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Double Variants in TSHR and DUOX2 in a Patient with Hypothyroidism: Case Report

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Double Variants in TSHR and DUOX2 in a Patient with Hypothyroidism: Case Report Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2019 Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report Sasivari, Zerin ; Szinnai, Gabor ; Seebauer, Britta ; Konrad, Daniel ; Lang-Muritano, Mariarosaria Abstract: Thyroid dyshormonogenesis (TDH) is characterized by the defective synthesis of thyroid hor- mones. We present a patient with congenital hypothyroidism (CH) who presented in newborn screening with elevated serum thyroid-stimulating hormone (TSH), decreased free thyroxine (fT<jats:sub>4</jats:sub>) and increased thyroglobulin (Tg) concentrations. Ultrasound scan revealed a properly structured thyroid gland. Treatment with L-thyroxine was initiated. At the age of 2 years, thyroxine replacement was stopped. The patient remained untreated until 6 years of age when TSH levels progressively increased and L-thyroxine treatment was restarted at a dose of 12.5 ฀g/day. Genetic analysis revealed a double heterozygosity for likely pathogenic variants of dual oxidase 2 (<jats:italic>DUOX2</jats:italic>) and thyroid stimulating hormone receptor <jats:italic>(TSHR</jats:italic>). Both genes were earlier shown to be associated with CH. In a literature review, our patient was compared to previously published patients with similar clinical characteristics, and a good genotype-phenotype correlation was identified. DOI: https://doi.org/10.1515/jpem-2019-0051 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-178432 Journal Article Published Version Originally published at: Sasivari, Zerin; Szinnai, Gabor; Seebauer, Britta; Konrad, Daniel; Lang-Muritano, Mariarosaria (2019). Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report. Journal of Pediatric Endocrinology Metabolism, 32(11):1299-1303. DOI: https://doi.org/10.1515/jpem-2019-0051 J Pediatr Endocrinol Metab 2019; 32(11): 1299–1303 Case Report Zerin Sasivari, Gabor Szinnai, Britta Seebauer, Daniel Konrad and Mariarosaria Lang-Muritano* Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report https://doi.org/10.1515/jpem-2019-0051 Received February 27, 2019; accepted August 12, 2019; previously Introduction published online September 21, 2019 Congenital hypothyroidism (CH) occurs with an incidence Abstract: Thyroid dyshormonogenesis (TDH) is charac- of 1:3000–1:4000 [1]. Neonatal screening for CH was intro- terized by the defective synthesis of thyroid hormones. duced in Switzerland in 1977 to prevent mental retardation We present a patient with congenital hypothyroidism in affected newborns [2]. Newborn screening in Swit- (CH) who presented in newborn screening with elevated zerland determines thyroid-stimulating hormone (TSH) serum thyroid-stimulating hormone (TSH), decreased free but not thyroxine (T4) concentration. Thus, newborns thyroxine (fT4) and increased thyroglobulin (Tg) concen- with central or secondary hypothyroidism are missed in trations. Ultrasound scan revealed a properly structured Switzerland. thyroid gland. Treatment with L-thyroxine was initiated. Primary CH can be classified into two forms: thyroid At the age of 2 years, thyroxine replacement was stopped. dysgenesis, which accounts for approximately 80–85% of The patient remained untreated until 6 years of age when all cases with permanent primary CH including resistance TSH levels progressively increased and L-thyroxine treat- to TSH, and thyroid dyshormonogenesis (TDH), account- ment was restarted at a dose of 12.5 µg/day. Genetic ing for 10–15% of cases. Thyroid dysgenesis is caused by analysis revealed a double heterozygosity for likely path- disordered development of the thyroid gland and results ogenic variants of dual oxidase 2 (DUOX2) and thyroid in athyreosis, hypoplastic or ectopic thyroid gland. TSH stimulating hormone receptor (TSHR). Both genes were resistance can cause hypoplastic or normally sized thyroid earlier shown to be associated with CH. In a literature gland. TDH is characterized by eutopic thyroid gland of review, our patient was compared to previously published normal size, or goiter [1]. patients with similar clinical characteristics, and a good Most forms of TDH are transmitted autosomal reces- genotype-phenotype correlation was identified. sively and so far variants in seven different genes coding for the following proteins have been identified: thyroid Keywords: congenital hypothyroidism; DUOX2 variant; peroxidase (TPO), thyroglobulin (TG), pendrin (causing TSHR variant. Pendred syndrome [SLC26A4/PDS]), sodium iodide trans- porter (SLC5A5/NIS), dual oxidase 2 (DUOX2), dual oxidase maturation factor (DUOXA2) and iodotyrosine deiodinase (IYD) [3]. *Corresponding author: Mariarosaria Lang-Muritano, MD, DUOX2 Department of Paediatric Endocrinology and Diabetology, University is a transmembrane protein. It generates H2O2, Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, which is required for the synthesis of thyroid hormones. Switzerland; and