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

AimWe 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.ObjectiveWe investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations.PatientsTwenty-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 (fT4) levels (0.17–1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine.MethodsWe analyzed the DUOX2, thyroid peroxidase, Na+/I− 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.ResultsAll 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.ConclusionThe 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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Transient Congenital Hypothyroidism Caused by Biallelic Mutations of the Dual Oxidase 2 Gene in Japanese Patients Detected by a Neonatal Screening Program

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0856 ◽

2008 ◽

Vol 93 (11) ◽

pp. 4261-4267 ◽

Cited By ~ 68

Author(s):

Yoshihiro Maruo ◽

Hiroko Takahashi ◽

Ikumi Soeda ◽

Noriko Nishikura ◽

Katsuyuki Matsui ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Neonatal Screening ◽

Screening Program ◽

Thyroid Peroxidase ◽

Compound Heterozygous ◽

Recessive Trait ◽

Dual Oxidase ◽

Neonatal Screening Program ◽

Biallelic Mutations ◽

Transient Congenital Hypothyroidism

Context: Mutations in dual oxidase (DUOX2) have been proposed as a cause of congenital hypothyroidism. Previous reports suggest that biallelic mutations of DUOX2 cause permanent congenital hypothyroidism and that monoallelic mutations cause transient congenital hypothyroidism. Objective: To clarify the inheritance of hypothyroidism, we looked at the DUOX2 gene in patients with transient congenital hypothyroidism. Design: DUOX2, thyroid peroxidase, Na+/I− symporter and dual oxidase maturation factor 2 genes were analyzed in eight patients with transient congenital hypothyroidism, using the PCR-amplified direct sequencing method. Patients: The eight patients were found by a neonatal screening program. Six of these patients belonged to two independent families; the other two were unrelated. Their serum TSH values varied from 24.8–233.0 mU/liter. Six of the eight patients had a low serum freeT4 level (0.19–0.84 ng/dl). Seven of the eight patients were treated with thyroid hormone replacement therapy, which ceased to be necessary by 9 yr of age. Results: Eight novel mutations were detected in the DUOX2 gene. Four patients in one family were compound heterozygous for p.L479SfsX2 and p.K628RfsX10. Two patients in a second family were compound heterozygous for p.K530X and p.[E876K;L1067S]. The two remaining unrelated patients were also compound heterozygous, for p.H678R/p.L1067S and p.A649E/p.R885Q, respectively. Conclusion: All eight patients had biallelic mutations in the DUOX2 gene. We find that loss of DUOX2 activity results in transient congenital hypothyroidism and that transient congenital hypothyroidism caused by DUOX2 mutations is inherited as an autosomal recessive trait.

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Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02202 ◽

2018 ◽

Vol 103 (5) ◽

pp. 1889-1898 ◽

Cited By ~ 16

Author(s):

Minjing Zou ◽

Ali S Alzahrani ◽

Ali Al-Odaib ◽

Mohammad A Alqahtani ◽

Omer Babiker ◽

...

Keyword(s):

Saudi Arabia ◽

Congenital Hypothyroidism ◽

Screening Program ◽

Genetic Defects ◽

Newborn Screening Program ◽

Endocrine Disorder ◽

Thyroid Dysgenesis ◽

Thyroid Dyshormonogenesis ◽

Biallelic Mutations ◽

Saudi Patients

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

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Biallelic Inactivation of the Dual Oxidase Maturation Factor 2 (DUOXA2) Gene as a Novel Cause of Congenital Hypothyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2020 ◽

2008 ◽

Vol 93 (2) ◽

pp. 605-610 ◽

Cited By ~ 110

Author(s):

Ilaria Zamproni ◽

Helmut Grasberger ◽

Francesca Cortinovis ◽

Maria Cristina Vigone ◽

Giuseppe Chiumello ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Critical Role ◽

