Screening Tests for Congenital Hypothyroidism May Miss Patients With DUOX2/DUOXA2 Mutations

Current cutoffs for blood spot TSH levels in congenital hypothyroidism screening may fail to identify patients with congenital hypothyroidism secondary to DUOX2/DUOXA2 mutations.

Current cutoffs for blood spot thyroid-stimulating hormone (TSH) levels in neonatal screening for congenital hypothyroidism (CH) may fail to identify patients with CH secondary to DUOX2 or DUOXA2 mutations, according to study results published in Thyroid.

Primary CH is the most common neonatal endocrine disorder. The UK newborn screening program for CH, introduced in 1983, has had good results with near elimination of the profound impairments associated with delayed diagnosis and treatment for CH. However, there is a significant variability in the cutoff thresholds used in blood spot TSH screening.

Mutations in DUOX2 and its accessory protein DUOXA2 may cause CH; in these cases, it is possible to find borderline blood spot TSH elevation with markedly low free thyroxine levels. The goal of the study was to assess the frequency of these mutations in borderline blood spot TSH with gland in situ CH.

Of 361,839 infants screened for CH at Great Ormond Street Hospital in London, United Kingdom, between January 2013 and December 2015, the researchers identified patients with an initial blood spot TSH between 6 and 19.9 mU/L and a second blood spot TSH >6 mU/L a week later. The cross-sectional study enrolled 52 eligible infants (27 boys, 25 girls) with parental consent and available DNA samples. DUOX2 was screened in all cases, and when no mutation was identified, DUOXA2 sequencing was completed.

Of the 52 participants, 26 patients (50%) harbored mutations in either DUOX2 (20 patients; 38%) or DUOXA2 (6 patients; 12%) that were either known or likely to be pathogenic.

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Mean blood spot TSH results were similar in patients with and without mutation, but patients with 1 of the mutations had greater TSH elevation on venous confirmatory testing. There was also a tendency for higher absolute value of the second blood spot TSH test in patients with 1 of the mutations (mean blood spot TSH, 23.1 ± 2.91 vs 16.6 ± 1.7 mU/L; P =.05).

Almost half the patients (46%) with a mutation had ≥1 blood spot TSH level <10 mU/L; therefore, these patients would have been missed using a blood spot TSH screening cutoff of >10 mU/L, although most of them had moderate to severe CH on venous testing (mean free thyroxine, 9.5 pmol/L [range, <3.9-15.8 pmol/L] for DUOX2 mutations).

“Our study indicates that use of current, recommended [cutoffs for blood spot TSH] in screening for CH would fail to identify individuals with true dyshormonogenetic CH due to DUOX2 and DUOXA2 mutations, with DUOX2/DUOXA2 cases comprising 50% of our borderline CH cohort,” wrote the investigators, adding that “targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort will have a high diagnostic yield.”

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Peters C, Nicholas AK, Schoenmakers E, et al. DUOX2/DUOXA2 mutations frequently cause congenital hypothyroidism which evades detection on UK newborn screening [published online May 2, 2019]. Thyroid. doi:10.1089/thy.2018.0587