Endocrine Abstracts

JOINT870

Over the past few decades, the diagnosis of congenital hypothyroidism with a thyroid gland in situ (CH-GIS) has significantly increased, partially due to the widespread implementation of newborn screening programs. Although recent advancements in genetic research have enabled the identification of a genetic etiology in approximately 40-60% of CH-GIS cases, the etiology of this condition remains not completely understood.

Methods: In this study, we performed Targeted Next Generation Sequencing (NGS) of 18 thyroid-related genes in 78 pediatric patients with CH-GIS identified through newborn screening in Emilia-Romagna, Italy, from 2003 to 2021. All patients were diagnosed with permanent CH after diagnostic reevaluation. The goal was to genetically characterize this cohort, identify pathogenic variants, and explore the correlation between genotype and clinical phenotype.

Results: NGS analysis revealed 72 potentially pathogenic allelic variants (AVs) in 44 out of 78 patients, distributed across 10 genes: DUOX2, DUOXA2, GLIS3, IYD, NKX2-5, SLC26A4, TG, TPO, THRB, and TSHR. Of these, 78% were in genes involved in thyroid hormone synthesis, with DUOX2 being the most frequently affected gene (34.7%). We identified 25 AVs not previously reported, mostly missense mutations (18/25). A monogenic inheritance pattern was suggested for 22 patients: 8 with a single variant in a dominant gene and 14 with two variants in the same gene. Nine patients exhibited two or more variants in different genes, suggesting oligogenic inheritance. Additionally, 13 patients had a single variant in genes with autosomal recessive inheritance. Regarding the genotype-phenotype relation, the 14 patients with two AVs on the same gene presented a more severe phenotype, with median blood TSH levels of 200 µU/mL at diagnosis (significantly higher than other groups, P = 0.006), lower fT4 levels (P = 0.002) and an increased need for levothyroxine at 36 months of age.

Conclusion: NGS is a valuable diagnostic tool for the etiological characterization of CH-GIS. The confirmation of a relationship between genotype and clinical phenotype found in our population allows us to state that the early application of NGS can help define the etiologic diagnosis and plan appropriate follow-up. Despite this, in line with what has already been reported in the literature, abou half of the cases in our sample remain partially or completely genetically unsolved, highlighting the need for further investigation into alternative etiopathogenetic mechanisms.