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

CASE REPORT

The presented multi-generation family consists of relatives born between 1896 (subject I-1) and 2017 (sub-ject V-3) as illustrated in the family pedigree in Figure 1. Among the descendants, seven males and four females across four generations developed clinical features of hyperthyroidism but did not show characteristics of autoimmune hyperthyroidism [ophthalmopathy, dermopathy, TSH receptor antibodies (TSHAb), thyroglobulin (TG) antibodies; thyroid peroxidase (TPO) antibodies, hypoechoic pattern at an ultrasound, lymphocytic infiltration on histology]. All affected members shared some physical characteristics, they were tall, slim, had long thin fingers, aquiline nose, and staring eyes. Their clinical characteristics are summarized in Table 1. Patients who were initially diagnosed in this family belonged to the second generation, while their father (subject I-1) was not clinically diagnosed but had similar physical characteristics. Patients II-1, II-4, II-5 and II-9 in the second generation were born between 1923 and 1940 and were diagnosed as hyperthyrotic after they had developed cardiac complications (rhythm disorders, thromboembolic events, cardiac insufficiency) when they were 40 to 60 years old (Table 1). Conservative treatment, namely antithyroid drugs and subtotal thyroidectomy, resulted in frequent relapses. They became long-term euthyrotic after they received I-131 administration, or total thyroidectomy and permanent substitutions of thyroid hormone. In this generation, clinical data were not available for subjects II-3, II-6, II-7, II-8, while brother II-2 was not affected. In the next generation born between 1951 and 1973, hyperthyroidism was diagnosed in four out of nine descendants (subjects III-2, III-5, III-6 and III-9). The diagnosis was made earlier between ages 17 and 40, mostly due to the awareness of the familial history. They were treated accordingly, and in contrast to the initially diagnosed generation, only subject III-5 developed cardiac complications after the diagnosis of hyperthyroidism. Clinical data was not available for subject III-4. In the fourth generation, born between 1980 and 2004, hyperthyroidism was confirmed in childhood before they were 10 years old. Pediatric treatment was conventional but no permanent remission was attained until I-131 administration. Children in the fifth generation were born between 2010 and 2017. So far, they are healthy. Originally, genetic testing was carried out for subjects IV-2 and IV-3. We performed Sanger sequencing of the whole coding region and intron-exon junctions of the TSHR gene using the in-house designed primers (sequences available upon request), BigDye® Terminator v3.1 kit and ABI PRISM® 3500 Genetic Analyzer (Applied Biosystems, Waltham, MA, USA). Both initially analyzed subjects carried a heterozygous TSHR variant changing methionine to valine at amino acid position 453 (NP_000360.2: p.Met453Val, NM_000369.2: c.1357A>G) (Figure 2). The variant has not been reported in the TSHR mutation database [4], professional version of the Human Gene Mutation Database (HGMD) [9] database, ClinVar [10] or in general population in the Genome Aggregation Database (GnomAD) [11]. In silico models Sorting Intolerant from Tolerant SIFT [12], Polymorphism Phenotyping v2 (PolyPhen-2) [13], MutationTaster [14], and Combined Annotation Dependent Depletion (CADD) (score 25.2) [15], predicted it to be pathogenic. The variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) 2015 guidelines [16] with the following grades: PM1 (located in mutational hot-spot), PM2 (absent from general population), PM5 (novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen), PP1 (co-segregation with the disease in multiple affected family members in a gene definitely known to cause the disease), PP3 (multiple lines of computational evidence supporting the deleterious effect), PP4 (patients phenotype and family history are highly specific for a disease with a single genetic etiology). Therefore, the novel p.Met453Val variant was predicted to be causative for the FNAH, and this prediction was later confirmed by segregation analysis of the variant in other affected family members. Family members were examined only for the presence of the family TSHR variant, and the analyses confirmed the presence of this variant in all tested family members who were affected. The analysis was not performed in all family members [marked as NA (not analyzed) in Figure 1].



Number 26
Number 26 VOL. 26(2), 2023 All in one
Number 26
VOL. 26(2), 2023
Number 26
VOL. 26, 2023 Supplement
Number 26
VOL. 26(1), 2023
Number 25
VOL. 25(2), 2022
Number 25
VOL. 25 (1), 2022
Number 24
VOL. 24(2), 2021
Number 24
VOL. 24(1), 2021
Number 23
VOL. 23(2), 2020
Number 22
VOL. 22(2), 2019
Number 22
VOL. 22(1), 2019
Number 22
VOL. 22, 2019 Supplement
Number 21
VOL. 21(2), 2018
Number 21
VOL. 21 (1), 2018
Number 21
VOL. 21, 2018 Supplement
Number 20
VOL. 20 (2), 2017
Number 20
VOL. 20 (1), 2017
Number 19
VOL. 19 (2), 2016
Number 19
VOL. 19 (1), 2016
Number 18
VOL. 18 (2), 2015
Number 18
VOL. 18 (1), 2015
Number 17
VOL. 17 (2), 2014
Number 17
VOL. 17 (1), 2014
Number 16
VOL. 16 (2), 2013
Number 16
VOL. 16 (1), 2013
Number 15
VOL. 15 (2), 2012
Number 15
VOL. 15, 2012 Supplement
Number 15
Vol. 15 (1), 2012
Number 14
14 - Vol. 14 (2), 2011
Number 14
The 9th Balkan Congress of Medical Genetics
Number 14
14 - Vol. 14 (1), 2011
Number 13
Vol. 13 (2), 2010
Number 13
Vol.13 (1), 2010
Number 12
Vol.12 (2), 2009
Number 12
Vol.12 (1), 2009
Number 11
Vol.11 (2),2008
Number 11
Vol.11 (1),2008
Number 10
Vol.10 (2), 2007
Number 10
10 (1),2007
Number 9
1&2, 2006
Number 9
3&4, 2006
Number 8
1&2, 2005
Number 8
3&4, 2004
Number 7
1&2, 2004
Number 6
3&4, 2003
Number 6
1&2, 2003
Number 5
3&4, 2002
Number 5
1&2, 2002
Number 4
Vol.3 (4), 2000
Number 4
Vol.2 (4), 1999
Number 4
Vol.1 (4), 1998
Number 4
3&4, 2001
Number 4
1&2, 2001
Number 3
Vol.3 (3), 2000
Number 3
Vol.2 (3), 1999
Number 3
Vol.1 (3), 1998
Number 2
Vol.3(2), 2000
Number 2
Vol.1 (2), 1998
Number 2
Vol.2 (2), 1999
Number 1
Vol.3 (1), 2000
Number 1
Vol.2 (1), 1999
Number 1
Vol.1 (1), 1998

 

 


 About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact
 Copyright © Balkan Journal of Medical Genetics 2006