Phenotypic variability of patients with PAX8 variants presenting congenital hypothyroidism and eutopic thyroid.
Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. PAX8 is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in-vitro functional studies.Patients: Nine pediatric patients from the Catalan-screening program of Congenital Hypothyroidism, with a eutopic thyroid gland. Scintigraphies showed absent, low or normal uptake. Only one patient had a hypoplastic gland. In reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, eight patients showed permanent mild or severe hypothyroidism. Methods: Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In-vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays.We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and five variants showed a statistically significant impaired transcriptional activity of TG promoter: 51-78% versus the wild type.Nine patients presented PAX8 candidate variants. All presented eutopic thyroid gland and seven had deleterious variants. Phenotype of affected patients varies considerably, even within the same family; but, all, except the homozygous patient, presented normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that six PAX8 variants are deleterious. Our studies have proven their effectiveness in evaluating these variants.