Congenital Hypothyroidism Patients With Thyroid Hormone Receptor Variants Are Not Rare: A Systematic Review

Abstract

Background Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an important role in CH. Aim To explore the occurrence of pathogenic TSHR variants in CH. Methods We searched published articles in PubMed, Web of Science, and Cochrane Library databases, from the establishment of the database to September 26, 2021. Studies with sequencing partial or full exons of TSHR in CH patients were included. Gene polymorphism was excluded. Results A total of 66 articles (44 case-control studies and 22 case reports) were selected from the database. Though case-control studies, we found the incidence of pathogenic TSHR variants were not rare (range from 0% to 30.6%) and varied greatly in different countries and race. The pathogenic genotypes varied in different regions. All the variants were “loss-of-function” mutations, in which the p.(Arg450His) variant was the most common variant. In addition, we analyzed the case reports and found that CH patients with a family genetic background expressed homozygous genotypes. Homozygotes had more obvious symptoms of hypothyroidism and higher risk of comorbidities than heterozygotes. Conclusion Pathogenic TSHR variants are not uncommon cause of the CH, especially in the Arabs. The role of TSHR gene detection in the treatment of children with CH needs to be further studied.

Can inactivation mutation in the thyroid stimulating hormone receptor gene and hyperthyroidism coexist?: A case report

“…[9] Previous reports have shown that carriers of homozygous or compound heterozygous mutations are more likely to develop congenital hypothyroidism, while subjects with monoallelic heterozygous mutation in the TSHR gene may present with normal thyroid function or subclinical hypothyroidism. [5,10] According to numerous studies results, 2 modes of inheritance of TSHR inactivation mutations causing diseases are identified including autosomal recessive and autosomal dominant inheritance. [11][12][13] Previous study found that the G132R mutation would reduce cAMP production and binding activity, and the patient had normal thyroid ultrasound and increased TSH level.…”

Pathogenic <i>TSHR</i> variants in children with thyroid dysgenesis

“…На долю гипоплазии и гемиагенезии приходится 10 и 2% соответственно. Известно, что гипоплазия в ряде случаев обусловлена мутациями в гене TSHR [ 13 ].…”

“…2021 г. [ 13 ], включавшему анализ данных 3975 детей с ВГ из 23 стран (представленных в 44 исследованиях «случай-контроль»), средняя частота патогенных вариантов в гене TSHR составила 7,83%. Частота патогенных вариантов в гене TSHR зависит от популяций и варьирует от 0 (Бразилия) до 29% (Израиль).…”

“…Резистентность к гену TSHR зависит от зиготности и типа мутации [7,13] Не выявлено резистентности к ТТГ связана с типом и локализацией мутации гена TSHR: полная потеря функции вследствие биаллельных инактивирующих мутаций обычно приводит к тяжелому ВГ с характерными клиническими проявлениями, в то время как носители других биаллельных мутаций (гомозиготные или компаунд-гетерозиготы) имеют легкую форму заболевания, проявляющуюся в виде субклинического гипотиреоза [7,30]. Пациенты с моноаллельными дефектами гена TSHR, с учетом частичной компенсации, могут не выявляться при неонатальном скрининге [31].…”

“…и соавт. [13] опубликован крупный систематический обзор, касающийся изучения патогенных вариантов TSHR при ВГ, частоты их встречаемости и клинических особенностей пациентов с этим генотипом. Отечественные публикации ограничены единичными исследованиями [14][15][16].…”