title: Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings.
abstract: One of the steps in thyroid hormone biosynthesis is the generation of hydrogen peroxide by dual oxidases (DUOX). Only one study reported mutations in DUOX2 gene in congenital hypothyroidism (CH) associated with total iodide organification defect (TIOD) in homozygosity or with partial iodide organification defect (PIOD) in heterozygous patients. We report genetic and phenotypic characterization of a family affected with isolated CH. The proband was positive at neonatal TSH screening. High serum TSH with low FT4 confirmed the diagnosis. At 4 years, TSH was high after L-T(4) withdrawal and (123)I scintigraphy with perchlorate discharge test revealed a PIOD. His brother was negative at TSH screening, but perinatal iodine overload was documented by urinary test. Serum TSH was elevated at postnatal day 11 and progressively increased together with a decline in urinary iodine. Reevaluation at 4 years confirmed a persistent hyperthyrotropinemia associated with PIOD. Both siblings resulted compound heterozygotes for two novel DUOX2 variants, a nonsense mutation (c.2524C>T, p.Arg842X) and a missense substitution (c.1126C>T, p.Arg376Trp), undetected in 140 control alleles. The parents had normal thyroid function and were heterozygous carriers of mutant alleles. In conclusion, we report two novel sequence variants in DUOX2 gene that are associated with persistent mild hypothyroidism and PIOD in two siblings. Different neonatal iodine supply apparently acted as disease modifier, justifying the discrepant results at TSH screening in the two siblings with same DUOX2 genotype and suggesting that mild dyshormonogenic defects may remain undisclosed in areas characterized by elevated iodine intake.
authors.affiliation: Department of Pediatrics, Endocrine Unit, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Vigone
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zamproni
authors.forename: Arianna
authors.initials: A
authors.lastname: Passoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Candia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiumello
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Weber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003409:Congenital Hypothyroidism; D000074623:Dual Oxidases; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000235:genetics*; D015997:Neonatal Screening; D016415:Sequence Alignment; D035781:Siblings; D013960:Thyroid Function Tests
chemical_list: D005420:Flavoproteins; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human