[Pathogenic TSHR variants in children with thyroid dysgenesis].

BACKGROUND: Loss-of-function mutations in the TSH receptor gene (TSHR) (NP_000360.2) are the potential causes of thyroid dysgenesis in patients with congenital hypothyroidism. Heterozygous variants of the TSHR gene lead to partial resistance to TSH, homozygous and compound heterozygous variants have been shown to cause CH due to thyroid hypoplasia or TSH resistance. Recently more and more articles in this field have appeared in the international literature sources, while local publications are limited. The studies are necessary to understand the etiology, pathogenesis of the disease, to improve the management of these patients. AIM: To assess the frequency of incidence of pathogenic variants of the TSHR gene in children with CH due to thyroid dysgenesis. To study inheritance and phenotypic patterns of CH in families. MATERIALS AND METHODS: In this single-center interventional one-stage non-comparative study a group of CH patients was examined. The patients underwent neck ultrasound and radionuclide imaging. The examination was performed 14 days after hormone replacement therapy suspension or prior to its initiation. The structure of thyroid dysgenesis was estimated, genetic testing for mutations in the TSHR gene was performed using the NGS method. RESULTS: The study included 95 children with primary CH (75 girls; 20 boys). The patients' median age at the time of examination was 6.2 years [4.5; 8.9], the median level of neonatal TSH was 157.5 mU/l [60.9; 257.2]. Ectopic thyroid was found in 52% of children, aplasia in 36%, hypoplasia and hemiagenesis in 10% and 2%, respectively. In 5.4% of cases (in 5 out of 95 patients), different variants of the TSH gene were detected. Two children had heterozygous p.R450H and p.D487N variants in TSHR gene, two patients was homozygous for the p.S49Afs * 9 variant, one child had compound heterozygous variants (p.A485D and p.R450H). According to ultrasound imaging, all patients had thyroid hypoplasia of varying severity. Three children underwent thyroid scintigraphy, which revealed decreased 99mТc pertechnetate uptake (0.3-0.9%). CONCLUSION: In our study, the incidence of different variants in the TSHR gene in children with CH was 5.3%. Our analysis uncovered two previously undescribed variants. Genetic testing may be able to help with making the diagnosis, patient's management, and genetic counseling.

[Ectopic thyroid gland: clinical features and diagnostics in children].

BACKGROUND: The frequency of ectopia of thyroid gland among all types of dysgenesis varies from 30 to 70%, its most common localization is the root of the tongue. Otorhinolaryngologists, oncologists, pediatricians can take lingual ectopia for hypertrophy of the lingual tonsil or fibroma of the tongue root, which leads to unreasonable surgical treatment. Thyroid scintigraphy plays a key role in the diagnosis of ectopia. AIM: To assess the etiological structure of congenital hypothyroidism (CH) and demonstrate the clinical course in patients with ectopic thyroid tissue in the root of the tongue. MATERIALS AND METHODS: A group of patients with CH was examined. All patients underwent neck ultrasound and radionuclide imaging. The examination was carried out against the background of the abolition of hormone replacement therapy for 14 days or before its initiation. Patients with ectopia in the root of the tongue underwent videofibrolaryngoscopy. Some patients underwent a genetic study with using genes panel of a panel of candidate genes responsible for the development of CH using the NGS method. The molecular genetic study was conducted to some patients, next-generation sequencing with the genes panel. RESULTS: The study included 73 patients with primary CH aged from 2 weeks to 17.3 years: 69 children were diagnosed based on the results of neonatal screening, 4 children with thyroid ectopia were first examined older than 6 years. The median age of patients at the time of the examination was 6.9 years [4.8; 10.0]. By data of ultrasound aplasia was diagnosed in 47.9% of patients, one child had hemiagenesis and ectopic thyroid tissue of various localization was detected in 26.0% of  children. In 24.7% of children thyroid tissue was found in a typical location. Scintigraphy confirmed thyroid aplasia in 65.7% of children. Examination revealed various variants of ectopically located thyroid tissue in 31 children (42.4%): thyroid ectopia in the root of the tongue in 25 children (80.6%), ectopia in the sublingual region in 5 children (16.2%), double ectopia was detected in 1 child. The median level of TSH in newborns with ectopic thyroid gland was 124 IU/ml and was significantly lower than in children with aplasia - 219 IU/ml, p<0.05. On the other side the level of TG in children with ectopia was significantly higher than in children with aplasia - 37.12 ng/ml versus 0.82 ng/ml, p><0.05. CONCLUSION: Combination of two methods is the best diagnostic approach to determine the etiology of CH - ultrasound and scintigraphy studies compensates deficiencies of each other. Our study demonstrates the importance of scintigraphy in children with CH and patients with the formation of the root of the tongue and the anterior surface of the neck in order to avoid unnecessary removal of the thyroid gland. In case of confirmation of thyroid ectopia in the root of the tongue and in the absence of symptoms of obstruction or bleeding, it is recommended to refer the patient to an endocrinologist for conservative treatment. ><0.05. On the other side the level of TG in children with ectopia was significantly higher than in children with aplasia - 37.12 ng/ml versus 0.82 ng/ml, p< 0.05. CONCLUSION: Combination of two methods is the best diagnostic approach to determine the etiology of CH - ultrasound and scintigraphy studies compensates deficiencies of each other. Our study demonstrates the importance of scintigraphy in children with CH and patients with the formation of the root of the tongue and the anterior surface of the neck in order to avoid unnecessary removal of the thyroid gland. In case of confirmation of thyroid ectopia in the root of the tongue and in the absence of symptoms of obstruction or bleeding, it is recommended to refer the patient to an endocrinologist for conservative treatment.