Central TSH Dysregulation in a Patient with Familial Non-Autoimmune Autosomal Dominant Hyperthyroidism Due to a Novel Thyroid-Stimulating Hormone Receptor Disease-Causing Variant

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Abstract

Background and Objectives. Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) is a rare cause of childhood hyperthyroidism. It is caused by the thyroid-stimulating hormone receptor ( TSHR) gene variants. So far, only around 40 families with FNAH have been reported. Patients with activating TSHR variants demonstrated the same classical signs and symptoms of hyperthyroidism as seen in patients with Graves’ disease. Since 2012, ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences. Case Presentation. We presented a young adult male patient with a novel heterozygous TSHR disease-causing variant p.Arg418Lys (c.1253G>A) in the exon 10, who presented with a mild but progressive FNAH, with a follow-up since infancy. Discussion. Constantly suppressed TSH, including during the euthyreosis in childhood and hypothyreosis after iodine ablation therapy, suggested central dysregulation of the TSH secretion.

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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Ultra short-loop feedback control of thyrotropin secretion.

W. Wiersinga, Leon J S Brokken, M Prummel (2004)

Evidence is accumulating that pituitary hormone secretion is not only regulated by feedback from hormones produced in the target organs (long feedback) on the pituitary and the hypothalamus (feedforward), but also by a feedback of the hypophyseal hormones at the hypothalamic (short feedback) and the pituitary (ultra-short feedback) level. Inhibition of thyrotropin (TSH) and MSH secretion by pituitary preparations by adding exogenous TSH or MSH to the medium was already observed in the 1960s, as was the phenomenon that adrenocorticotropic hormone (ACTH) injected in the hypothalamus lowered plasma corticosterone levels. These early observations have now been corroborated by the demonstration of the receptors for various pituitary hormones in the hypothalamus and the adenohypophysis. The thyrotropin receptor (TSHR) is found on folliculo-stellate cells in the pituitary, which are known to influence the neighboring endocrine cells. This pituitary TSR-receptor is also recognized by TSHR receptor autoantibodies, which can downregulate TSH secretion independently from thyroid hormone levels, and are therefore thought to be responsible for the frequently observed suppressed TSH levels in patients with Graves' disease who are otherwise euthyroid.

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Hyperthyroidism in Childhood: Causes, When and How to Treat

Juliane Léger, Jean-Claude Carel (2013)

Graves’ disease (GD) is the most common cause of hyperthyroidism in children. This review gives an overview and update of management of GD. Antithyroid drugs (ATD) are recommended as the initial treatment, but the major problem is the high relapse rate (30%) as remission is achieved after a first course of ATD. More prolonged medical treatment may increase the remission rate up to 50%. Alternative treatments, such as radioactive iodine or thyroidectomy, are considered in cases of relapse, lack of compliance, or ATD toxicity. Therefore, clinicians have sought prognostic indicators of remission. Relapse risk decreases with longer duration of the first course of ATD treatment, highlighting the positive impact of a long period of primary ATD treatment on outcome. The identification of other predictive factors such as severe biochemical hyperthyroidism at diagnosis, young age, and absence of other autoimmune conditions has made it possible to stratify patients according to the risk of relapse after ATD treatment, leading to improvement in patient management by facilitating the identification of patients requiring long-term ATD or early alternative therapy. Neonatal autoimmune hyperthyroidism is generally transient, occurring in only about 2% of the offspring of mothers with GD. Cardiac insufficiency, intrauterine growth retardation, craniostenosis, microcephaly and psychomotor disabilities are the major risks in these infants and highlight the importance of thyroid hormone receptor antibody determination throughout pregnancy in women with GD, as well as highlighting the need for early diagnosis and treatment of hyperthyroidism. Conflict of interest:None declared.

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Spyridoula Maraka: Role: Academic Editor

Journal

Journal ID (nlm-ta): Medicina (Kaunas)

Journal ID (iso-abbrev): Medicina (Kaunas)

Journal ID (publisher-id): medicina

Title: Medicina

Publisher: MDPI

ISSN (Print): 1010-660X

ISSN (Electronic): 1648-9144

Publication date (Electronic): 25 February 2021

Publication date Collection: March 2021

Volume: 57

Issue: 3

Electronic Location Identifier: 196

Affiliations

[1 ]Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, 1000 Ljubljana, Slovenia; jasna.suputomladic@ 123456kclj.si (J.S.O.); urh.groselj@ 123456kclj.si (U.G.); magdalena.avbelj@ 123456mf.uni-lj.si (M.A.S.); mojca.zerjav-tansek@ 123456mf.uni-lj.si (M.Z.T.); primoz.kotnik@ 123456mf.uni-lj.si (P.K.); tadej.battelino@ 123456mf.uni-lj.si (T.B.)

[2 ]Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; katarina.trebusakpodkrajsek@ 123456mf.uni-lj.si

[3 ]Department of Paediatric Surgery and Intensive Care, University Medical Centre Ljubljana, Bohoričeva 20, 1000 Ljubljana, Slovenia; pajek.maja@ 123456gmail.com

[4 ]Clinical Institute for Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Vrazov trg 1, 1000 Ljubljana, Slovenia

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[* ]Correspondence: darja.smigoc@ 123456kclj.si ; Tel.: +386-1-522-9235; Fax: +386-1-232-0190

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Urh Groselj https://orcid.org/0000-0002-5246-9869

Katarina Trebusak Podkrajsek https://orcid.org/0000-0002-0154-3547

Magdalena Avbelj Stefanija https://orcid.org/0000-0002-0836-5114

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Publisher ID: medicina-57-00196

DOI: 10.3390/medicina57030196

PMC ID: 7996546

PubMed ID: 33669123

SO-VID: d9c2d45e-5b24-4775-9913-9f4cfacc15a7

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Central TSH Dysregulation in a Patient with Familial Non-Autoimmune Autosomal Dominant Hyperthyroidism Due to a Novel Thyroid-Stimulating Hormone Receptor Disease-Causing Variant

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Most cited references 39

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Ultra short-loop feedback control of thyrotropin secretion.

Hyperthyroidism in Childhood: Causes, When and How to Treat

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