Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). The most prevalent cause of thyroid dyshormonogenesis is TPO deficiency (Park ... Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). The most prevalent cause of thyroid dyshormonogenesis is TPO deficiency (Park and Chatterjee, 2005). Defects in TPO cause a severe form of congenital hypothyroidism characterized by a complete and immediate release of accumulated radioiodide from the thyroid after sodium perchlorate administration (Bakker et al., 2000). This release of radioiodide represents total iodine organification defect (TIOD), a disruption of the process by which iodide present in the thyroid is oxidized by hydrogen peroxide and bound to tyrosine residues in thyroglobulin (TG; 188450) to form iodotyrosine.
Haddad and Sidbury (1959) first demonstrated an in vitro deficiency of thyroid peroxidase activity in a patient with a thyroid hormone organification defect. A peroxide generating system did not improve activity.
Hagen et al. (1971) described ... Haddad and Sidbury (1959) first demonstrated an in vitro deficiency of thyroid peroxidase activity in a patient with a thyroid hormone organification defect. A peroxide generating system did not improve activity. Hagen et al. (1971) described an intelligent, euthyroid child of normal stature with recurrent goiter. She and her similarly affected sister had normal hearing. Like patients with Pendred syndrome (274600), she discharged 50% of the thyroidal iodide after perchlorate. Her thyroid tissues showed no iodide peroxidation or tyrosine iodination activity. Addition of excessive hematin, the prosthetic group of peroxidase, restored tyrosine iodination. Niepomniszcze et al. (1973) described a cretinous child with a goiter who completely discharged radioiodide after administration of perchlorate. The total in vitro peroxidase deficiency was not improved by peroxide, hematin, or enzyme solubilization. Pommier et al. (1974) found that tissue from a euthyroid woman with a recurrent goiter and partial iodide discharge had normal iodide peroxidation but deficient thyroglobulin iodination. Partial solubilization of the enzyme resulted in a 3-fold increase in thyroglobulin iodination activity. Wolff (1983) stated that only 22 persons with this abnormality had been reported.
In a patient with partial iodide organification defect, Abramowicz et al. (1992) identified a mutation in the TPO gene (606765.0001).
In a patient with congenital hypothyroidism, a large nodular goiter, and a total iodide organification defect, ... In a patient with partial iodide organification defect, Abramowicz et al. (1992) identified a mutation in the TPO gene (606765.0001). In a patient with congenital hypothyroidism, a large nodular goiter, and a total iodide organification defect, Bikker et al. (1994) found homozygosity for a 20-bp duplication in the TPO gene (606765.0002) Both parents of the patient were heterozygous for the mutation. Hypothyroidism had been discovered at the age of 4 months, the neonatal period having been complicated by prolonged icterus. In a family with 2 of 5 sibs affected with severe congenital hypothyroidism, Bikker et al. (1996) identified homozygosity for a nonsense mutation in the TPO gene (606765.0003). Thyroid tissue from 1 patient was available for study; TPO activity was absent and thyroglobulin (188450) was not iodinated, showing that iodination in vivo did not occur. Pannain et al. (1999) performed genomewide homozygosity analysis in the youngest generation of 5 nuclear families belonging to an inbred Amish kindred segregating a complete iodide organification defect, which localized the defect close to the TPO gene. Sequencing of the TPO gene revealed 2 missense mutations, E799K (606765.0007) and R648Q (606765.0009); the former was found in homozygosity in 11 affected individuals and both mutations were present in 3 affected compound heterozygotes. One family member with hypothyroidism who had no mutation in the TPO gene also had insignificant discharge of radioiodide after administration of sodium perchlorate, indicating a different etiology for his thyroid hormone deficiency. Medeiros-Neto et al. (1998) reported an infant girl born with a large cervical tumor that extended to the upper mediastinum. Pathologic examination after thyroidectomy revealed a follicular carcinoma of the thyroid (see 188470) and probable dyshormonogenetic hyperplastic goiter; she was subsequently found to have lung and bone metastases. DGGE analysis of PCR fragments corresponding to exon 14 of the TPO gene indicated the presence of a mutant TPO allele (606765.0008) in the propositus, her father, and her paternal grandmother. The authors concluded that the aggressive thyroid metastatic carcinoma arose from a dyshormonogenetic goiter caused by a defective TPO protein.
Total iodide organification defect, in which iodide taken up by the thyroid gland cannot be oxidized and bound to protein, was found by Bikker et al. (1995) to be the most common hereditary inborn error causing congenital hypothyroidism ... Total iodide organification defect, in which iodide taken up by the thyroid gland cannot be oxidized and bound to protein, was found by Bikker et al. (1995) to be the most common hereditary inborn error causing congenital hypothyroidism in the Netherlands. Bakker et al. (2000) established the incidence of TIOD in the Netherlands to be 1 in 66,000.