Chinese Patient ◽

Catalytic Core ◽

Genetic Event ◽

Hormone Synthesis ◽

Maturation Factor ◽

Dual Oxidase ◽

Organification Defect

Abstract Context: Dual oxidase 2 (DUOX2) is the catalytic core of the H2O2 generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis. DUOX2 deficiency produces congenital hypothyroidism (CH) in humans and mice. We recently cloned a novel gene, the product of which (dual oxidase maturation factor 2; DUOXA2) is required to express DUOX2 enzymatic activity. Objective: Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis. Patients: Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect. Results: One Chinese patient born to nonconsanguineous parents was homozygous for a nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking transmembrane helix 5 and the C-terminal cytoplasmic domain. The mutant protein was inactive in reconstituting DUOX2 in vitro. Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening. One heterozygous carrier of Y246X was identified in unrelated Chinese controls (n = 92) but not in Caucasian or Japanese controls, indicating that homozygosity for Y246X could be a frequent cause of CH in Chinese. Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially compensate DUOXA2 deficiency, consistent with the proband having a milder CH phenotype than patients with biallelic DUOX2 nonsense mutations. Conclusions: We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter. Results of our studies provide evidence for the critical role of DUOXA2 in thyroid hormonogenesis. Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.

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Faculty Opinions recommendation of Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104786.560760 ◽

2008 ◽

Author(s):

Hector Targovnik

Keyword(s):

Congenital Hypothyroidism ◽

Maturation Factor ◽

Dual Oxidase

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High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0400 ◽

2016 ◽

Vol 29 (7) ◽

Cited By ~ 12

Author(s):

Kumihiro Matsuo ◽

Yusuke Tanahashi ◽

Tokuo Mukai ◽

Shigeru Suzuki ◽

Toshihiro Tajima ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Japanese Patients ◽

Sequence Variants ◽

Transient Hypothyroidism ◽

High Prevalence ◽

Dual Oxidase

AbstractDual oxidase 2 (Forty-eight Japanese DH patients were enroled and analysed for sequence variants ofFourteen sequence variants ofOur results suggest that

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Increased Prevalence of TG and TPO Mutations in Sudanese Children With Congenital Hypothyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz297 ◽

2019 ◽

Vol 105 (5) ◽

pp. 1564-1572 ◽

Cited By ~ 2

Author(s):

Ryan J Bruellman ◽

Yui Watanabe ◽

Reham S Ebrhim ◽

Matthew K Creech ◽

Mohamed A Abdullah ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Molecular Basis ◽

Genetic Selection ◽

Gene Mutations ◽

Thyroid Peroxidase ◽

Acid Extraction ◽

Thyroid Function Tests ◽

Genetic Sequencing ◽

Dual Oxidase ◽

And Function

Abstract Context Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan. Objective To investigate the molecular basis of CH in Sudanese families. Design Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing. Setting University research center. Patients Twenty-six Sudanese families with CH. Intervention Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations. Results Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05). Conclusions All described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.

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Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2

Molecular Endocrinology ◽

10.1210/me.2007-0085 ◽

2007 ◽

Vol 21 (7) ◽

pp. 1593-1602 ◽

Cited By ~ 69

Author(s):

Kenneth R. Johnson ◽

Coleen C. Marden ◽

Patricia Ward-Bailey ◽

Leona H. Gagnon ◽

Roderick T. Bronson ◽

...

Keyword(s):

Thyroid Hormone ◽

Congenital Hypothyroidism ◽

Genetic Model ◽

Mutant Mice ◽

Tectorial Membrane ◽

Thyroid Peroxidase ◽

Hormone Synthesis ◽

Thyroid Hormone Synthesis ◽

Organ Systems ◽

Dual Oxidase

Abstract Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named “thyroid dyshormonogenesis” (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50–60 decibels (dB) above those of controls.

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Faculty Opinions recommendation of Missense mutations of dual oxidase 2 (DUOX2) implicated in congenital hypothyroidism have impaired trafficking in cells reconstituted with DUOX2 maturation factor.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1071080.524069 ◽

2007 ◽

Author(s):

Luca Persani

Keyword(s):

Congenital Hypothyroidism ◽

Missense Mutations ◽

Maturation Factor ◽

Dual Oxidase ◽

In Cells

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Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

10.21203/rs.3.rs-1239485/v1 ◽

2022 ◽

Author(s):

Maricel F. Molina ◽

Patricia Papendieck ◽

Gabriela Sobrero ◽

Viviana A. Balbi ◽

Fiorella S. Belforte ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Bioinformatic Analysis ◽

Thyroid Stimulating Hormone ◽

Motor Deficits ◽

Thyroid Peroxidase ◽

Solute Carrier Family ◽

Dual Oxidase ◽

Thyroid Dyshormonogenesis ◽

Solute Carrier ◽

And Function

Abstract Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

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