The diagnosis of congenital hypothyroidism can be confirmed by genetic testing, says a study published in the European Thyroid Journal wherein genetic testing resulted in change in diagnosis in 10 children with congenital hypothyroidism and also allowed cessation of L-thyroxine treatment in five patients.¹

Forty-eight patients, 31 males and 17 females, with primary congenital hypothyroidism with normal, goitrous (n = 5) or hypoplastic thyroid (n = 5) were included in this study. Based on the features at presentation, during follow-up or during a re-evaluation at age 2 to 3 years,15 patients were categorized as transient congenital hypothyroidism (TCH), 26 as permanent congenital hypothyroidism (PCH) and seven as persistent hyperthyrotropinemia (PHT). The three groups of patients were examined again after genetic testing using a custom-designed high-throughput sequencing 23-gene panel. The objective of the study was to examine the genetic etiology of these conditions and the impact of genetic testing on the management and prognosis of these patients.

Genetic testing resulted in a change in initial diagnosis in 10 patients; five children with PHT were reclassified as TCH; two children with PCH were re-categorised as PHT and three children with PCH were reclassified as TCH finally resulting in 23 children with transient congenital hypothyroidism, 21 in the permanent congenital hypothyroidism group and four with persistent hyperthyrotropinemia.

Treatment could be discontinued after genetic testing in five patients because of the presence of monoallelic TSHR or DUOX2 genes, or no pathogenic variants following genetic analysis. Presence of monoallelic TSHR variants and the misdiagnosis of thyroid hypoplasia on neonatal ultrasound in low birthweight infants were the major contributors to changes in diagnosis and treatment.

A total of 41 genetic variants, mainly affecting thyroglobulin (TG), TSH receptor gene (TSHR) and DUOX2 genes, were identified in 65% (n = 31) of the participants after genetic testing, which definitely explained the genetic etiology in 46% (n = 22) indicating a decisive link between the genotype and phenotype. However, the genetic etiology was ambiguous with weaker causal link in 19% (n = 9) patients, while the etiology remained unsolved in the remaining participants with no pathogenic variant identified in the targeted genes. Molecular diagnosis rate was significantly higher in patients with PCH (57%, n =12) than TCH (26%, n = 6).

This study demonstrates that genetic testing helped to make a final diagnosis enabling change in treatment in some children with congenital hypothyroidism thereby improving outcomes. “The resulting benefit may outweigh the burden of lifelong follow-up and treatment” concluded the researchers. While genetics plays a crucial role in the management of patients with congenital hypothyroidism, treatment decisions are still determined by thyroid function tests.

Reference

1. Kara C, et al. Genetic testing can change diagnosis and treatment in children with congenital hypothyroidism. Eur Thyroid J. 2023 Mar 1;12(3):e220212. doi: 10.1530/ETJ-22-0212.