Alternative titles; symbols
SNOMEDCT: 124204003; ORPHA: 95716; DO: 0112186;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p25.3 | Thyroid dyshormonogenesis 2A | 274500 | Autosomal recessive | 3 | TPO | 606765 |
A number sign (#) is used with this entry because thyroid dyshormonogenesis-2A (TDH2A) is caused by homozygous or compound heterozygous mutation in the thyroid peroxidase gene (TPO; 606765) on chromosome 2p25.
For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (274400).
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 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.
Perez-Cuvit et al. (1977) described partial iodide discharge in the euthyroid, identical twin grandnieces of a normal member of a sibship which included 4 children with severe retardation and complete thyroid iodide organification defect. The twins' hearing was normal and their parents were unrelated. The findings were interpreted as indicating a partial peroxidase defect resulting from compound heterogeneity for 2 different abnormal alleles. Medeiros-Neto et al. (1982) described thyroid peroxidase deficiency in a congenitally goitrous, mentally retarded, hypothyroid child, whose parents were first cousins. Both parents showed a thyroid abnormality. Couch et al. (1985) reported a Hutterite kindred with 9 affected persons including identical twins.
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.
In 5 families, which included 9 goitrous subjects with complete or partial TPO deficiency, Mangklabruks et al. (1991) found a lod score (2.08) compatible with linkage of the disorder to a RFLP in the TPO gene in 1 family with inbreeding. In 2 other families, the lod score was inconsistent with linkage between the disease and the TPO gene. In a fourth family, partial deletion of the TPO gene was suggested by Southern blotting. Anker et al. (1992) identified a tetranucleotide repeat (AATG) in intron 10 of the TPO gene. By study of CEPH pedigrees, they found a heterozygosity of 67% and a PIC value of 0.61. By linkage studies, they subregionalized TPO to 2pter-p23.
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.
In a Hispanic family in which 3 children had congenital hypothyroidism and goiter due to thyroid dyshormonogenesis resulting from compound heterozygous missense mutations in the TPO gene (T321N and T526I), Furman et al. (2021) also identified heterozygosity for a missense variant (R132H) in the iodothyronine deiodinase type-1 gene (DIO1; 147892) that was present in the 2 more severely affected girls but not in their less-affected brother. DIO1 variants have been associated with abnormal thyroid hormone metabolism (THMA2; 619855). The authors suggested that the more severe developmental delay in the 2 affected sisters might be due to the additional deleterious DIO1 defect, which they postulated might act as a modifier of the congenital hypothyroidism phenotype, causing a reduction in thyroid hormone availability by reducing the generation of T3 from exogenous thyroid hormone.
Nunez et al. (1976) showed that thyroid peroxidase catalyzes 3 different reactions and exists in 2 interchangeable forms, A and B. Form A catalyzes iodide oxidation and high-rate thyroglobulin iodination, whereas form B catalyzes low-rate thyroglobulin iodination and iodotyrosyl coupling. Pommier et al. (1974) studied thyroid tissue from a euthyroid patient with a childhood goiter in whom iodide oxidation was normal and thyroglobulin iodination was only slightly reduced, yet coupling of the iodotyrosines was markedly reduced. The authors proposed that the defect in this patient was secondary to a lack of conformational change from form A to form B. Both a defect in the third peroxidase reaction (primary coupling defect) and alteration of amino acid sequence within thyroglobulin, changing the total number or the intramolecular position of the iodotyrosines (secondary coupling defect), could result in the same phenotype. Some patients have been cretinous while others only had goiters; therefore, heterogeneity may exist in this group of patients. Stanbury and Dumont (1983) indicated that the coupling defects represent a 'poorly defined group, which is almost surely heterogeneous.'
Pommier et al. (1976) summarized the in vitro kinetics and proposed mechanisms for the 3 peroxidase reactions: (1) iodide oxidation, (2) thyroglobulin (TG; 188450) iodination, and (3) iodothyronine coupling. Niepomniszcze et al. (1975) called this the 'apo-enzyme-prothetic group defect' and pointed out that an organification defect may be produced by a defective or deficient iodide acceptor (i.e., thyroglobulin).
Discharge of a significant percentage of labeled iodide from the thyroid upon administration of thiocyanate or perchlorate in a thyroid function test indicates a defect in converting accumulated iodide to organically bound iodine (iodide organification defect, or IOD). Discharge may be partial or complete, indicating partial (PIOD) or total (TIOD) iodide organification defect. Thyroid dyshormonogenesis characterized by such a discharge was originally categorized here as type 2, with type 2A representing thyroid peroxidase (TPO) deficiency and 2B representing Pendred syndrome (274600). Later molecular studies showed IODs to be related to diverse molecular mechanisms, including mutations in DUOX2 (606759) and DUOXA2 (612772) (Cavarzere et al., 2008).
