AUTHOR=Zdraveska Nikolina , Kocova Mirjana , Nicholas Adeline K. , Anastasovska Violeta , Schoenmakers Nadia 

TITLE=Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

JOURNAL=Frontiers in Endocrinology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.00413

DOI=10.3389/fendo.2020.00413

ISSN=1664-2392

ABSTRACT=<p>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-<italic>in-situ</italic> (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as <italic>TSHR</italic> and <italic>PAX8</italic> 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 (<italic>n</italic> = 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 &gt;3,000 <italic>g</italic>, and thyroid morphologies included goiter (<italic>n</italic> = 11), thyroid hypoplasia (<italic>n</italic> = 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 <italic>TSHR</italic> in GIS cases and <italic>TSHR</italic> and <italic>PAX8</italic> 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 <italic>TPO</italic> (<italic>n</italic> = 4), <italic>TG</italic> (<italic>n</italic> = 3), <italic>TSHR</italic> (<italic>n</italic> = 4), <italic>DUOX2</italic> (<italic>n</italic> = 4), and <italic>PAX8</italic> (<italic>n</italic> = 2). No mutations were detected in <italic>DUOXA2, NIS, IYD</italic>, and <italic>SLC26A7</italic>. 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.</p>