Alternative titles; symbols
SNOMEDCT: 237934001; ICD10CM: D51.2; ORPHA: 859; DO: 0050818;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.2 | Transcobalamin II deficiency | 275350 | Autosomal recessive | 3 | TCN2 | 613441 |
A number sign (#) is used with this entry because transcobalamin II deficiency (TCN2D) is caused by homozygous or compound heterozygous mutation in the gene encoding transcobalamin II (TCN2; 613441) on chromosome 22q12.
Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by Haberle et al., 2009).
Hall (1981) gave a clinically oriented review of congenital defects of vitamin B12 transport, and Frater-Schroder (1983) gave a genetically oriented review.
Hakami et al. (1971) described megaloblastic anemia and other manifestations of vitamin B12 deficiency in 2 infant sibs who had normal levels of serum B12. Deficiency of transcobalamin II was demonstrated. A partial deficiency in both parents and other hematologically normal relatives indicated autosomal recessive inheritance. Decreased intestinal absorption of B12, uncorrected by intrinsic factor (609342), suggested that transcobalamin II is involved in B12 absorption. Other B12-responsive megaloblastic anemias of the pediatric age group include a form due to lack of intrinsic factor (261000) and a form due to a defect in intestinal absorption with associated proteinuria (261100).
Scott et al. (1972) concluded that no defect in homocysteine methyltransferase or methylmalonyl CoA mutase occurs in patients with TC II deficiency, and that TC II is normally necessary mainly for delivery of the cobalamin molecule to the hematopoietic system. Immunodeficiency can occur in some families with deficiency of TC II.
The patient with TC II deficiency reported by Hitzig et al. (1974) came from a Moroccan family in which 2 sons had died of severe infections in early infancy. The diagnosis of severe congenital neutropenia (Kostmann infantile genetic agranulocytosis; 610738) was initially made. The proband was delivered by cesarean section and maintained in a sterile unit for 115 days, in anticipation of bone marrow transplantation at a later stage. Agammaglobulinemia and lack of antibody response to strong antigenic stimuli were found. Cellular immune reactions were normal. After removal from isolation, he developed severe diarrhea and an upper respiratory infection. Severe atrophy of the intestinal mucosa and deficiency of disaccharidases were found. At 7 months of age he developed macromegaloblastic anemia with low reticulocyte counts, leukopenia with granulocytopenia, and thrombocytopenia with severe hemorrhagic diathesis. While in the sterile environment he had received vitamin B12 and folic acid; vitamin B12 quickly restored him to normal health. The blood, the intestine and the immune system returned to normal. With B12 therapy, an anomalous B12-binding protein, possibly 'transcobalamin III,' or fetal vitamin B12-binding globulin, appeared in the patient's serum.
Seligman et al. (1980) described a patient with megaloblastic anemia who represented a compound heterozygote for absent TC II and defective TC II that failed to bind cobalamin. The father was heterozygous for the absence of TC II and the mother was heterozygous for the defective form. The proband had 2 children: a heterozygote for absence of TC II and a heterozygote for abnormal TC II. The abnormality would not have been recognized if tested only for immunoreactive TC II. Continued treatment with only folate, to which the anemia responded, would have led to serious neurologic abnormality.
Thomas et al. (1982) described a child of Maltese ancestry who presented in early infancy with megaloblastic anemia and was treated with folinic acid from 6 weeks of age when the diagnosis of dihydrofolate reductase deficiency (see 126060) was made (Case 2, Tauro et al., 1976). TC II deficiency was not recognized until age 2 years by which time he had severe mental retardation, ataxia, and a pyramidal deficit in the limbs. Following treatment with intramuscular hydroxycobalamin, his condition slowly improved, but at age 7 years he was left with severe neurologic deficit. Hoffbrand et al. (1984) reported that this patient had no serum transcobalamin II binding capacity, whereas his parents and sisters had values about 50% of normal. Immunoreactive TC II was present in the patient's serum but at about 39% of normal.