Abramowicz, M. J., Targovnik, H. M., Varela, V., Cochaux, P., Krawiec, L., Pisarev, M. A., Propato, F. V. E., Juvenal, G., Chester, H. A., Vassart, G. Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J. Clin. Invest. 90: 1200-1204, 1992. [PubMed: 1401057] [Full Text: https://doi.org/10.1172/JCI115981]
Alexander, N. M., Burrow, G. N. Thyroxine biosynthesis in human goitrous cretinism. J. Clin. Endocr. 30: 308-315, 1970. [PubMed: 4189569] [Full Text: https://doi.org/10.1210/jcem-30-3-308]
Anker, R., Steinbrueck, T., Donis-Keller, H. Tetranucleotide repeat polymorphism at the human thyroid peroxidase (hTPO) locus. Hum. Molec. Genet. 1: 137 only, 1992. [PubMed: 1339470] [Full Text: https://doi.org/10.1093/hmg/1.2.137]
Bakker, B., Bikker, H., Vulsma, T., De Randamie, J. S. E., Wiedijk, B. M., De Vijlder, J. J. M. Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total iodide organification defects (an update). J. Clin. Endocr. Metab. 85: 3708-3712, 2000. [PubMed: 11061528] [Full Text: https://doi.org/10.1210/jcem.85.10.6878]
Bikker, H., den Hartog, M. T., Baas, F., Gons, M. H., Vulsma, T., de Vijlder, J. J. M. A 20-basepair duplication in the human thyroid peroxidase gene results in a total iodide organification defect and congenital hypothyroidism. J. Clin. Endocr. Metab. 79: 248-252, 1994. [PubMed: 8027236] [Full Text: https://doi.org/10.1210/jcem.79.1.8027236]
Bikker, H., Vulsma, T., Baas, F., de Vijlder, J. J. M. Identification of five novel inactivating mutations in the human thyroid peroxidase gene by denaturing gradient gel electrophoresis. Hum. Mutat. 6: 9-16, 1995. [PubMed: 7550241] [Full Text: https://doi.org/10.1002/humu.1380060104]
Bikker, H., Waelkens, J. J. J., Bravenboer, B., de Vijlder, J. J. M. Congenital hypothyroidism caused by a premature termination signal in exon 10 of the human thyroid peroxidase gene. J. Clin. Endocr. Metab. 81: 2076-2079, 1996. [PubMed: 8964831] [Full Text: https://doi.org/10.1210/jcem.81.6.8964831]
Cavarzere, P., Castanet, M., Polak, M., Raux-Demay, M.-C., Cabrol, S., Carel, J. C., Liger, J., Czernichow, P. Clinical description of infants with congenital hypothyroidism and iodide organification defects. Horm. Res. 70: 240-248, 2008. [PubMed: 18772598] [Full Text: https://doi.org/10.1159/000151597]
Couch, R. M., Dean, H. J., Winter, J. S. D. Congenital hypothyroidism caused by defective iodide transport. J. Pediat. 106: 950-953, 1985. [PubMed: 3998954] [Full Text: https://doi.org/10.1016/s0022-3476(85)80249-3]
Furman, A., Hannoush, Z., Barrera Echegoyen, F., Dumitrescu, A., Refetoff, S., Weiss, R. E. Novel DIO1 gene mutation acting as phenotype modifier for novel compound heterozygous TPO gene mutations causing congenital hypothyroidism. Thyroid 31: 1589-1591, 2021. [PubMed: 34128397] [Full Text: https://doi.org/10.1089/thy.2021.0210]
Haddad, H. M., Sidbury, J. B., Jr. Defect of the iodinating system in congenital goitrous cretinism: report of a case with biochemical studies. J. Clin. Endocr. 19: 1446-1457, 1959. [PubMed: 13830735] [Full Text: https://doi.org/10.1210/jcem-19-11-1446]
Hagen, G. A., Niepomniszcze, H., Haibach, H., Bigazzi, M., Hati, R., Rapoport, B., Jimenez, C., DeGroot, L. J., Frawley, T. F. Peroxidase deficiency in familial goiter with iodide organification defect. New Eng. J. Med. 285: 1394-1398, 1971. [PubMed: 4330593] [Full Text: https://doi.org/10.1056/NEJM197112162852502]
Leszynsky, H. E. Genetic studies in familial goitrous cretinism. (Abstract) Acta Endocr. 46: 103-110, 1964.
