Endocrine Abstracts

Neonatal screening for congenital hypothyroidism (CH) in the Republic of Macedonia was piloted in 2002 and implemented nationally in 2007, demonstrating a CH incidence of 1 in 1916. 52.7% cases exhibit a normally-located gland-in-situ (GIS CH), however, although this may indicate genetically-mediated dyshormonogenesis, genetic stratification has not previously been undertaken. We selected singleton GIS CH cases (n=22), born at term, with birth weight >3000 g in whom genetically-mediated dyshormonogenesis was likely, e.g. with scintigraphic features of dyshormonogenesis, goitre, familial cases, or with unexplained transient or subclinical CH. TG, TPO, IYD and DUOX2 were sequenced in seven cases with thyroid stimulating hormone (TSH) concentrations greater than 50 mU/l (including two sibling pairs) and TSHR, DUOX2 and DUOXA2 were screened in fifteen milder cases with TSH11.9-41 mU/l, including one sibling pair. SLC5A5 (NIS) was sequenced in cases lacking pertechnate scan data; otherwise normal isotope uptake was assumed to indicate preserved SLC5A5 function. One case with TSH >150 mU/l harbored compound heterozygous pathogenic TPO mutations (p.E17Dfs*77 and p.R438H) and two siblings with severe CH harboured a heterozygous pathogenic TPO mutation (p.A397Pfs*76). Three mild cases harboured rare, heterozygous variants; TSHR p.E506K (novel, predicted to be pathogenic), TSHRc.692+1_692+4delGTGA (uncertain significance) and DUOX2 p.E1546G (known pathogenic). 24 hour urinary iodine concentrationswere assessed in ten mutation-negative casesand did not show iodine deficiency (range 124–329 μg/l). Our small, iodine replete GIS CH series demonstrated few candidate gene mutations (maximum frequency 27% assuming pathogenicity of all variants). Autoantibody titres were not routinely assessed, but were negative in the only case with a maternal history of thyroid disease. Although GIS CH due to dyshormonogenesis may be difficult to ascertain clinically, and targeted sequencing may miss unexpected defects, we postulate that novel genetic aetiologies underlie dyshormonogenesis, especially in familial cases with severe goitrous CH.