ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2016) 45 OC5.7 | DOI: 10.1530/endoabs.45.OC5.7

Frequent occurrence of DUOX2 and DUOXA2 mutations in cases with borderline bloodspot screening TSH who develop 'True' congenital hypothyroidism

Catherine Peters1, Adeline K. Nicholas2, Greta Lyons2, Shirley Langham1, Eva G. Serra3, Erik Schoenmakers2, Marina Muzza4, Laura Fugazzola4 & Nadia Schoenmakers2

1Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK; 2University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK; 3Department of Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK; 4Department of Clinical Sciences and Community Health, University of Milan, Milan, UK.

The UK newborn screening programme for congenital hypothyroidism (CH) facilitates prevention of neurodevelopmental delay in CH by enabling prompt diagnosis and treatment. Although the UK Newborn Screening Programme Centre (UKNSPC) defines a borderline bloodspot screening TSH (bsTSH) concentration as 10–20 mU/l, the lower cutoff used at Great Ormond Street Hospital (6 mU/l), enables diagnosis of true and transient CH in cases missed using UKNSPC criteria. We hypothesised that mutations in DUOX2 and its accessory protein DUOXA2 may be common in borderline CH cases and have broader management implications.

We screened 40 term babies with eutopic gland-in-situ, including 21 with Asian/Chinese ethnicity (53%). Biochemical recruitment criteria comprised a 1st bsTSH measuring 6–20 mU/l, and confirmatory venous TSH (vTSH) >25 mU/l. DUOX2 was sequenced initially, followed by DUOXA2 in mutation negative cases. Mutations were classified as pathogenic based on in silico predictions including molecular modeling for DUOX2 mutations affecting the peroxidase-like domain.

In total of 19 cases (47.5%) harboured likely disease-causing mutations in either DUOX2 (n=13, 32.5%) or DUOXA2 (n=6,15%) and confirmatory venous thyroid hormone levels in mutation-positive cases demonstrated subnormal mean free T4 9.1±0.8 (NR 12.5–24.6 pmol/l). Initial or repeat bsTSH was below the UKNSPC cutoff (10 mU/l) in 42% of mutation-positive cases. We detected 7 rare novel DUOX2 mutations and 6 novel DUOXA2 mutations; two DUOX2 mutations (p.Q570L, p.F966Sfs*29) were recurrent and occurred more frequently (MAF ≤0.01). Significant enrichment of DUOXA2 variants in our cohort compared with healthy populations (15% vs 1%, P=1.70×10−5) supported an aetiological contribution of both monoallelic (n=5) and biallelic mutations (n=1).

Recommended TSH screening cut offs fail to detect individuals with true dyshormonogenesis who develop at least moderate CH, despite borderline bsTSH concentrations. Targetted sequencing of DUOXA2 and DUOX2 in such cases will have a high diagnostic yield, especially in Asian/Chinese populations, and genetic ascertainment will facilitate prompt diagnosis in familial cases.