Sacher et al. (1983) described a boy, born healthy, who developed diarrhea, vomiting, and ulcerative stomatitis together with megaloblastic anemia, thrombocytopenia, and neutropenia at the age of 5 weeks. Serum apo-TC2 was not detectable. Cultured skin fibroblasts failed to secrete functioning TC II. Both parents and the maternal grandfather, who were asymptomatic, were shown to be heterozygous for a silent TCN2 allele. The authors noted that the level of serum cobalamin is usually normal in cases of TC II deficiency because the bulk of serum cobalamin normally circulates attached to R binder protein rather than to TC II. However, Meyers and Carmel (1984) observed a case of TC II deficiency with subnormal serum cobalamin.
Barshop et al. (1990) reported the case of a black infant with severe TC II deficiency. The infant had not only megaloblastic anemia but also thrombocytopenia and neutropenia, i.e., pancytopenia. Methylmalonic acid and homocystine were found in the urine.
The patient reported by Kaikov et al. (1991) presented at 6 weeks of age with failure to thrive, diarrhea, macrocytic anemia, and decreased IgG. Both parents had intermediate levels of transcobalamin II consistent with the heterozygous state.
Vance et al. (1993) reported the cytogenetic findings of bone marrow aspirates and identified fragile site expression in the hematopoietic cells of a patient with TC II deficiency.
Haberle et al. (2009) reported 3 patients with TC II deficiency. The first was a Lebanese girl, born of consanguineous parents, who had diarrhea, vomiting, hypotonia, and failure to thrive at age 3 weeks. Laboratory studies showed pancytopenia, methylmalonic aciduria, and megaloblastic anemia. Cobalamin supplementation resulted in clinical improvement. The other 2 patients were sibs, born of consanguineous Turkish parents, who both showed onset in the first weeks of life of failure to thrive, pancytopenia, and methylmalonic aciduria, and both responded to hydroxycobalamin treatment. Both had normal psychomotor development at ages 9 and 11 years, respectively.
Because of the evidence presented by Porck et al. (1983) that the TC II of cord blood is of fetal origin, cord blood can be used in the neonatal diagnosis of deficiency.
Mayes et al. (1987) studied the production of transcobalamin II by amniotic cells in a pregnancy at risk for deficiency. They predicted heterozygosity which was confirmed in the live-born child.
Haberle et al. (2009) reported successful molecular diagnosis of TC II using cDNA from cultured skin fibroblasts or lymphocytes.
Hypogammaglobulinemia (Hitzig and Kenny, 1975) and disturbed phagocytic function of leukocytes (Seger et al., 1980) found in some patients with TC II deficiency can be corrected by appropriate therapy.
Arrabal et al. (1988) reported normal growth and mental development of a Spanish brother and sister with TC II deficiency after 10 years of vitamin B12 therapy. Two sibs had died at 1.5 and 2 months of age and were apparently affected.
The transmission pattern of TCN2D in the family reported by Li et al. (1994) and the family reported by Namour et al. (2003) was consistent with autosomal recessive inheritance.
Since TC2 synthesis had been demonstrated in cultured skin fibroblasts from normal patients, Li et al. (1994) studied skin fibroblasts from an affected child and his parents. They found that the affected child was a compound heterozygote with a gross deletion of the maternally derived allele and a 4-bp deletion in the coding region (613441.0001) of the paternally derived allele. Both of these deletions caused markedly reduced levels of TC2 mRNA and protein.
In 3 sisters with TCN2 deficiency who were previously reported by Bibi et al. (1999), Namour et al. (2003) identified a homozygous mutation in the TCN2 gene (613441.0003).
In 3 patients, including 2 sibs, with TCN2 deficiency, Haberle et al. (2009) identified 2 different homozygous mutations in the TCN2 gene (613441.0004 and 613441.0005, respectively).
Acklin, M., Frater-Schroder, M., Haller, O., Lundin, L. G., Prochazka, M., Skow, L. C. Localization of transcobalamin II (Tcn-2) on chromosome 11: linkage to waved-2 (wa-2) and the hemoglobin alpha-chain locus (Hba). Mouse News Lett. 70: 107-108, 1984.
