ESPE Abstracts

Background: The PAX8 gene (Paired box gene 8) is located on the long arm of chromosome 2 (2q12–q14), contains 12 exons and encodes a similarly named PAX8 protein. This protein is a transcription factor which in the thyroid gland is essential for the follicular cells formation and takes part in the expression of the thyroid-specific genes (TG, TPO, and SLC5A5). Variants in the gene have been previously associated with autosomal dominant thyroid dysgenesis with hypoplasia, and in rare cases with athyreosis and thyroid ectopy. Variants in PAX8 were also reported to cause urogenital tract defects. Here we report two patients in the same family with congenital hypothyroidism (CH), attributed to the novel PAX8 gene mutation inherited from the healthy mother.

Case Report: Patient 1 (P1), a 2 year old boy and Patient 2 (P2), a 14-day old newborn girl were referred with CH. Patients were born at full-term with normal height and weight to unrelated parents and showed no abnormalities of the genitourinary tract.

P1: Screening TSH was 33 mU/l (reference ≤ 9 mU/L) with confirmation on day 11 (TSH 17 mU/l, T4L 14.7 pmol/l). Ultrasound examination at 2 years of age showed thyroid hypoplasia. Treatment started on the 11th day after birth.

P2: Screening TSH was 38 mU/l with confirmation on day 9 (TSH 73 mU/l, T4L 9 pmol/l). Ultrasound examination at 1 year of age also showed thyroid hypoplasia. Treatment started on the 9th day after birth. According to the NGS-based genetic testing both children were showed to possess a previously unreported heterozygous variant in exon 4 of PAX8 gene (NM_003466.4:c.368C>G:p.P123R) which was classified as likely pathogenic according to the ACMG criteria. There were no other rare variants found in the gene, the coding regions and the adjacent intronic areas were completely covered. The parents were also subjected to the same genetic test which for the mother yielded two previously unreported heterozygous variants in the PAX8 gene: the one found in both children, and another one in exon 11 (NM_003466.4:c.1151G>A:p.G384D) which was classified as uncertain significance by ACMG.

Conclusion: Two children, both presented with congenital hypothyroidism associated with thyroid hypoplasia, and their healthy mother we shown to possess a previously unreported likely pathogenic heterozygous variant in the PAX8 gene. Differences in the clinical course can be attributed to the incomplete penetrance of the variant.