ESPE Abstracts

Non-autoimmune hypothyroidism is characterized by high serum TSH level, normal or low thyroid hormones, absence of autoantibodies and normal or hypoplasic in situ thyroid gland. It is known that heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance which clinically ranges from isolated hyperthyrotropinemia to non-autoimmune hypothyroidism. Despite this, an absence of mutations in the TSHR gene has been reported for several cases of non-autoimmune subclinical hypothyroidism, suggesting a more complex pathogenesis involving other genetic and environmental factors.

Methods: We performed Next Generation Sequencing (NGS) analysis of 18 genes related to hypothyroidism in 39 pediatric patients (21 male, 18 female) affected by non-autoimmune subclinical or overt hypothyroidism, all with thyroid in situ and normal newborn screening. 18/39 needed to start levothyroxine therapy for TSH level constantly above 10 µU/ml.

Results: 16/39 patients (41%) carried at least one variant in one of the genes related to hypothyroidism, and 3/16 of those had two variants in distinct candidate genes. As expected most variations were identified on TSHR (17,5%): 6 previously described and one novel missense variation (TSHR p.Phe423Ser). In a female patient with goiter, non-autoimmune hypothyroidism and a family history of goiter (mother and grandmother), we identified the variation FOXE1: p.Ala248Gly described in literature as related to familial non-medullary thyroid carcinoma. The same variation was also present in her mother without history of thyroid carcinoma. We identified 13 new variations: 12 novel missense variations on six genes (DUOX2, TPO, IYD, FOXE1, SLC5A5) with the highest prevalence in DUOX2 (46%) and one frameshift variation (GLIS3 c.553delG). All the detected variants are currently classified as probably pathogenic or of uncertain significance, (genetic data updated to May 2024).

Conclusion: Our data suggested a genetic substrate in about half of our patients with non-autoimmune hypothyroidism. As expected, the highest prevalence of genetic variations was found in TSHR gene but the use of a NGS panel allowed us to identify novel variations on other genes. The pathogenicity of these variations remains unclear and will need to be confirmed by further studies. In some cases, the finding of variations on distinct genes in the same patient, suggested a complex and oligogenic inheritance, as already reported in literature for congenital hypothyroidism. The pathogenesis and the inheritance pattern of non-autoimmune forms of hypothyroidism remain controversial and poorly understood, but the routine use of NGS panels in clinical practice may to clarify the pathogenesis of non-autoimmune hypothyroidism.