title: The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects.
abstract: BACKGROUND
  Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect.
  
  
  OBJECTIVE
  This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD).
  
  
  METHODS
  Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature.
  
  
  RESULTS
  In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Sciences and Community Health (M.M., V.C., M.A.M., P.B.-P., L.F.), University of Milan, and Endocrine Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Ca' Granda, 20122 Milan, Italy; Department of Pediatrics (S.R., M.C.V., I.Z., K.M., G.W.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 21032 Milan, Italy; Department of Clinical Sciences and Community Health (L.P.), University of Milan, Milan, and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, 20149 Milan, Italy; Department of Pediatrics (L.B.), A. Manzoni Hospital, 73100 Lecco, Italy; Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Pediatrics (F.G.), Perrino Hospital, 72100 Brindisi, Italy; and Department of Clinical Genetics (S.-M.P.), Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Muzza
authors.forename: S
authors.initials: S
authors.lastname: Rabbiosi
authors.forename: M C
authors.initials: MC
authors.lastname: Vigone
authors.forename: I
authors.initials: I
authors.lastname: Zamproni
authors.forename: V
authors.initials: V
authors.lastname: Cirello
authors.forename: M A
authors.initials: MA
authors.lastname: Maffini
authors.forename: K
authors.initials: K
authors.lastname: Maruca
authors.forename: N
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: L
authors.initials: L
authors.lastname: Beccaria
authors.forename: F
authors.initials: F
authors.lastname: Gallo
authors.forename: S-M
authors.initials: SM
authors.lastname: Park
authors.forename: P
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: L
authors.initials: L
authors.lastname: Persani
authors.forename: G
authors.initials: G
authors.lastname: Weber
authors.forename: L
authors.initials: L
authors.lastname: Fugazzola
mesh_terms: D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D000074623:Dual Oxidases; D005787:Gene Frequency; D056726:Genetic Association Studies; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human