ESPE Abstracts (2022) 95 P1-397


1Paediatric Endocrinology Department, Vall d'Hebron University Hospital, Barcelona, Spain; 2Clinical and molecular genetics Department, Vall d'Hebron Research Institute. Vall d'Hebron University Hospital, Barcelona, Spain; 3Paediatric Endocrinology Department, Mútua Terrassa University Hospital, Terrassa, Spain; 4Paediatric Endocrinology Department, Palamós Hospital, Palamós, Spain; 5Paediatric Endocrinology Department, Germans Trias i Pujol University Hospital, Badalona, Spain; 6Paediatric Endocrinology Department, Sant Joan de Déu University Hospital, Esplugues de Llobregat, Spain; 7Paediatric Endocrinology Department, Arnau de Vilanova University Hospital, Lleida, Spain; 8Paediatric Endocrinology Department, Hospital del Mar University Hospital, Barcelona, Spain; 9Paediatric Endocrinology Department, Joan XXIII University Hospital, Tarragona, Spain; 10Paediatric Endocrinology Department, Sant Joan de Reus University Hospital, Reus, Spain; 11Growth and Development Group, Vall d’Hebron Research Institute. Hospital UniversitarioVall d’Hebron, Barcelona, Spain

Introduction: Subclinical hypothyroidism (SH) is a biochemical condition characterized by serum levels of TSH above the reference range upper limit (4,5μUI/mL), with normal concentrations of thyroid hormones. In cases of non-autoimmune subclinical hypothyroidism (NASHT), genetic defects have been described and can determine disorders in the biosynthesis process of thyroid hormones, such as heterozygous mutations in the TSH receptor gene (TSHR) and in the gene encoding dual oxidase2 (DUOX2). In addition, it is suspected that other genes that regulate or participate in the biosynthesis of thyroid hormones could be involved in NASHT, although to date very few studies have evaluated its genetic basis.

Objective: To perform a molecular characterization and identify genotype-phenotype correlations in patients with SH

Patients and methods: Descriptive, multicentre study in a cohort of 49 patients diagnosed with NASHT who presented in two separate determinations a TSH above 7μUI/mL. The molecular analysis was performed using a high-throughput sequencing panel (Cell3 Target Custom Panel tier 2, NONACUS) that includes 14 genes of which the most important were: TG, TPO, DUOX2, DUOXA2, PAX8, TSHR, SLC5A5, SLC26A4.

Results: A total of 49 patients with a mean age at diagnosis of 5.5±3.4years were studied. Eight centres from Catalonia participated. Twenty-seven patients (55%) were male. Twenty-eight (57%) patients received treatment with levothyroxine. The mean TSH at diagnosis was 9.2±2.0mU/l and the maximum TSH was 11.4±3.6mU/L. Thirty-one patients (63.3%) presented variants in the studied genes, of which twenty-five (80.6%) were heterozygous, five (16%) were digenic and one patient was compound heterozygous of DUOX2 (Table 1). Of the heterozygous patients, sixteen (60%) presented a variant classified as pathogenic (PAT) or probably pathogenic (PPAT) and ten (40%) presented a variant of uncertain significance (VUS). Family segregation studies are being carried out to confirm the inheritance.

Table1: Patient genotypes and variants detected
Compound heterozygote 1/31 DUOX2 PAT+VUS
Heterozygotes 25/31 TG (5patients) 1PAT,4VUS
DUOX2 (4patients) 2PAT,1PPAT,1VUS
PAX 8 (2patients) 1PAT,1PPAT
TSHR (11patients) 5PAT,3PPAT,3VUS
SLC5A5 (1patient) VUS
SLC26A4 (2patients) 1PPAT,1VUS
Digenic 5/31 DUOX2(VUS)-DUOXA2(PPAT)

Conclusion: A significant percentage of patients (63.3%) with non-autoimmune subclinical hypothyroidism have variants in genes related to thyroid dyshormonogenesis and several have not been previously described. The functional studies of the undescribed variants have been designed to establish the genotype-phenotype relationship. These genetic findings can help to better characterize the patients to define the prognosis and the need for treatment.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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