Abstract
Neonatal screening in Macedonia detects congenital hypothyroidism (CH) with an incidence of 1 in 1,585, and more than 50% of cases exhibit a normally located gland-in-situ (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as TSHR and PAX8 defects. The genetic architecture of Macedonian CH cases has not previously been studied. We recruited screening-detected, non-syndromic GIS CH or thyroid hypoplasia cases (n = 40) exhibiting a spectrum of biochemical thyroid dysfunction ranging from severe permanent to mild transient CH and including 11 familial cases. Cases were born at term, with birth weight >3,000 g, and thyroid morphologies included goiter (n = 11), thyroid hypoplasia (n = 6), and apparently normal-sized thyroid. A comprehensive, phenotype-driven, Sanger sequencing approach was used to identify genetic mutations underlying CH, by sequentially screening known dyshormonogenesis-associated genes and TSHR in GIS cases and TSHR and PAX8 in cases with thyroid hypoplasia. Potentially pathogenic variants were identified in 14 cases, of which four were definitively causative; we also detected digenic variants in three cases. Seventeen variants (nine novel) were identified in TPO (n = 4), TG (n = 3), TSHR (n = 4), DUOX2 (n = 4), and PAX8 (n = 2). No mutations were detected in DUOXA2, NIS, IYD, and SLC26A7. The relatively low mutation frequency suggests that factors other than recognized monogenic causes (oligogenic variants, environmental factors, or novel genes) may contribute to GIS CH in this region. Future non–hypothesis-driven, next-generation sequencing studies are required to confirm these findings.
Highlights
Congenital hypothyroidism (CH) is traditionally divided into dysgenesis and dyshormonogenesis, where thyroid hormone biosynthesis is inadequate despite a structurally normal or goitrous thyroid
After the implementation of CH neonatal screening, studies investigating the incidence of CH generally reported an incidence of approximately 1:3,000, of which the majority was due to thyroid dysgenesis, with only 20% occurring due to dyshormonogenesis
Mutations in TSHR, the G-protein–coupled receptor for thyroid-stimulating hormone (TSH) cause a spectrum of phenotypes ranging from severe thyroid hypoplasia to a normal-sized GIS, with the severity correlating with the number of mutated TSHR alleles and the degree of receptor functional impairment [6]
Summary
Congenital hypothyroidism (CH) is traditionally divided into dysgenesis (abnormal thyroid development) and dyshormonogenesis, where thyroid hormone biosynthesis is inadequate despite a structurally normal or goitrous thyroid. Thyroid dysgenesis usually occurs because of an ectopic thyroid or athyreosis, and thyroid hypoplasia remains the least common thyroid developmental abnormality [1,2,3]. The etiology of GIS CH is generally unclear; some cases may harbor mutations in genes involved in thyroid hormone biosynthesis or development. Mutations in TSHR, the G-protein–coupled receptor for thyroid-stimulating hormone (TSH) cause a spectrum of phenotypes ranging from severe thyroid hypoplasia to a normal-sized GIS, with the severity correlating with the number of mutated TSHR alleles and the degree of receptor functional impairment [6]. Isolated thyroid hypoplasia may occur because of PAX8 or TSHR mutations, and mutations in the transcription factors NKX2-1 and FOXE1 cause CH in association with more extensive developmental syndromes [1]
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