Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism

Schwab, KO; Gerlich, M.; Broecker, M.; Söhlemann, P.; Derwahl, Michael; Lohse, Martin J.

doi:10.1016/s0022-3476(97)70040-4

Cited by 51 publications

(24 citation statements)

References 24 publications

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“…In hyperthyroxinemic disorders, neonatal Graves' disease (NGD) is thought to be the most prevalent and the occurrence is estimated as one in 10,000 to 50,000 newborn infants (7)(8)(9). Activating mutation of TSH receptor mutations and gain of function mutations of Gs␣ protein McCnune-Albright syndrome has been also reported to cause hyperthyroidism in neonatal period (10,11).…”

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confidence: 99%

Elevated Free Thyroxine Levels Detected by a Neonatal Screening System

Tajima

Fujikura

et al. 2009

Pediatr Res

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ABSTRACT:In Sapporo city of Japan, neonatal screening for congenital hypothyroidism has used the measurement of free thyroxine (T4) and thyroid-stimulating hormone (TSH) in the filter-paper blood spot. This system has enabled us to identify hyperthyroxinemic diseases. Filter papers were collected from neonatal infants born at 4 -6 d of age and neonates who showed elevated free T4 (Ͼ4.0 ng/dL, 4 SD above the mean) were studied. Between January 2000 and December 2006, 83,232 newborns were screened. Eleven infants demonstrated persistent hyperthyroxinemia. One patient with slightly elevated free T4 and normal TSH was diagnosed as having familial dysalbuminemic hyperthyroxinemia (FDH). The other two patients with elevated free T4 without suppressed TSH were considered as having resistance of thyroid hormone (RTH), and analysis of thyroid hormone receptor (TR) ␤ gene confirmed the diagnosis. The remaining eight patients were diagnosed as having neonatal Graves' disease (NGD). Seven of eight pregnant women were treated with antithyroid drug and thus only one unrecognized NGD during pregnancy was detected by screening. Our screening system enables for early awareness of RTH and FDH. Regarding Graves' disease, the benefit of elevated free T4 screening is small, because most pregnant women with Graves' disease were managed. (Pediatr Res 66: 312-316, 2009) C ongenital hypothyroidism is the most prevalent endocrine disorder in the newborn, with a rather constant worldwide incidence of permanent congenital hypothyroidism of 1:3000 to 1:4000 newborns (1,2). The main purpose of neonatal mass screening for congenital hypothyroidism is early detection and treatment to hypothyroidism. During the past three decades, this screening has been very successful with the vast majority of patients with congenital hypothyroidism achieving normal neurologic outcome (1-3). Two methods for the screening system are now used. Most screening programs in Europe and Asia, including Japan, use primary thyroidstimulating hormone (TSH) screening. Another program is thyroxine (T4) or free T4-based neonatal screening (4 -6). T4 or free T4 screening enables the detection of hyperthyroxinemia in addition to congenital hypothyroidism. In hyperthyroxinemic disorders, neonatal Graves' disease (NGD) is thought to be the most prevalent and the occurrence is estimated as one in 10,000 to 50,000 newborn infants (7-9). Activating mutation of TSH receptor mutations and gain of function mutations of Gs␣ protein McCnune-Albright syndrome has been also reported to cause hyperthyroidism in neonatal period (10,11). LaFranchi et al. (12) have reported the first systematic study to screen neonatal hyperthyroxinemia using T4 screening in Oregon. According to their study, any case with NGD among 80,884 infants was not detected. Instead, 10 had thyroxinebinding globulin excess, five were thought to be familial dysalbuminemic hyperthyroxinemia (FDH), and two had resistance of thyroid hormone (RTH). After this report, the study of differential diagnosis of neonatal hyperth...

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confidence: 99%

Elevated Free Thyroxine Levels Detected by a Neonatal Screening System

Tajima

Fujikura

et al. 2009

Pediatr Res

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“…Obviously, this denomination is relatively inappropriate because these neomutants if properly treated would be able to transmit the disease to their descendants. This is clearly demonstrated in three families (23,35,36) where the less severe mutations led to a delayed diagnosis. The early age of clinical manifestation indicates a more severe phenotype, presumably related to a higher activation of the receptor.…”

Section: Particular Aspects Of Scnahmentioning

confidence: 89%

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

Hebrant¹,

Staveren²,

Maenhaut³

et al. 2011

European Journal of Endocrinology

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Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

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“…(3) The presence of goiter, which is generally diffuse in children and tends to become multinodular later in life [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17] (http://tsh-receptor-mutation-database.org). Very rarely, goiter is absent [18].…”

Section: Introductionmentioning

confidence: 99%

“…(4) A highly variable age of manifestation of hyperthyroidism, which ranges between the neonatal period [8] and 60 years [14]. It is also highly variable within the same family, for example 10–36 years in the Nancy family [19], 18 months to 53 years in the Reims family [19], 2–21 years in the Cardiff family [3] and 4–60 years in the family reported by Karges et al [14] (http://tsh-receptor-mutation-database.org).…”

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%

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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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Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism

Cited by 51 publications

References 24 publications

Elevated Free Thyroxine Levels Detected by a Neonatal Screening System

Elevated Free Thyroxine Levels Detected by a Neonatal Screening System

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR 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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