ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This cohort study identified genetic variants associated with thyroid dyshormonogenesis as a cause of congenital hypothyroidism in Southern Taiwan. It reviewed 876 CH patients diagnosed between 2011 and 2022 and examined the genetic etiology in 47 cases of TDH using whole-exome sequencing (WES).

The etiology of congenital hypothyroidism (CH) can be attributed to either thyroid dysgenesis (TD) or thyroid dyshormonogenesis (TDH) with TD usually identified in 75-85% of cases. Several studies have shown significant variation in the incidence of TDH that may be due to demographic shifts and genetic “hot spots”. The investigators utilized the current technology for whole-exome sequencing to determine the genotype of a large cohort of patients with TDH seen in a single center in Taiwan. 876 cases of (CH) were identified at the National Cheng Kung University Hospital from 2011 to 2022. 121 cases were classified as permanent CH based on requirement for levothyroxine for a minimum of 3 years after birth and, of these, 47 (40%) were classified as TDH based on imaging-confirmed presence of bilateral normal thyroid structures on ultrasound or Tc99m scan. Whole-exome sequencing was performed on 45 patients, with causative variants identified in 32 patients (71.1%). The most common mutations were in genes for DUOX2 (15 cases), TG (8 cases), TSHR (7 cases), TPO (5 cases), and DUOXA2 (1 case). Four recurrent mutations were identified and four novel variants discovered. While previous studies have identified mutations in TG as the most common cause of TDH in Western populations, this study support previous identification of DUOX2 as more common in Asian countries. The DUOX2 R1110Q mutation accounted for 13.3% in this study, higher than the 2.2% in mainland China previously reported, suggesting regional differences in the genetic variations that may be related to demographic shifts.

These findings underscore the utility of WES in providing a molecular diagnosis for cases of TDH. It highlights the diversity of genetic etiologies in Taiwan and the potential regional differences in genetic mutations. Wider routine use of WES would allow for a more detailed analysis of the genetic causes of TDH.

References: 1. Stoupa A, Kariyawasam D, Polak M, Carré A. Genetics of congenital hypothyroidism: modern concepts. Pediatr Investig. 2022;6(2): 123–34.2. Kara C, Mammadova J, Abur Ü, Gumuskaptan C, _ Izci Güllü E, Dagdemir A, et al. Genetic testing can change diagnosis and treatment in children with congenital hypothyroidism. Eur Thyroid J. 2023;12(3):e220212.