Alternative titles; symbols
SNOMEDCT: 254122007; ORPHA: 2785; DO: 0110941;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q21.2 | Osteopetrosis, autosomal recessive 3, with renal tubular acidosis | 259730 | Autosomal recessive | 3 | CA2 | 611492 |
A number sign (#) is used with this entry because this form of autosomal recessive osteopetrosis (OPTB3) is caused by homozygous or compound heterozygous mutation in the gene encoding carbonic anhydrase II (CA2; 611492) on chromosome 8q21.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700).
Sly et al. (1972) described 3 sisters, aged 22, 17, and 15 years, born to normal unrelated North American parents, with a form of osteopetrosis distinct from both the malignant form (see OPTB1, 259700) and the benign autosomal dominant form (see OPTA1, 607634). The disorder was manifest in the first 2 years because of fractures. Other features were short stature, mental retardation, dental malocclusion, and visual impairment from optic nerve compression. Mild anemia in infancy improved later and radiographic features of osteopetrosis improved some at puberty. Serum acid phosphatase was elevated and electrolyte changes suggested mild tubular acidosis. Whyte et al. (1980) provided a definitive report of these sibs. During adolescence basal ganglion calcification developed in 2. Renal tubular acidosis (type I) was diagnosed in each in early adulthood. Electron microscopy of bone suggested that osteoclasts failed to form 'ruffled membranes' characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations.
Guibaud et al. (1972) described 2 brothers with renal tubular acidosis and mild osteopetrosis. The unaffected parents, from North Africa, were cousins. Ohlsson et al. (1980) observed the syndrome, which they referred to as marble brain disease, in children of 3 Saudi families. They had striking facial similarities and cerebral calcifications. Bourke et al. (1981) observed this syndrome in 2 Kuwaiti Bedouin sibs. One sib showed basal ganglion calcification and mental subnormality. The major clinical manifestation in both was periodic hypokalemic paresis.
Consanguinity was present in 9 of 12 pedigrees reported by Sly et al. (1985). More than half the known cases have been in families from Kuwait, Saudi Arabia, and North Africa. Ohlsson et al. (1986) described the findings in 4 new Saudi Arabian cases from 2 families, including the first description in a neonate. They reviewed the 17 previously reported cases. Cochat et al. (1987) added a case and reviewed the findings in 30 reported patients. Al Rajeh et al. (1988) described 2 affected sisters in a Saudi Arabian family.
Strisciuglio et al. (1990) described 3 affected Italian sibs, the offspring of first cousins once removed. They had osteopetrosis with fractures and severe mental retardation. Whereas most previous patients had a mixed (proximal and distal) renal tubular acidosis, these patients had only proximal tubular acidosis.
Aramaki et al. (1993) reported in detail the findings in 3 unrelated Japanese patients with CA II deficiency. Two of the 3 were born of first-cousin parents. All exhibited poor activity and poor appetite in the neonatal period and then developed psychomotor retardation. Two of them were diagnosed as having osteopetrosis at 10 months and 36 years of age, respectively, and the third as having osteomalacia at 28 years of age. All 3 had recurrent episodes of muscle weakness. Their parents exhibited approximately 50% normal levels of CA II activity in protein. The development of osteomalacia was considered to be related to the renal tubular acidosis.
Sly et al. (1983) were prompted to examine carbonic anhydrase (CA) in this disorder because sulfonamide inhibitors of CA can produce renal tubular acidosis and block the parathormone-induced release of calcium from bone. Although the relationship of CA deficiency to brain calcification was unclear, it was known that one CA, CA II, is present in brain and that CA inhibitors reduce CSF production and affect electric activity of the brain. CA II is the one of the 3 CAs that is expressed in both brain and kidney. Since it also is expressed in the red cell, Sly et al. (1983) could study CA II in this tissue of their patients; they found very low levels in affected persons and intermediate levels in obligatory heterozygotes. The results indicate a role of CA II in osteoclast function and bone resorption. The RTA in this disorder is a hybrid of a mild proximal and prominent distal type. CA II is the only cytosolic isozyme in the kidney. Red cell CA I (114800) has been found to be normal in distal RTA.
Fathallah et al. (1997) traced the origin of this disorder in 24 Tunisian families with CA II deficiency. All were descended from a common ancestor who emigrated from the Arabian Peninsula to North Africa in the 10th century.
Venta et al. (1990, 1991) sequenced the CA2 gene in a patient with osteopetrosis and renal tubular acidosis from the consanguineous Belgian family first described by Vainsel et al. (1972) and identified homozygosity for a missense mutation (H107Y; 611492.0004).
