The Clinical and Molecular Characterization of Patients With Dyshormonogenic Congenital Hypothyroidism Reveals Specific Diagnostic Clues for DUOX2 Defects

Muzza, Marina; Rabbiosi, Sarah; Vigone, Maria Cristina; Zamproni, I.; Cirello, Valentina; Maffini, Maria Antonia; Maruca, Katia; Schoenmakers, Nadia; Beccaria, Luciano; Gallo, Francesco; Park, S.-M.; Beck‐Peccoz, Paolo; Persani, Luca; Weber, Giovanna; Fugazzola, Laura

doi:10.1210/jc.2013-3618

Cited by 74 publications

(74 citation statements)

References 25 publications

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“…In contrast, the in silico assays suggested that the three polymorphic variants -p.P138L, p.H678R, and p.L1067S -were silent polymorphisms. This was consistent with a previous expression study (25). Previous studies showed that p.H678R did not reduce H 2 O 2 production (14,34).…”

Section: Discussionsupporting

confidence: 93%

“…Other reports have shown that biallelic DUOX2 mutations cause mild to moderate CH (13,14,15,16,19,22,30). Recently, some studies have shown that DUOX2 defects are the predominant cause of CH associated with dyshormonogenesis (13,14,15,16,25,26).…”

Section: Discussionmentioning

confidence: 99%

“…(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%

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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: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Course Of Patients With Biallelic Mutations In Duox2mentioning

confidence: 99%

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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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“…Patients with DUOX2 variants usually show borderline blood spot TSH levels at first neonatal screening and subsequently high serum TSH at confirmatory tests (TSH >100 mIU/L) with low FT4, higher thyroglobulin (Tg) levels, and hyperplastic thyroid gland at birth [47]. …”

Section: Mild Hypothyroidism In Neonatesmentioning

confidence: 99%

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

Vigone

Capalbo

Weber

et al. 2018

Journal of the Endocrine Society

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Mild hypothyroidism, also known as subclinical hypothyroidism (SH), is biochemically defined as serum TSH levels above the upper limit of the reference range, in the presence of normal serum concentrations of total T4 and free T4 (FT4). In the neonatal period, mild hypothyroidism can be defined by the presence of a TSH value between 6 and 20 mIU/L and normal FT4 levels. After the neonatal period, SH can be defined mild if TSH ranges between 4.5 and 10 mIU/L. The management of mild hypothyroidism in childhood is challenging. The major concern is to establish whether this condition should always be considered an expression of mild thyroid dysfunction. Indeed, the effects of untreated mild hypothyroidism are still not completely defined. In the neonatal period, concern exists about neurocognitive outcome; in children, although there is no clear evidence of alterations in growth or neurocognitive development, subtle cardiovascular abnormalities have been documented. Therefore, there is still uncertainty about the need of treatment across all ages, and the management should be based on the age of the child, the etiology, and the degree of TSH elevation, as well as on other patient factors. This review updates current evidences on diagnosis and management of mild hypothyroidism in childhood.

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“…Disease-causing mutations are usually biallelic, with the exception of monoallelic DUOX2 , IYD, and TSHR mutations, which may also confer a phenotype (1). Phenotypic heterogeneity in cases harboring similar causative mutations suggests that mono- and polygenic factors and environmental modulators may also play a role in determining disease severity (7, 8). …”

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confidence: 99%

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Nicholas

Serra

Cangül

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective:Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS.Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results:Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.Conclusions:The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

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The Clinical and Molecular Characterization of Patients With Dyshormonogenic Congenital Hypothyroidism Reveals Specific Diagnostic Clues for DUOX2 Defects

Abstract: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

Cited by 74 publications

References 25 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

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

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