Children’s Research Centre, University Children’s Variants in the DUOX2 gene may result in transient or per- Hospital, Zurich, Switzerland, Phone: +41 44 266 72 73, manent dyshormonogenesis [3]. E-mail: [email protected] The TSH receptor (TSHR) gene codes for the TSH- Zerin Sasivari: Department of Paediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland receptor, which is a transmembrane protein binding Gabor Szinnai: Department of Paediatric Endocrinology and TSH and consequently stimulating thyroid hormone Diabetology, University Children’s Hospital, Basel, Switzerland production. Its variant causes TSH resistance resulting Britta Seebauer: Department of Medical Genetics, University in increased TSH levels in an effort to maintain normal Hospital Basel, University of Basel, Basel, Switzerland thyroid hormone secretion, which is not always achieva- Daniel Konrad: Department of Paediatric Endocrinology and TSHR Diabetology, University Children’s Hospital, Zurich, Switzerland; ble. pathogenic variants cause variable phenotypes, and Children’s Research Centre, University Children’s Hospital, ranging from asymptomatic to severe hyper or hypo- Zurich, Switzerland thyroidism. Carriers of inactivating biallelic TSHR gene Bereitgestellt von | provisional account Unangemeldet Heruntergeladen am | 09.01.20 10:00 1300 Sasivari et al.: Dyshormonogenesis due to double variants variants are likely to be identified by neonatal screening, substitution 4 weeks earlier. Scintigraphy with 4MBq whereas those with autosomal dominant-inherited mono- 123Jcd revealed homogenous accumulation of the radio- allelic variants appear in milder forms and may be missed nuclide in a correctly located thyroid gland. in the screening [4, 5]. After discontinuation of thyroid hormone replace- Herein, we present a boy with mild CH due to double ment, TSH concentration increased and remained slightly TSHR DUOX2 variants in the and gene. elevated (Figure 1), whereas fT4 was always within normal limits. At this time, the patient showed no symptoms. Therefore, therapy was not restarted as subclinical hypo- Case report thyroidism should not be treated unless there are signs or symptoms of hypothyroidism [6]. The patient remained untreated until the age of The patient was born of non-consanguineous parents 6 years when complaints of fatigue and dry skin appeared. at term, his body weight was 3370 g (P50), and his birth At presentation, the patient was clinically examined and length was 50 cm (P50). Pregnancy and spontaneous showed no signs of infection, so no blood test for infec- vaginal delivery were uneventful. In the newborn screen- tion parameters was done. As a differential diagnosis for ing on the 10th postnatal day, serum TSH concentration fatigue, serology tests for celiac disease were done with was elevated (79.1 mU/L [normal range: 0.1–10.5]). In the negative results. recall test after a few days, the TSH level was 222 mU/L and As TSH levels were also increasing, L-thyroxine free thyroxine (fT ) was decreased (0.27 ng/dL [0.8–2.31]). 4 replacement was restarted with a dose of 12.5 µg/day. At Thyroglobulin (Tg) was massively increased (980 µg/mL the time of treatment reinstitution, the patient’s height [<75 µg/mL]). At this point, treatment with L-thyroxine was 119.4 cm (P 50, +0.05 standard deviation [SD]), was started with a dose of 25 µg/day. Five days later, weight was 24.5 kg (P 75, +0.84 SD) and body mass index the dose was increased to 50 µg/day. Further evaluation (BMI) was 17.2 kg/m2 (P 75–90; z-score +1.2 SD). Thus, the revealed thyroid peroxidase, Tg and TSH receptor antibod- patient was not overweight. ies within the normal range. Ultrasound was performed During follow-up, TSH levels remained stable within during a follow-up visit 4 weeks after birth, showing a the normal range, fatigue disappeared and L-thyroxine homogenous thyroid gland loco classico with a longitudi- therapy was continued with a dose of 25 µg/day until nal dimension of 15 mm and each lobe having a width of adulthood when the patient was transitioned to adult 7 mm. Family history was unremarkable for thyroid prob- endocrinology. lems except for the maternal grandmother, who devel- oped hypothyroidism after menopause. All these findings suggested a likely diagnosis of TDH. A perchlorate test to Materials and methods distinguish from a thyroid dysgenesis was not performed. At the age of 2 years, the patient’s thyroid function To analyze the patient’s DNA, a custom-designed Illumina sequenc- was reevaluated after cessation of L-thyroxine (50 µg) ing panel containing genes involved in thyroid dysgenesis (FOXE1, Start of therapy End of therapy Restart of therapy 250 8 25 µg L- 12.5 µg L-thyroxine, daily thyroxine, 7 200 daily 6 25 g L-thyroxine, End of therapy µ 5 daily 150 50 µg L- 4 thyroxine, 100 daily 3 TSH level, mU/L TSH level, mU/L 2 50 End of 1 therapy 0 0 2.26 2.33 2.36 2.41 2.45 2.56 2.83 3.38 3.47 3.97 4.62 5.49 6.54 6.98 9.91 11.25 0.7 0.03 0.04 0.06 0.08 0.12 0.21 0.39 0.97 1.47 2.26 Age, years Age, years Figure 1: Course of TSH concentration over time.
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