DUOX2/DUOXA2 Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom.

Catherine Peters,Marina Muzza,Greta Lyons,Erik Schoenmakers,Laura Fugazzola,Shirley Langham,Adeline K Nicholas,Neil J Sebire,Eva G Serra,Nadia Schoenmakers

doi:10.1089/thy.2018.0587

Abstract

Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort.Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6–19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized.Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 (n = 20; 38%) or DUOXA2 (n = 6; 12%), including novel gene variants (DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (M = 9.3 pmol/L, range <3.9–15.8 pmol/L),Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

Highlights

Primary congenital hypothyroidism (CH) is the commonest neonatal endocrine disorder, for which prompt diagnosis and initiation of levothyroxine (LT4) therapy is required to prevent irreversible neurodevelopmental delay
This study is the first to investigate the frequency of Dual oxidase 2 (DUOX2) or DUOXA2 mutations in a borderline GIS CH cohort with a first bloodspot TSH (bsTSH) between 6 and 19.9 mIU/L, unlike previous studies that have studied cases recruited on the basis of higher bsTSH levels or known organification defect [10,12]
The observations suggest that DUOX2/DUOXA2 mutations are a more common cause of borderline CH than anticipated and are consistent with the high frequency of defective iodide organification, likely due to underlying DUOX2/DUOXA2 defects, in cases with borderline CH (TSH

Summary

Introduction

Primary congenital hypothyroidism (CH) is the commonest neonatal endocrine disorder, for which prompt diagnosis and initiation of levothyroxine (LT4) therapy is required to prevent irreversible neurodevelopmental delay. Despite bsTSH being

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