DUOX2/DUOXA2 mutations frequently cause congenital hypothyroidism which evades detection on UK newborn screening

[helvella]

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.

ncbi.nlm.nih.gov/pubmed/310...

[Dingoatemybaby]

My son has congenital hypothyroidism and I’ve hashimotos (Diagnosed since Feb and was tested after his birth and annually - nothing).

He also has been gene tested but I haven’t got the results yet.

The concerns feel worlds apart, totally different though... or maybe it’s because you’re the parent but... An infant with CH must begin to rapidly come in to range within the first three weeks of life. Putting it bluntly, if their brains fail to thrive at a critical time in their development, and if they ‘miss’ developing at that moment, the window is gone and the damage is done. It is terrifying as a parent to consider that your baby may be losing their intelligence potential right in front of your eyes.

Paediatric Endo’s focus heavily on getting TSH close as, to 1. Children grow so rapidly the dose has to adjust a lot and their Growth is monitored. The first two years are pretty intense - lots of bloods and consultant appointments every few weeks. Very overwhelming time. Strange to think of it now. He’s still only wee - he’s 3.5 and doing amazing. He was slow to do a lot of things but not delayed, and remained in the same trajectory for height and growth from birth.

[porter5]

FYI about 6 weeks ago.there was a comment in the Times signed by a number of

professors from different UK universities.

The comment was in response to an article in the Times about adding nutrients to

the food supply.

The author of the article omitted iodine in the professors opinion. They went on to add that more than 50% of women of childbearing age were low in iodine ,that the ministry of health knew about the situation but hadn't done anything, despite the fact that low iodine in the first trimester can cause serious problems for the developing fetus.

[TSH110]

I have struggled to find what one needs to search for in 23&me raw data to know if one has mutations.

The only snp with reference to that gene I could find gave me a TT the significance (or otherwise) of which eludes me.

[helvella Administrator Thyroid UK in reply to TSH110]

23&me is only partial. No certainty that any particular SNP will be covered, and the assay has changed a few times over the years.

I'm afraid my understanding is very limited and the post was very much a hypothetical question - not really expecting anyone to know!

[TSH110]

Thanks - I found plenty about it but nothing clear about relevant SNPs. I don’t really understand what methods are used in research for DNA analysis or why many articles never cover SNPs at all. Never even got to the starting blocks for a raw data search ☹️