A UK paper with potentially great significance to those affected.
I have already seen papers questioning the precise timing of bloodspot analysis, and that only TSH is measured (not Free T4). This appears to increase the argument in the direction of enhanced testing of neonates.
Of course, these gene variants might exist in many of us - but for one reason or another they did not cause overt hypothyroidism early in life. Would be interesting to see their prevalence among members.
Thyroid. 2019 May 2. doi: 10.1089/thy.2018.0587. [Epub ahead of print]
DUOX2/DUOXA2 mutations frequently cause congenital hypothyroidism which evades detection on UK newborn screening.
Peters C1, Nicholas AK2, Schoenmakers E3, Lyons G4, Langham S5, Serra EG6, Sebire NJ7, Muzza M8, Fugazzola L9,10, Schoenmakers N11.
Author information
Abstract
Background
The aetiology, course and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening TSH (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. We 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. Our study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort.
Methods
We undertook a cross sectional study of patients with borderline CH at Great Ormond Street Hospital, a tertiary, UK paediatric centre. DUOX2 was sequenced in 52 patients with bsTSH 6-19.9 mU/L, venous TSH (vTSH) > 25 mU/L and eutopic thyroid gland-in-situ. DUOXA2 was sequenced in DUOX2 mutation negative cases and novel DUOXA2 mutations were functionally characterized.
Results
26 patients (50%) harboured 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 < 10mU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous FT4 levels in these patients were in the moderate CH range (mean FT4 9.3, 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 harbouring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.
PMID: 31044655
DOI: 10.1089/thy.2018.0587
Full paper is behind paywall.