Arrabal, M. C., Villegas, A., Mariscal, E., Lentijo, B., Luck, W., Hoffbrand, A. V. Transcobalamin II deficiency: long-term follow-up of two cases. Acta Haemat. 80: 162-166, 1988. [PubMed: 3143215] [Full Text: https://doi.org/10.1159/000205624]
Barshop, B. A., Wolff, J., Nyhan, A. L., Yu, A., Prodanos, C., Jones, G., Sweetman, L., Leslie, J., Holm, J., Green, R., Jacobsen, D. W., Cooper, B. A., Rosenblatt, D. Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin. Am. J. Med. Genet. 35: 222-228, 1990. [PubMed: 2309761] [Full Text: https://doi.org/10.1002/ajmg.1320350216]
Bibi, H., Gelman-Kohan, Z., Baumgartner, E. R., Rosenblatt, D. S. Transcobalamin II deficiency with methylmalonic aciduria in three sisters. J. Inherit. Metab. Dis. 22: 765-772, 1999. [PubMed: 10518276] [Full Text: https://doi.org/10.1023/a:1005507204491]
Burman, J. F., Mollin, D. L., Sourial, N. A., Sladden, R. A. Inherited lack of transcobalamin II in serum and megaloblastic anaemia: a further patient. Brit. J. Haemat. 43: 27-38, 1979. [PubMed: 508619] [Full Text: https://doi.org/10.1111/j.1365-2141.1979.tb03716.x]
Chanarin, I., Muir, M., Hughes, A., Hoffbrand, A. V. Evidence for intestinal origin of transcobalamin II during vitamin B12 absorption. Brit. Med. J. 1: 1453-1455, 1978. [PubMed: 647333] [Full Text: https://doi.org/10.1136/bmj.1.6125.1453]
Frater-Schroder, M. Genetic patterns of transcobalamin II and the relationships with congenital defects. Molec. Cell. Biochem. 56: 5-31, 1983. [PubMed: 6355816] [Full Text: https://doi.org/10.1007/BF00228765]
Haberle, J., Pauli, S., Berning, C., Koch, H. G., Linnebank, M. TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations. J. Hum. Genet. 54: 331-334, 2009. [PubMed: 19373259] [Full Text: https://doi.org/10.1038/jhg.2009.34]
Hakami, N., Neiman, P. E., Canellos, G. P., Lazerson, J. Neonatal megaloblastic anemia due to inherited transcobalamin II deficiency in two siblings. New Eng. J. Med. 285: 1163-1170, 1971. [PubMed: 5096637] [Full Text: https://doi.org/10.1056/NEJM197111182852103]
Hall, C. A. Congenital disorders of vitamin B12 transport and their contributions to concepts. II. Yale J. Biol. Med. 54: 485-495, 1981. [PubMed: 7342493]
Hitzig, W. H., Dohmann, U., Pluss, H. J., Vischer, D. Hereditary transcobalamin-II deficiency--clinical findings in a new family. J. Pediat. 85: 622-628, 1974. [PubMed: 4138209] [Full Text: https://doi.org/10.1016/s0022-3476(74)80503-2]
Hitzig, W. H., Kenny, A. B. The role of vitamin B12 and its transport globulins in the production of antibodies. Clin. Exp. Immun. 20: 105-111, 1975. [PubMed: 128427]
Hoffbrand, A. V., Tripp, E., Jackson, B. F. A., Luck, W. E., Frater-Schroder, M. Hereditary abnormal transcobalamin II previously diagnosed as congenital dihydrofolate reductase deficiency. (Letter) New Eng. J. Med. 310: 789-790, 1984. [PubMed: 6700662] [Full Text: https://doi.org/10.1056/nejm198403223101217]
Kaikov, Y., Wadsworth, L. D., Hall, C. A., Rogers, P. C. J. Transcobalamin II deficiency: case report and review of the literature. Europ. J. Pediat. 150: 841-843, 1991. [PubMed: 1743216] [Full Text: https://doi.org/10.1007/BF01955004]
Li, N., Rosenblatt, D. S., Kamen, B. A., Seetharam, S., Seetharam, B. Identification of two mutant alleles of transcobalamin II in an affected family. Hum. Molec. Genet. 3: 1835-1840, 1994. [PubMed: 7849710] [Full Text: https://doi.org/10.1093/hmg/3.10.1835]
