ESPE Abstracts (2022) 95 P1-593

ESPE2022 Poster Category 1 Thyroid (44 abstracts)

Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis Associated with Defects in The TSH Receptor (TSHR)

Núria Camats-Tarruella 1,2 , Noelia Baz-Redón 1 , Mónica Fernández-Cancio 1,2 , María Antolín 3 , Elena Garcia-Arumí 3,2 , Eduard Mogas 1 , Ariadna Campos 1 , Anna Fàbregas 1 , Núria Gonzalez-Llorens 1 , Laura Soler 1 , María Clemente 1,2 & Diego Yeste 1,2

1Growth and Development Group, Vall d’Hebron Institut de Recerca (VHIR) – Paediatric Endocrinology Section, Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Spain; 2CIBERER, ISCIII, Madrid, Spain; 3Clinical and Molecular Genetics Area, HUVH, Barcelona, Spain

Introduction: The thyrotropin receptor (TSHR) has a key role in the thyroid gland. It is involved in folliculogenesis, differentiation, organogenesis, and thyroid hormone synthesis and production. Its genetic defects can cause poor differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis, TD). Therefore, its phenotype spectrum is wide, ranging from severe congenital hypothyroidism (CH) to mild hyperthyrotropinemia. Some heterozygous genetic variants have been associated with non-autoimmune subclinical hypothyroidism (SH) and normal-sized or hypoplastic glands. In addition, TSHR variants with variable expressivity have been reported. More than 200 TSHR variants have been published, many of them still uncharacterized in vitro.

Objectives: (1) To genetically characterise patients diagnosed with TD or SH associated with TSHR defects; (2) to study the effect of the genetic candidate variants by in vitro functional studies in order to establish the genotype-phenotype relationship.

Patients and Methods: Paediatric patients with DT (n=114) and SH (n=47) were analyzed by high-throughput techniques using a panel of 14 genes related to thyroid development and function. The DT patients were diagnosed through the Catalan CH neonatal screening program (confirmation TSH range: 18.4-100 mIU/L). To determine the variant pathogenicity, in vitro functional studies were performed based specifically on measuring the TSH-dependent activation of the cAMP response element (CRE), using a CRE-reporter vector and a luciferase test. Studies of localization and expression in the membrane were undertaken.

Results: Twelve patients diagnosed with severe or mild TD (n=7, 6.1%) or HS (n=5, 10.6%) presented candidate variants in TSHR. Eleven different variants were detected in these patients, four of which had not been published. The patients had variable genotypes: 3 homozygous, 2 compound heterozygous, 1 double heterozygous and 6 heterozygous (most with SH). Five of these variants did not have associated functional studies. Our in vitro studies show a different functional profile for each variant (completely/partially deleterious, or non-deleterious). Furthermore, some variants have a mild or totally deleterious effect depending on if they are heterozygous or homozygous, respectively, whereas others show partial deficiency in both heterozygosis and homozygosis.

Conclusions: 7.4% of our patients -- diagnosed with subclinical, mild or severe HC -- present candidate variants in TSHR. Our design of the in vitro functional studies will contribute to the confirmation of the pathogenicity of the variants studied. In addition, our studies highlight the importance of studying the effect of the patient’s genotype for a correct diagnostic confirmation.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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