Hyperthyroidism Caused by a Germline Activating Mutation of the Thyrotropin Receptor Gene: Difficulties in Diagnosis and Therapy

Bertalan, Rita; Sallai, Ágnes; Sándor, János; Lotz, Gábor; Szabó, István; Kovács, Balázs; Szabó, Erzsébet; Patócs, Attila; Rácz, Kàroly

doi:10.1089/thy.2009.0182

Cited by 15 publications

(11 citation statements)

References 44 publications

(39 reference statements)

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“…2012;56/8 TSHR mutation in congenital hyperthyroidism when withdrawal was attempted, persisting hyperthyroid until almost 7 years of age, when thyroidectomy was performed. Antithyroid drugs were administered in all previously reported cases without good response, and radioiodine therapy was indicated in 6 cases, but near total thyroidectomy seems to be the treatment of choice for these patients (10,(15)(16)(17). Various consequences of prolonged neonatal hyperthyroidism, including multinodular goiter, microcephaly, craniosynostosis, psychomotor disturbances, mental retardation, intrauterine growth retardation, prematurity and low birth weight, have been reported in the literature, but none of these complications developed in our patient.…”

Section: Discussionmentioning

confidence: 66%

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

Scaglia

Chiesa

Bastida³

et al. 2012

Arq Bras Endocrinol Metab

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Activating mutations in the TSH Receptor (TSHR) gene have been identified as the molecular basis for congenital non-autoimmune hyperthyroidism. We describe the clinical findings and molecular characterization in a girl who presented severe non-autoimmune hyperthyroidism since birth, born to a mother with autoimmune thyroid disease. She was treated with methylmercaptoimidazol and β-blockers, but remained hyperthyroid and required total thyroidectomy. To characterize the presence of an activating mutation, the whole coding sequence and intron-exon boundaries of TSHR gene were analyzed. The patient was heterozygous for p.Ser281Asn mutation and p.Asp727Glu polymorphism. This recurrent mutation, p.Ser281Asn, characterized in vitro by increased basal production of cAMP, is the unique germline activating gene variant described so far in the extracellular domain of TSH receptor. Interestingly, the patient's mother presented hyperthyroidism but without any TSHR gene activating mutation. Although congenital non-autoimmune hyperthyroidism is a rare condition, it should be investigated when severe disease persists, even in a newborn from an autoimmune hyperthyroid mother, in order to differentiate it from the more common congenital autoimmune disease. Arq Bras Endocrinol Metab. 2012;56(8):513-8

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Section: Discussionmentioning

confidence: 66%

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

Scaglia

Chiesa

Bastida³

et al. 2012

Arq Bras Endocrinol Metab

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“…The dramatic clinical courses with first manifestation of hyperthyroidism in utero (11,15,18) as well as excessive thyroid enlargement, prematurity, craniosynostosis, mental retardation, and a markedly advanced bone age (13,15,19,59) accompanied by relapses of hyperthyroidism after thyroid surgery (near-total or sub-total thyroidectomy) and/or after radio-iodine therapy (9,15,16,18,23,59) described for patients with SCNAH are in line with their distinctly higher basal cAMP activities. The higher IVA of the sporadic mutations compared with the familial mutations (Fig.…”

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confidence: 61%

“…For sporadic congenital nonautoimmune hyperthyroidism (SCNAH), there is no apparent correlation of the mutations' in vitro activities (IVAs) with the clinical phenotype (5). Constitutively activating germline thyrotropin receptor (TSHR) mutations have been reported to date for 15 patients with sporadic mutations (http://innere.uniklinikum-leipzig.de/tsh; accession date July 15, 1999) (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) and for 24 families with FNAH (http://innere.uniklinikum-leipzig.de/tsh, accession date July 15, 1999) (7, (Table 1). A very preliminary analysis of 15 patients with hot thyroid nodules did not show significant differences in clinical presentation and thyroid hormone levels between patients with or without somatic TSHR mutations (48).…”

Section: Introductionmentioning

confidence: 99%

Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More ActiveIn VitroActivities than Familial Thyrotropin Receptor Mutations