Mayes, J. S., Say, B., Marcus, D. L. Prenatal studies in a family with transcobalamin II deficiency. (Letter) Am. J. Hum. Genet. 41: 686-687, 1987. [PubMed: 3661564]
Meyers, P. A., Carmel, R. Hereditary transcobalamin II deficiency with subnormal serum cobalamin levels. Pediatrics 74: 866-871, 1984. [PubMed: 6493881]
Namour, F., Helfer, A.-C., Quadros, E. V., Alberto, J.-M., Bibi, H. M., Orning, L., Rosenblatt, D. S., Jean-Louis, G. Transcobalamin deficiency due to activation of an intra exonic cryptic splice site. Brit. J. Haemat. 123: 915-920, 2003. [PubMed: 14632784] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04685.x]
Niebrugge, D. J., Benjamin, D. R., Christie, D., Scott, C. R. Hereditary transcobalamin II deficiency presenting as red cell hypoplasia. J. Pediat. 101: 732-735, 1982. [PubMed: 7131148] [Full Text: https://doi.org/10.1016/s0022-3476(82)80304-1]
Porck, H. J., Frater-Schroder, M., Frants, R. R., Kierat, L., Eriksson, A. W. Genetic evidence for fetal origin of transcobalamin II in human cord blood. Blood 62: 234-237, 1983. [PubMed: 6860794]
Rosenblatt, D. S., Hosack, A., Matiaszuk, N. Expression of transcobalamin II by amniocytes. Prenatal Diag. 7: 35-39, 1987. [PubMed: 3823005] [Full Text: https://doi.org/10.1002/pd.1970070107]
Sacher, M., Paky, F., Frater-Schroder, M. Vererbter Transcobalamin-II-Mangel: klinische, genetische Untersuchungen und Diagnose in der Fibroblastenkultur. Helv. Paediat. Acta 38: 549-558, 1983. [PubMed: 6668202]
Scott, C. R., Hakami, N., Teng, C. C., Sagerson, R. N. Hereditary transcobalamin II deficiency: the role of transcobalamin II in vitamin B12 dependent reactions in man. J. Pediat. 81: 1106-1111, 1972. [PubMed: 4643028] [Full Text: https://doi.org/10.1016/s0022-3476(72)80239-7]
Seger, R., Wildfeuer, A., Frater-Schroder, M., Linnel, J., Hitzig, W. H. Granulocyte dysfunction in transcobalamin II deficiency responding to leucovorin or hydroxocobalamin-plasma transfusion. J. Inherit. Metab. Dis. 3: 3-9, 1980. [PubMed: 6774168] [Full Text: https://doi.org/10.1007/BF02312515]
Seligman, P. A., Steiner, L. L., Allen, R. H. Studies of a patient with megaloblastic anemia and an abnormal transcobalamin II. New Eng. J. Med. 303: 1209-1212, 1980. [PubMed: 7421948] [Full Text: https://doi.org/10.1056/NEJM198011203032105]
Tauro, G. P., Danks, D. M., Rowe, P. B., Van der Weyden, M. B., Schwarz, M. A., Collins, V. L., Neal, B. W. Dihydrofolate reductase deficiency causing megaloblastic anemia in two families. New Eng. J. Med. 294: 466-470, 1976. [PubMed: 1060915] [Full Text: https://doi.org/10.1056/NEJM197602262940903]
Thomas, P. K., Hoffbrand, A. V., Smith, I. S. Neurological involvement in hereditary transcobalamin II deficiency. J. Neurol. Neurosurg. Psychiat. 45: 74-77, 1982. [PubMed: 7062075] [Full Text: https://doi.org/10.1136/jnnp.45.1.74]
Vance, G. H., Moncino, M., Heerema, N. A. Cytogenetic findings of a child with transcobalamin II deficiency. Am. J. Med. Genet. 46: 615-619, 1993. [PubMed: 8362900] [Full Text: https://doi.org/10.1002/ajmg.1320460602]
Zeitlin, H. C., Sheppard, K., Baum, J. D., Bolton, F. G., Hall, C. A. Homozygous transcobalamin II deficiency maintained on oral hydroxocobalamin. Blood 66: 1022-1027, 1985. [PubMed: 4052627]