Roth et al. (1992) analyzed the molecular basis of carbonic anhydrase II deficiency in the American family in which the association of CA2 deficiency with a clinical syndrome was first recognized by Sly et al. (1972). The 3 affected sisters were found to be compound heterozygotes for a maternally inherited H107Y mutation (611492.0004) and a paternally inherited splice site mutation (611492.0005). Roth et al. (1992) suggested that residual activity of the H107Y mutant enzyme, demonstrated in expression studies in bacteria, might explain the absence of mental retardation and relatively mild phenotype in affected members of this family.
Hu et al. (1992) pointed out that of the 39 reported cases of carbonic anhydrase deficiency syndrome, 72% were patients from North Africa and the Middle East countries, most, if not all, of whom were of Arab descent. They showed that members of 6 unrelated Arab kindreds were in 5 instances homozygous and in 1 instance heterozygous for a splice site mutation in intron 3 of the CA2 gene (611492.0006). Called the 'Arabic mutation,' it introduces a new Sau3A1 restriction site useful in PCR-based diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of patients with the Arabic mutation from that of American and Belgian patients with the H107Y mutation.
In a 23-year-old Japanese woman previously reported by Aramaki et al. (1993) ('patient 1' of pedigree A) with carbonic anhydrase II deficiency, osteopetrosis, renal tubular acidosis, symmetrical cerebral calcification, and mental retardation, Soda et al. (1995) found a Y40X mutation in exon 2 of the CA2 gene resulting from a TAT-to-TAG transversion.
Soda et al. (1996) identified the H107Y mutation in 2 unrelated Japanese patients previously described by Aramaki et al. (1993), both born of consanguineous parents, who had osteopetrosis and renal tubular acidosis as well as severe mental retardation. The authors stated that the basis for the more severe expression of the H107Y mutation, including mental retardation, in Japanese patients was unclear.
Hu et al. (1997) identified 7 novel mutations in the CA2 gene in patients with osteopetrosis and mental retardation or developmental delay. All but 1 pair of Mexican sibs had renal tubular acidosis also.
Borthwick et al. (2003) described 2 consanguineous Turkish kindreds with distal RTA and osteopetrosis. In affected members of 1 kindred, the authors identified homozygosity for a frameshift mutation in the CA2 gene (611492.0008). The authors excluded defects in CA2 in the other kindred, in which the proband had RTA and osteopetrosis but his sister manifested only RTA with sensorineural hearing loss and never developed osteopetrosis. In this kindred, Borthwick et al. (2003) found that the osteopetrosis (259700) was the result of a homozygous deletion in the TCIRG1 gene (604592.0007), whereas the distal RTA with hearing loss (267300) was the result of a homozygous mutation in the ATP6V1B1 gene (192132.0005). Borthwick et al. (2003) concluded that coinheritance of these 2 rare recessive disorders created a phenocopy of CA2A deficiency in this kindred, and commented that this case illustrates the importance of clinical characterization of all affected members of a kindred.
Al Rajeh, S., El Mouzan, M. I., Ahlberg, A., Ozaksoy, D. The syndrome of osteopetrosis, renal acidosis and cerebral calcification in two sisters. Neuropediatrics 19: 162-165, 1988. [PubMed: 3221988] [Full Text: https://doi.org/10.1055/s-2008-1052422]
Aramaki, S., Yoshida, I., Yoshino, M., Kondo, M., Sato, Y., Noda, K., Jo, R., Okue, A., Sai, N., Yamashita, F. Carbonic anhydrase II deficiency in three unrelated Japanese patients. J. Inherit. Metab. Dis. 16: 982-990, 1993. [PubMed: 8127074] [Full Text: https://doi.org/10.1007/BF00711514]
Borthwick, K. J., Kandemir, N., Topaloglu, R., Kornak, U., Bakkaloglu, A., Yordam, N., Ozen, S., Mocan, H., Shah, G. N., Sly, W. S., Karet, F. E. A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J. Med. Genet. 40: 115-121, 2003. [PubMed: 12566520] [Full Text: https://doi.org/10.1136/jmg.40.2.115]
