ESPE Abstracts (2022) 95 P2-280

ESPE2022 Poster Category 2 Thyroid (22 abstracts)

From overt hyperthyroidism to normal thyroid function in TSH receptor activating mutations: reports of two families with novel pathogenetic variants and suggestion of a phenotypical sexual dimorphism

Valeria Citterio 1 , Claudia Giavoli 2,3 , Elisa Stellaria Grassi 4,5 , Giuditta Rurale 5 , Eriselda Profka 3 , Giulia Rodari 2,3 , Federico Giacchetti 3 , Valentina Collini 1 , Irene Campi 5 , Maura Arosio 2,3 & Luca Persani 4,5

1University of Milan, Milan, Italy; 2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 3Endocrinology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; 4Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy; 5Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

Introduction: Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) is a rare cause of childhood hyperthyroidism caused by an activating variant of the thyroid stimulating hormone receptor (TSHR) gene. This disorder may occur as a result of an autosomal dominant inheritance or sporadically through de novo variation. The severity of hyperthyroid symptoms is variable and phenotype differences have been described in subjects harbouring the same mutation. We hereby describe two families bearing heterozygous variants of first description in the TSHR gene, who presented with FNAH of different severity.

Case presentation: The first family presented a novel mutation in heterozygosis located on exon 10 of the TSHR gene (P.N670H, c.2008A>C) affecting two siblings and their mother. The girl (5.8 years old) complained tachycardia and nervousness and showed a regular growth at the higher percentiles. Investigations revealed overt primary hyperthyroidism (TSH 0.01 mcUl/ml, FT4 2.87 ng/dl (0.7-1.7), FT3 7.46 pg/ml (2-4)), with negative thyroid antibodies and normal ultrasonography. Patient started treatment with methimazole allowing satisfactory thyroid control. The patient’s brother (13 years old) presented tachycardia and mild FNAH (TSH 0.05 mcIU/ml, FT4 18.8 pmol/l (8-17), FT3 6.2 pg/ml (2.5-5.3)), with normal thyroid ultrasonography. Methimazole therapy was started with rapid achievement of hormonal and clinical control. At puberty, the need for methimazole progressively decreased until withdrawal. Their mother underwent thyroidectomy for thyroid nodule and is currently on L-thyroxine treatment. The second family presented a heterozygous variant in the TSHR gene of first description (P.C636G, c.1906T>G), affecting two twins and their mother. The girl (16.6 yrs) revealed overt FNAH (TSH 0.02 mcIU/ml, FT4 1.67 ng/dl (0.83-1.43), FT3 5.18 pg/ml (3-4.7)), with normal thyroid ultrasound. On methimazole she achieved stable euthyroidism. After a self-discontinuation of treatment, hyperthyroidism recurred and methimazole was reintroduced with rapid hormonal control. In this family as well, the male was affected by a milder thyroid dysfunction, with initial subclinical hyperthyroidism (TSH 0.25 mcIU/ml, FT4 1.11 ng/dl (0.83-1.43), FT3 4.57 pg/ml (3-4.7)) and remission at puberty. To date, he has never needed anti-thyroid therapy. In both siblings, thyroid scintigraphy (99-Tc) showed a diffuse uptake. Their mother reported hyperthyroidism treated with radioablation and subsequent hypothyroidism on L-thyroxine therapy.

Conclusion: We present two different novel variants of TSHR gene, inherited in an autosomal dominant pattern, with phenotypic variability with respect to the patient’s gender. Functional studies are ongoing to substantiate this hypothesis.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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