlns="http://www.w3.org/1999/xhtml"><p>Activating disease-causing variants in the thyrotropin-receptor (<italic>TSHR</italic>) gene are associated with familial or sporadic congenital non-autoimmune hyperthyroidism. Familial non-autoimmune hyperthyroidism (FNAH) is a rare form of hyperthyroidism with 41 families reported so far in the <italic>TSHR</italic> gene mutation database. We present clinical and genetic features of 11 patients with FNAH across four generations of a Slovenian family. They all developed clinical features of hyperthyroidism but did not show characteristics of autoimmune hyperthyroidism. Members of the initially diagnosed generation were diagnosed as hyperthyrotic after they developed cardiac complications (rhythm disorders, thromboembolic events, cardiac insufficiency), while patients in the younger generations were diagnosed earlier, and consequently, early cardiovascular complications were less frequent. All patients had a novel heterozygous <italic>TSHR</italic> variant NP_ 000360.2: p.Met453Val (NM_000369.2: c.1357A>G) predicted to be pathogenic. Therefore, besides expending the mutational spectrum of the activating <italic>TSHR</italic> variants in FNAH, our experience with this multi-generation family confirms the need for early diagnosis and appropriate treatment of FNAH.</p></abstract>

Activating disease-causing variants in the thyrotropin-receptor (TSHR) gene are associated with familial or sporadic congenital non-autoimmune hyperthyroidism. Familial non-autoimmune hyperthyroidism (FNAH) is a rare form of hyperthyroidism with 41 families reported so far in the TSHR gene mutation database. We present clinical and genetic features of 11 patients with FNAH across four generations of a Slovenian family. They all developed clinical features of hyperthyroidism but did not show characteristics of autoimmune hyperthyroidism. Members of the initially diagnosed generation were diagnosed as hyperthyrotic after they developed cardiac complications (rhythm disorders, thromboembolic events, cardiac insufficiency), while patients in the younger generations were diagnosed earlier, and consequently, early cardiovascular complications were less frequent. All patients had a novel heterozygous TSHR variant NP_ 000360.2: p.Met453Val (NM_000369.2: c.1357A>G) predicted to be pathogenic. Therefore, besides expending 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.

Familial non-autoimmune hyperthyroidism in family members across four generations due to a novel disease-causing variant in the thyrotropin receptor gene

Balkan Journal of Medical Genetics

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Activating disease-causing variants in the thyrotropin-receptor (TSHR) gene are associated with familial or sporadic congenital non-autoimmune hyperthyroidism....

Patient	Born	Died	Age at Onset		Antibodies (IU/mL)		Treatment
			Hyp	CVC	AntiTG	AntiTPO	Antithyroid Drugs	Thyroidectomy	131-Iodine
I-1	1896	1963	NK	NK	NK	NK	NK
II-1	1923	2008	42	60	55	37	3 years	[+]
II-4	1930	2004	45	46	48	54	9 years		[+]
II-5	1932	1998	51	50	negative	negative	7 years		[+]
II-9	1940	1991	40	40	NK	NK	2 years		[+]
III-2	1952		40	–	negative	negative	6 years		[+]
III-5	1954	2007	24	26	negative	negative	3 years		[+]
III-6	1958		23	–	negative	negative	4 years	[+]	[+]
III-9	1973		17	–	negative	negative	1 year	[+]
IV-2	1984		10	–	80	>1000	14 years
IV-3	1988		6	–	negative	negative	14 years		[+]

Familial non-autoimmune hyperthyroidism in family members across four generations due to a novel disease-causing variant in the thyrotropin receptor gene

Article Category: Case report

Pubblicato online: 23 mar 2021

Pagine: 87 - 92

DOI: https://doi.org/10.2478/bjmg-2020-0022

Parole chiave
Activating variant, Familial non-autoimmune hyperthyroidism (FNAH), thyrotropin receptor, gene

© 2020 Malej A, Avbelj Stefanija M, Bratanič N, Trebušak Podkrajšek K, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Figure 2

Summary of the clinical characteristics of the family members with hyperthyroidism. Additionally, all patients were tall and slim, they had long, thin fingers, aquiline nose, staring eyes and no exophthalmos.

Familial non-autoimmune hyperthyroidism in family members across four generations due to a novel disease-causing variant in the thyrotropin receptor gene

Article Category: Case report

Pubblicato online: 23 mar 2021

Pagine: 87 - 92

DOI: https://doi.org/10.2478/bjmg-2020-0022

Parole chiaveActivating variant, Familial non-autoimmune hyperthyroidism (FNAH), thyrotropin receptor, gene

© 2020 Malej A, Avbelj Stefanija M, Bratanič N, Trebušak Podkrajšek K, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Figure 2

Summary of the clinical characteristics of the family members with hyperthyroidism. Additionally, all patients were tall and slim, they had long, thin fingers, aquiline nose, staring eyes and no exophthalmos.

Parole chiave
Activating variant, Familial non-autoimmune hyperthyroidism (FNAH), thyrotropin receptor, gene