ESPE Abstracts (2022) 95 P1-195

1Growth and Development Group, Vall d’Hebron Research Institute (VHIR) – Paediatric Endocrinology Unit, Hospital UniversitarioVall d’Hebron (HUVH), Barcelona, Spain; 2CIBERER, ISCIII, Madrid, Spain; 3Clinical and Molecular Genetics Area, HUVH, Barcelona, Spain

Introduction: Thyroid dyshormonogenesis (TD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. It presents clinical heterogeneity, from subclinical hypothyroidism (SH) to goitre. The clearer understanding of the pathways and enzymatic activities involved in the synthesis of thyroid hormones has allowed us to identify an important number of causal genes. Defective organification of iodine is caused by abnormalities of thyroglobulin, TPO synthesis, or H2O2 production, in which DUOX2 oxidase (DUOX2 gene, MIM:606759) is involved. Genetic variants in DUOX2 can cause partial to total iodination defects.

Objectives: To undertake a molecular characterisation and genotype-phenotype correlation in patients with TD and candidate variants in the DUOX2.

Patients and Methods: 114 paediatric patients with congenital hypothyroidism from the Catalan Neonatal Screening Programme have been analysed using a high-throughput sequencing panel (Cell3 Target Custom Panel tier 2, NONACUS) including 14 genes.

Results: A total of 24 (21.1%) patients presented variants in the DUOX2 gene that could explain their phenotype. Eleven (45.8%) patients were heterozygous, six (25%) compound heterozygous, and four (16.7%) homozygous. In the remaining three patients, family segregation studies are required to confirm inheritance. In addition, seven (29.2%) of these patients presented variants in other genes, suggesting a possible digenic inheritance for TD: five patients presented variants in TG, one in DUOX1, and one in TPO. A total of 26 variants were described: 17 missense, 3 splicing, 3 frameshift, 2 nonsense, and 1 small deletion. Eleven (42.3%) of these variants have not been previously described in the literature. Sixteen (61.6%) were classified as variants of uncertain significance (VUS), seven (26.9%) as pathogenic, and three (11.5%) as probably pathogenic. The most frequent variant in our cohort has been c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. Ten of the 24 patients have been reevaluated, four were diagnosed with hyperthyrotropinemia, three had transient hypothyroidism, and four with permanent hypothyroidism (three mild and one severe). A clear genotype-phenotype correlation could not be identified; therefore, functional studies are being designed to analyse the H2O2 synthesis.

Conclusion: 22.8% of patients with congenital hypothyroidism in our cohort presented variants in DUOX2. A clear genotype-phenotype correlation could not be described; therefore, clinical reevaluation of these patients is advisable. Alternatively, in vitro functional studies could be a useful tool to confirm the pathogenicity of the described genotypes.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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