Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene

Satoh, Mari; Aso, Keiko; Ogikubo, Sayaka; Yoshizawa-Ogasawara, Atsuko; Saji, Tsutomu

doi:10.1515/jpem-2014-0078

Cited by 22 publications

(17 citation statements)

References 12 publications

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“…(10,13,19). The locations of all DUOX2 mutations reported to date (8,13,14,15,16,19,20,21,22,23,24,25,26,27,28) For most patients, the L-thyroxine dose could be reduced by about 2-4 years of age, except for the twins in cases 10, 11 and 21. Twenty-one of the 24 patients were able to receive reduced doses of L-thyroxine.…”

Section: Clinical Course Of Patients With Biallelic Mutations In Duox2mentioning

confidence: 99%

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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Aim: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism.Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. Objective: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. Patients: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT 4 ) levels (0.17-1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine. Methods: We analyzed the DUOX2, thyroid peroxidase, Na C /I K symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. Results: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. Conclusion: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old).

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Section: Clinical Course Of Patients With Biallelic Mutations In Duox2mentioning

confidence: 99%

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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“…The coexistence of multiple genetic alterations in the DUOX2 gene such as tri-allelic mutations has been associated with an increase in the severity of the disease [106,112,113]. In addition, increasing number of clinical case studies report DUOX2 pathogenic variants concomitant with genetic alterations in other genes involved in TH synthesis including TG [125,127], TSHr [102,109,118,132], TPO [133], Pendrin [115], and DUOXA2 [107,123]. Additional studies would clarify their functional relevance in the evolution of the pathology.…”

Section: Duox Functional Characterization In Heterologous Cell Systemsmentioning

confidence: 99%

DUOX Defects and Their Roles in Congenital Hypothyroidism

Deken

Miot

2019

Methods in Molecular Biology

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Extracellular hydrogen peroxide is required for thyroperoxidase-mediated thyroid hormone synthesis in the follicular lumen of the thyroid gland. Among the NADPH oxidases, dual oxidases, DUOX1 and DUOX2, constitute a distinct subfamily initially identified as thyroid oxidases, based on their level of expression in the thyroid. Despite their high sequence similarity, the two isoforms present distinct regulations, tissue expression, and catalytic functions. Inactivating mutations in many of the genes involved in thyroid hormone synthesis cause thyroid dyshormonogenesis associated with iodide organification defect. This chapter provides an overview of the genetic alterations in DUOX2 and its maturation factor, DUOXA2, causing inherited severe hypothyroidism that clearly demonstrate the physiological implication of this oxidase in thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in permanent but also in transient forms of congenital hypothyroidism. Moreover, accumulating evidence demonstrates that the high phenotypic variability associated with altered DUOX2 function is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors. The presence of two DUOX isoforms and their corresponding maturation factors in the same organ could certainly constitute an efficient redundant mechanism to maintain sufficient H 2 O 2 supply for iodide organification. Many of the reported DUOX2 missense variants have not been functionally characterized, their clinical impact in the observed phenotype remaining unresolved, especially in mild transient congenital hypothyroidism. DUOX2 function should be carefully evaluated using an in vitro assay wherein (1) DUOXA2 is co-expressed, (2) H 2 O 2 production is activated, (3) and DUOX2 membrane expression is precisely analyzed.

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“…In most cases, hypothyroidism is permanent due to thyroid mal-development (ectopic, hypoplasia and agenesis) or defects in hormone synthesis. Whereas, the transient type of the disease is less likely to be observed, attributed to the trans placental passage of maternal anti-thyroidal medication, Trans placental passage of a maternal thyrotropin receptor blocking antibody (TRB-Ab), gene mutation (heterozygote nonsense DUOX2 mutations), iodine deficiency or excess and immaturity of thyroidal iodine organification (4-6). The very low birth weight (< 1500 gm) and premature (< 37 weeks gestation) infants are especially at risk of hypothyroidism due to iodine deficiency (7, 8).…”

Section: Introductionmentioning

confidence: 99%

Permanent and Transient Congenital Hypothyroidism in Hamadan West Province of Iran

Razavi

Mohammadi

2016

Int J Endocrinol Metab

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BackgroundPrimary congenital hypothyroidism (CH) is the most common treatable cause of mental retardation and can be classified into permanent and transient types. The purpose of this study was to determine the prevalence of permanent and transient congenital hypothyroidism (CH) in Hamadan, West province of Iran.MethodsThe study population included all cases with primary congenital hypothyroidism, which were confirmed by thyroid function tests (TSH levels ≥ 10 mIU/L). All these patients had been followed up at the outpatient pediatric endocrine clinic of Besat hospital (Hamadan, Iran) for a period of time between May 2006 and March 2013. Biochemical findings at diagnosis and detailed medical records were collected. Patients were considered as permanent hypothyroidism if their TSH level was 10 (mIU/l) during 6 - 12 months of treatment. Also three years old patients with TSH level > 10 mU/L during one or three months after discontinuation of levothyroxine treatment were considered as permanent hypothyroidism.ResultsA total of 164 children (49.9% male and 50.6% female) diagnosed with CH completed the study. Female/male ratio was 1.02/1. The incidence of CH was about 1/1250 in Hamadan, West province of Iran. Of the 164 patients, 105 cases (64 %) were diagnosed as permanent CH and other 59 cases (36%) were proven to have transient hypothyroidism. Female to male ratio was 1.14 in patients suffering from permanent CH and 0.8 in patients with transient CH. The initial TSH level was found to be significantly higher in cases with permanent CH compared to the patients with transient CH (P = 0.001). Mean TSH level during the first year of treatment was higher in permanent CH cases compared to transient cases (P = 0.001). Children with transient CH had a lower TSH serum level during the three years of treatment (P = 0.000). A significant statistical difference was not found between the genders and permanent or transient CH (P = 0.352). Co-occurring congenital anomalies and birth order were significantly different between two groups (P = 0.028 and P = 0.024, respectively).ConclusionsOur regional follow-up data showed that about 40% of newborns with primary CH had transient thyroid dysfunction. Our results further clarify our previous research by providing evidences on the incidence rate of CH. The incidence rates of CH as well as transient type of CH in our region were higher than those reported by other studies which have been conducted in other regions of the world. The initial TSH level was the strongest predictor of treatment cessation. Given the high incidence of transient CH in our region, further studies are needed to confirm the etiology and to provide considerable insight into preventive and/or the treatment strategies.

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Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene

Cited by 22 publications

References 12 publications

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

DUOX Defects and Their Roles in Congenital Hypothyroidism

Permanent and Transient Congenital Hypothyroidism in Hamadan West Province of Iran

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