Genetics and management of congenital hypothyroidism

Molecular defects in thyroid dysgenesis

“…Moreover, deletions proximal to NKX2‐1 have also been implicated, suggesting the presence of an upstream enhancer in this region . Concerning the thyroidal abnormalities, a predominance of normal thyroid‐in‐situ over TD (hypoplasia or hemiagenesis, 35%‐50%; athyreosis, 10%) was reported . Only one case with NKX2‐1 mutation with a thyroid ectopy has been reported so far.…”

“…Inheritance is autosomal recessive. Thyroid involvement in GLIS3 ‐mutated patients include thyroid aplasia, diminished colloid with interstitial fibrosis, and apparently normal thyroid texture on ultrasound, but with temporary TSH resistance upon thyroxine treatment, perhaps explained by its actions downstream of TSH and the TSHR, because GLIS3 is indispensable for TSH/TSHR‐mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone …”

“…Accordingly, putative causative mutations have been only highlighted in about 10% of TD-affected subjects. 15 Moreover, only 2% of TD subjects has an affected relative.…”

“…49 Concerning the thyroidal abnormalities, a predominance of normal thyroid-in-situ over TD (hypoplasia or hemiagenesis, 35%-50%; athyreosis, 10%) was reported. 15 Only one case with NKX2-1 mutation with a thyroid ectopy has been reported so far. NKX2-1 mutations may exhibit autosomal dominant inheritance with variable expressivity and penetrance, but frequently occur de novo.…”

“…Because TD concordance between monozygotic twins is extremely low, it would indicate that monogenic germline mutations are not a frequent cause of TD. Accordingly, putative causative mutations have been only highlighted in about 10% of TD‐affected subjects . Moreover, only 2% of TD subjects has an affected relative.…”