Mangklabruks, A., Billerbeck, A. E., Wajchenberg, B., Knobel, M., Cox, N. J., De Groot, L. J., Medeiros-Neto, G. Genetic linkage studies of thyroid peroxidase (TPO) gene in families with TPO deficiency. J. Clin. Endocr. Metab. 72: 471-476, 1991. [PubMed: 1671388] [Full Text: https://doi.org/10.1210/jcem-72-2-471]
Medeiros-Neto, G. A., Okamura, K., Cavaliere, H., Taurog, A., Knobel, M., Bisi, H., Kallas, W. G., Mattar, E. Familial thyroid peroxidase defect. Clin. Endocr. 17: 1-14, 1982. [PubMed: 7116652] [Full Text: https://doi.org/10.1111/j.1365-2265.1982.tb02628.x]
Medeiros-Neto, G., Gil-Da-Costa, M. J., Santos, C. L. S., Medina, A. M., Costa e Silva, J., Tsou, R. M., Sobrinho-Simoes, M. Metastatic thyroid carcinoma arising from congenital goiter due to mutation in the thyroperoxidase gene. J. Clin. Endocr. Metab. 83: 4162-4166, 1998. [PubMed: 9814507] [Full Text: https://doi.org/10.1210/jcem.83.11.5264]
Morris, J. H. Defective coupling of iodotyrosine in familial goiters: report of two patients. Arch. Intern. Med. 114: 417-423, 1964. [PubMed: 14170622] [Full Text: https://doi.org/10.1001/archinte.1964.03860090151018]
Niepomniszcze, H., Castells, S., DeGroot, L. J., Refetoff, S., Kim, O. S., Rapoport, B., Hati, R. Peroxidase defect in congenital goiter with complete organification block. J. Clin. Endocr. 36: 347-357, 1973. [PubMed: 4345693] [Full Text: https://doi.org/10.1210/jcem-36-2-347]
Niepomniszcze, H., Rosenbloom, A. L., Degroot, L. J., Shimaoka, K., Refetoff, S., Yamamoto, K. Differentiation of two abnormalities in thyroid peroxidase causing organification defect and goitrous hypothyroidism. Metabolism 24: 57-67, 1975. [PubMed: 162974] [Full Text: https://doi.org/10.1016/0026-0495(75)90007-4]
Nunez, J., Pommier, J., Dominici, R., Rahmoun, B., Deme, D., Tourniaire, J. Peroxidases and thyroglobulins from different goiters. In: Robbins, J.; Braverman, L. E. (eds.): Thyroid Research. Proceedings of the 7th International Thyroid Conference, Boston, Mass., June 9-13, 1975. Amsterdam: Excerpta Medica (pub.) 1976.
Pannain, S., Weiss, R. E., Jackson, C. E., Dian, D., Beck, J. C., Sheffield, V. C., Cox, N., Refetoff, S. Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J. Clin. Endocr. Metab. 84: 1061-1071, 1999. [PubMed: 10084596] [Full Text: https://doi.org/10.1210/jcem.84.3.5541]
Park, S. M., Chatterjee, V. K. K. Genetics of congenital hypothyroidism. J. Med. Genet. 42: 379-389, 2005. [PubMed: 15863666] [Full Text: https://doi.org/10.1136/jmg.2004.024158]
Parker, R. H., Beierwaltes, W. H. Inheritance of defective organification of iodine in familial goitrous cretinism. J. Clin. Endocr. Metab. 21: 21-30, 1961. [PubMed: 13732855] [Full Text: https://doi.org/10.1210/jcem-21-1-21]
Perez-Cuvit, E., Crigler, J. F., Jr., Stanbury, J. B. Partial and total iodide organification defect in different sibships in a kindred. Am. J. Hum. Genet. 29: 142-148, 1977. [PubMed: 192074]
Pommier, J., Tourniaire, J., Deme, D., Chalendar, D., Bornet, H., Nunez, J. A defective thyroid peroxidase solubilized from a familial goiter with iodine organification defect. J. Clin. Endocr. 39: 69-80, 1974. [PubMed: 4835124] [Full Text: https://doi.org/10.1210/jcem-39-1-69]
Pommier, J., Tourniaire, J., Rahmoun, B., Deme, D., Pallo, D., Bornet, H., Nuzer, J. Thyroid iodine organification defects. J. Clin. Endocr. 42: 319-329, 1976. [PubMed: 1262432] [Full Text: https://doi.org/10.1210/jcem-42-2-319]
Stanbury, J. B., Dumont, J. E. Familial goiter and related disorders. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.) New York: McGraw-Hill (pub.) 1983. Pp. 231-269.
Valenta, L., Bode, H. H., Vickery, A. L., Maloof, F. Lack of thyroid peroxidase activity: a cause of congenital goitrous hypothyroidism. (Abstract) J. Clin. Invest. 50: 94A-95A, 1971.
Vono-Toniolo, J., Rivolta, C. M., Targovnik, H. M., Medeiros-Neto, G., Kopp, P. Naturally occurring mutations in the thyroglobulin gene. Thyroid 15: 1021-1033, 2005. [PubMed: 16187910] [Full Text: https://doi.org/10.1089/thy.2005.15.1021]
Wolff, J. Congenital goiter with defective iodide transport. Endocr. Rev. 4: 240-254, 1983. [PubMed: 6313338] [Full Text: https://doi.org/10.1210/edrv-4-3-240]