Thyroid Dyshormonogenesis 5


A number sign (#) is used with this entry because thyroid dyshormonogenesis-5 (TDH5) is caused by homozygous or compound heterozygous mutation in the DUOXA2 gene (612772) on chromosome 15q21.

For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (274400).

Clinical Features

Zamproni et al. (2008) described a female patient born to nonconsanguineous parents of Chinese origin who was diagnosed with congenital hypothyroidism neonatally using blood spot TSH (see 188540) screening (48 mU/l; reference range less than 20 mU/l). Ultrasonographic examination revealed an enlarged thyroid gland. A perchlorate discharge test at 7 years of age indicated a partial iodine discharge. Low dose T4 replacement therapy had been instituted at 43 days of age. After 1 month off therapy serum TSH was only slightly elevated, and free T4 and thyroglobulin (TG; 188450) concentrations were within the reference range. T4 replacement therapy was reinstated after 8 months because of persistent hyperthyrotropinemia. Parents and sibs of the proband had normal thyroid function and normal-sized thyroid glands.

Molecular Genetics

Zamproni et al. (2008) detected homozygosity for a nonsense mutation in the DUOXA2 gene (Y246X; 612772.0001) in a 7-year-old patient of Chinese origin with congenital hypothyroidism. Parents and sibs of the proband, all with normal thyroid function, were heterozygous carriers. Functional studies indicated that the Y246X mutation results in a complete loss of function of DUOXA2 activity and subsequently to a loss of DUOX2 (606759) activity.

Population Genetics

Genotyping of unrelated control individuals revealed 1 heterozygous carrier of the Y246X mutation among 92 Chinese screened, all from the Shanghai area; the mutation was not detected among 178 Caucasian alleles or 82 Japanese alleles. Assuming Hardy-Weinberg equilibrium, the frequency of affected homozygous for Y246X was estimated at 1 in 34,000 newborns in that Chinese population.