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      DUOX2/ DUOXA2 Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom

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          Abstract

          Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 ( DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort.

          Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6–19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized.

          Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 ( n = 20; 38%) or DUOXA2 ( n = 6; 12%), including novel gene variants ( DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range ( M = 9.3 pmol/L, range <3.9–15.8 pmol/L),

          Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/ DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

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          Most cited references30

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          Iodine status of UK schoolgirls: a cross-sectional survey.

          Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50-99 μg/L, moderate if 20-49 μg/L, and severe if less than 20 μg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14-15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June-July, 2009, and November-December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 μg/L (IQR 56·9-109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. Clinical Endocrinology Trust. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent.

            Dual oxidase 2 (DUOX2), an NADPH:O(2) oxidoreductase flavoprotein, is a component of the thyroid H(2)O(2) generator crucial for hormone synthesis at the apical membrane. Mutations in DUOX2 produce congenital hypothyroidism in humans. However, no functional DUOX-based NADPH oxidase has ever been reconstituted at the plasma membrane of transfected cells. It has been proposed that DUOX retention in the endoplasmatic reticulum (ER) of heterologous systems is due to the lack of an unidentified component required for functional maturation of the enzyme. By data mining of a massively parallel signature sequencing tissue expression data base, we identified an uncharacterized gene named DUOX maturation factor (DUOXA2) arranged head-to-head to and co-expressed with DUOX2. A paralog (DUOXA1) was similarly linked to DUOX1. The genomic rearrangement leading to linkage of ancient DUOX and DUOXA genes could be traced back before the divergence of echinoderms. We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane protein, allows ER-to-Golgi transition, maturation, and translocation to the plasma membrane of functional DUOX2 in a heterologous system. The identification of DUOXA genes has important implications for studies of the molecular mechanisms controlling DUOX expression and the molecular genetics of congenital hypothyroidism.
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              European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism

              Objective: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). Evidence: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Consensus Process: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. Recommendations: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T 4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.
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                Author and article information

                Journal
                Thyroid
                Thyroid
                thy
                Thyroid
                Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1050-7256
                1557-9077
                01 June 2019
                03 June 2019
                03 June 2019
                : 29
                : 6
                : 790-801
                Affiliations
                [ 1 ]Department of Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom.
                [ 2 ]University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
                [ 3 ]Department of Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
                [ 4 ]Department of Laboratory Medicine, Great Ormond Street Hospital for Children, London, United Kingdom.
                [ 5 ]Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
                [ 6 ]Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
                Author notes
                [*]Address correspondence to: Nadia Schoenmakers, PhD, University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom naaa2@ 123456cam.ac.uk
                Article
                10.1089/thy.2018.0587
                10.1089/thy.2018.0587
                6588112
                31044655
                f61e07e6-8dda-4228-b3bd-f335b0bdd101
                © Catherine Peters et al. 2019; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 3, Tables: 3, References: 35, Pages: 12
                Categories
                Thyroid Dysfunction: Hypothyroidism, Thyrotoxicosis, and Thyroid Function Tests

                congenital hypothyroidism,duox2,duoxa2,dyshormonogenesis,gland in situ

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