<i>DUOX2</i> Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype

Srichomkwun, Panudda; Takamatsu, Junta; Nickerson, Deborah A.; Bamshad, Michael J.; Chong, Jessica X.; Refetoff, Samuel

doi:10.1089/thy.2016.0469

Cited by 24 publications

(19 citation statements)

References 5 publications

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“…Patients 3 and 6 are the first reported cases of bi-allelic pathogenic mutations of DUOX2 associated with lifelong euthyroidism. Thus, subjects with biallelic DUOX2 mutations differ by age at presentation (congenital or acquired), transient or permanent hypothyroidism, presence or absence of goiter (5), and, as shown here, the very presence of hypothyroidism. A transient phenotype could result from the compensation of peroxide generation by the DUOX1/DUOXA1 complex when thyroid hormone requirements fall with age.…”

Section: Additional Studiessupporting

confidence: 57%

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism

Dufort

Larrivée-Vanier

Eugène

et al. 2019

Thyroid

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Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.

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Section: Additional Studiessupporting

confidence: 57%

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism

Dufort

Larrivée-Vanier

Eugène

et al. 2019

Thyroid

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“…However, subsequent studies have shown almost 40% discordancy with this observation; additionally, penetrance is highly variable and biallelic truncating mutations may be associated with both mild transient and severe permanent CH (69). Although sometimes associated with goitrous dyshormonogenesis, DUOX2 mutations may also cause a resistance to thyrotropin phenotype (70). Additionally, next-generation sequencing recently identified frequent DUOX2 NH 2 -terminal mutations in cases with thyroid ectopy, raising the possibility of a role for DUOX2 in thyroid development, for which the mechanism and putative H 2 O 2 dependency remain unclear (71).…”

Section: Clinical Phenotypes In Dyshormonogenesismentioning

confidence: 99%

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Peters

Trotsenburg

Schoenmakers

2018

European Journal of Endocrinology

124

103

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Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

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“…DUOX2 is an autosomal recessive gene related to thyroid hormone synthesis dysfunction (16). One case (ID 84066) harbored two DUOX2 variants, c.3391G>T(p.A1131S) and c.2202G>A(p.W734*).…”

Section: Comparisons Of Biochemical Screening and Genetic Resultsmentioning

confidence: 99%

Pilot study of expanded newborn screening for 573 genes related to severe diseases in China: results from 1173 newborns

Luo

Sun

et al. 2019

Preprint

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Background: Current newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false positive/negative results. To explore whether next-generation sequencing (NGS) for dried blood spots can increase the detecting rate of genetic disorders, we carried out a pilot study using NGS in 1,173 newborns who had been tested by traditional NBS. With a focus on inherited metabolic diseases (IMDs), our team investigated the current frequencies of genes related to common inherited metabolic diseases in this cohort. Methods: We designed an NGS panel of 573 genes related to severe diseases and performed NBS in 1,173 individuals who had been screened by tandem mass spectrometry (MS/MS) as well as for phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) abnormalities in a traditional biochemical NBS conducted in September 2016. We compared the biochemical results to the genetic variants and investigated the carrier frequencies of 77 genes related to disorders by MS/MS in these newborns.Results: The biochemical results showed that four newborns (all male) were positive for G6PD by enzymatic assay, while the other biochemical findings including MS/MS, Phe, TSH and 17-OHP were negative. Genetic analysis results revealed that all the four newborns with positive G6PD values harbored hemizygous G6PD mutations. The NGS results also revealed an individual (ID 84123) carrying two SLC22A5 mutations (c.760C>T/p.R254* and c.1400C>G/p.S467C) common in Chinese patients with carnitine deficiency, which were later verified to be in trans, who was biochemically negative in 2016. The MS/MS results in 2019 showed free carnitine deficiency, consistent with the genetic analysis findings. The top five genes with the highest carrier frequencies in these newborns were PAH (1.77%), ETFDH (1.24%), MMACHC (1.15%), SLC25A13 (0.98%), and GCDH (0.80%). Conclusions: Our study provided data combing biochemical results with genetic variants in 1,173 newborns and confirmed a primary carnitine deficiency patient with false-negative biochemical results. This is also the first study to report the carrier frequencies of 77 IMD-causing genes in China.

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DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype

Cited by 24 publications

References 5 publications

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Pilot study of expanded newborn screening for 573 genes related to severe diseases in China: results from 1173 newborns

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