Two decades of screening for congenital hypothyroidism in the Netherlands:TPO gene mutations in total iodide organification defects (an update)

Presented is a cohort study to assess the nature and frequency of thyroid p eroxidase (TPO) mutations in 45 patients (35 families) with congenital hypo thyroidism due to a total iodide organification defect; incidence is 1:66,0 00 in The Netherlands. The presentation is consistently similar with a seve re form of congenital hypothyroidism and also characterized by a complete a nd immediate release of accumulated radioiodide from the thyroid after sodi um perchlorate administration. Sixteen different mutations were found, including eight novel mutations; th e majority occurs in exons 8, 9, or 10. The GGCC insertion in exon 8 at nuc leotide 1277, leading to an early termination signal in exon 9, is the most frequently occurring mutation. These mutations were detected in 29 familie s in both TPO alleles (13 homozygous and 16 compound heterozygous). In one family, partial maternal isodisomy of 2p was detected, in four families onl y one mutated TPO allele could be detected, and in one family no inactivati ng TPO mutation could be found. Because all patients clearly had the clinicopathologic features of a total iodide organification defect, we conclude that in these five families the m utations in the (other) alleles could be either located in the intronic seq uences or in the promoter region. Mutations in the TPO gene result in total iodide organification defects.