Thyroid peroxidase (TPO) deficiency is frequently involved in total iodide organification defects (TIOD). According to the recessive mode of inheritance, mutations are found in homozygous or in compound heterozygous states. However, a single heterozygous TPO mutation is reported in a high percentage (approximately 20%) of patients with typical TIOD phenotype. In the present study, the genetic and clinical evaluation of a TIOD family is reported. The propositus is an Italian girl with congenital hypothyroidism and positive perchlorate discharge test. Two TPO frameshift mutations were documented: a C deletion at 477 in exon 5, and a GGCC duplication at 1277 in exon 8. Unaffected family members, heterozygous for one of the two TPO mutations, were also studied in order to evaluate in vivo the functional activity of a single TPO allele. They have been found to have normal thyroid morphology and function with normal perchlorate test. In conclusion, the present study reports the clinical and molecular investigations in an Italian TIOD family. The results show that the TIOD phenotype in the propositus is associated to a compound heterozygous pattern, while a single TPO mutation does not significantly affect in vivo the efficiency of iodide organification. Therefore, extensive analyses of TPO gene and 2p25 locus are needed in the frequent TIOD cases in whom conventional investigations disclosed only one mutant allele
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