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
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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].
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