Lueblinghoff¹,

Eszlinger²,

Jaeschke³

et al. 2011

Thyroid

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Background: Germline thyrotropin receptor (TSHR) mutations are associated with sporadic congenital nonautoimmune hyperthyroidism and familial nonautoimmune hyperthyroidism. Somatic TSHR mutations are associated with toxic thyroid nodules (TTNs). The objective of the study was to define a relation of the clinical appearance and the in vitro activity (IVA) of the TSHR mutations described by several authors for these thyroid disorders. Methods: We analyzed the IVAs published as linear regression analysis (LRA) of the constitutive activity as a function of the TSHR expression and the basal cyclic adenosine monophosphate (cAMP) values to determine differences between exclusively somatic, exclusively familial, and shared sporadic and somatic TSHR-mutations. Further, we investigated correlations of the LRAs/basal cAMP values with clinical activity characteristics (CACs) of TTNs, such as largest diameter of the TTN and the age of the patient at thyroid surgery. Results: Shared sporadic and somatic mutations showed higher median LRA (14.5) and higher median basal cAMP values (fivefold) than exclusively familial mutations (6.1, p ¼ 0.0002; 2.9-fold, p < 0.0001, respectively). Moreover, mutations shared between sporadic congenital nonautoimmune hyperthyroidism and toxic thyroid nodules (TTNs) showed higher median LRA/basal cAMP values ( p < 0.0001) than exclusively somatic mutations in TTNs (5.1; 3.89-fold, respectively). Exclusively somatic mutations and exclusively familial mutations showed no significant difference in their median LRA values ( p ¼ 0.786) but a significant difference for basal cAMP values ( p ¼ 0.0006). The two examined CACs showed no correlation with the IVA characterized by LRA/ basal cAMP values or with the presence or absence of a TSHR-mutation. Conclusions: This systematic analysis of published constitutively activating TSHR-mutations, their CACs, and their IVA provides evidence for higher IVA of shared sporadic and somatic TSHR mutations as compared with familial TSHR mutations. CACs of somatic TSHR mutations in TTNs did not have a clear association with the IVA as characterized by LRA or basal cAMP values.

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“…The goiters are mostly diffuse at the onset and become progressively nodular with increasing duration of the disease [29,30]. …”

Section: Introductionmentioning

confidence: 99%

“…To date, 27 families with FNAH [3,4,5,6,7,9,10,11,12,13,14,15,16,17,18,19,20,32,33,34,35,36,37,38,39,40] and 15 cases with PSNAH have been published [8,22,23,24,25,26,27,28,29,41,42,43,44,45,46,47,48,49]. Women are affected more frequently by the familial form (83 women compared to 69 men), but not by the sporadic form (TSH Receptor Mutation Database III, OMIM 609152).…”

Section: Introductionmentioning

confidence: 99%

2012 European Thyroid Association Guidelines for the Management of Familial and Persistent Sporadic Non-Autoimmune Hyperthyroidism Caused by Thyroid-Stimulating Hormone Receptor Germline Mutations

et al. 2012

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All cases of familial thyrotoxicosis with absence of evidence of autoimmunity and all children with persistent isolated neonatal hyperthyroidism should be evaluated for familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) or persistent sporadic non-autoimmune hyperthyroidism (PSNAH). First, all index patients should be analysed for the presence/absence of a thyroid-stimulating hormone (TSH) receptor (TSHR) germline mutation, and if they display a TSHR germline mutation, all other family members including asymptomatic and euthyroid family members should also be analysed. A functional characterization of all new TSHR mutations is necessary. Appropriate ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences, especially in children. Therefore, in children the diagnosis of FNAH or PSNAH needs to be established as early as possible in the presence of the clinical hallmarks of the disease.

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Hyperthyroidism Caused by a Germline Activating Mutation of the Thyrotropin Receptor Gene: Difficulties in Diagnosis and Therapy

Cited by 15 publications

References 44 publications

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More ActiveIn VitroActivities than Familial Thyrotropin Receptor Mutations

2012 European Thyroid Association Guidelines for the Management of Familial and Persistent Sporadic Non-Autoimmune Hyperthyroidism Caused by Thyroid-Stimulating Hormone Receptor Germline Mutations

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