Bourke, E., Delaney, V. B., Mosawi, M., Reavey, P., Weston, M. Renal tubular acidosis and osteopetrosis in siblings. Nephron 28: 268-272, 1981. [PubMed: 7312081] [Full Text: https://doi.org/10.1159/000182216]
Cochat, P., Loras-Duclaux, I., Guibaud, P. Deficit en anhydrase carbonique II: osteopetrose, acidose renale tubulaire et calcifications intracraniennes. Revue de la literature a'partir de trois observation. Pediatrie 42: 121-128, 1987. [PubMed: 3112731]
Fathallah, D. M., Bejaoui, M., Lepaslier, D., Chater, K., Sly, W. S., Dellagi, K. Carbonic anhydrase II (CA II) deficiency in Maghrebian patients: evidence for founder effect and genomic recombination at the CA II locus. Hum. Genet. 99: 634-637, 1997. [PubMed: 9150731] [Full Text: https://doi.org/10.1007/s004390050419]
Guibaud, P., Larbre, F., Freycon, M. T., Genoud, J. Osteopetrose et acidose renale tubulaire. Deux cas de cette association dans une fratrie. Arch. Franc. Pediat. 29: 269-286, 1972. [PubMed: 4661410]
Hu, P. Y., Lim, E. J., Ciccolella, J., Strisciuglio, P., Sly, W. S. Seven novel mutations in carbonic acid anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. Hum. Mutat. 9: 383-387, 1997. [PubMed: 9143915] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5]
Hu, P. Y., Roth, D. E., Skaggs, L. A., Venta, P. J., Tashian, R. E., Guibaud, P., Sly, W. S. A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. Hum. Mutat. 1: 288-292, 1992. [PubMed: 1301935] [Full Text: https://doi.org/10.1002/humu.1380010404]
Ohlsson, A., Cumming, W. A., Paul, A., Sly, W. S. Carbonic anhydrase II deficiency syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 77: 371-381, 1986. [PubMed: 3081869]
Ohlsson, A., Stark, G., Sakati, N. Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. Dev. Med. Child Neurol. 22: 72-84, 1980. [PubMed: 7358236] [Full Text: https://doi.org/10.1111/j.1469-8749.1980.tb04307.x]
Roth, D. E., Venta, P. J., Tashian, R. E., Sly, W. S. Molecular basis of human carbonic anhydrase II deficiency. Proc. Nat. Acad. Sci. 89: 1804-1808, 1992. [PubMed: 1542674] [Full Text: https://doi.org/10.1073/pnas.89.5.1804]
Sly, W. S., Hewett-Emmett, D., Whyte, M. P., Yu, Y.-S. L., Tashian, R. E. Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc. Nat. Acad. Sci. 80: 2752-2756, 1983. [PubMed: 6405388] [Full Text: https://doi.org/10.1073/pnas.80.9.2752]
Sly, W. S., Lang, R., Avioli, L., Haddad, J., Lubowitz, H., McAlister, W. Recessive osteopetrosis: new clinical phenotype. (Abstract) Am. J. Hum. Genet. 24: 34A, 1972.
Sly, W. S., Whyte, M. P., Sundaram, V., Tashian, R. E., Hewett-Emmett, D., Guibaud, P., Vainsel, M., Baluarte, H. J., Gruskin, A., Al-Mosawi, M., Sakati, N., Ohlsson, A. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. New Eng. J. Med. 313: 139-145, 1985. [PubMed: 3925334] [Full Text: https://doi.org/10.1056/NEJM198507183130302]
Sly, W. S. The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic Basis of Inherited Disease. Vol. II. (6th ed.) New York: McGraw-Hill (pub.) 1989. Pp. 2857-2866.
Soda, H., Yukizane, S., Yoshida, I., Aramaki, S., Kato, H. Carbonic anhydrase II deficiency in a Japanese patient produced by a nonsense mutation (TAT-to-TAG) at tyr-40 in exon 2, (Y40X). Hum. Mutat. 5: 348-350, 1995. [PubMed: 7627193] [Full Text: https://doi.org/10.1002/humu.1380050415]
Soda, H., Yukizane, S., Yoshida, I., Koga, Y., Aramaki, S., Kato, H. A point mutation in exon 3 (his107-to-tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. Hum. Genet. 97: 435-437, 1996. [PubMed: 8834238] [Full Text: https://doi.org/10.1007/BF02267062]
Strisciuglio, P., Sartorio, R., Pecoraro, C., Lotito, F., Sly, W. S. Variable clinical presentation of carbonic anhydrase deficiency: evidence for heterogeneity? Europ. J. Pediat. 149: 337-340, 1990. [PubMed: 2107079] [Full Text: https://doi.org/10.1007/BF02171561]
Sundaram, V., Rumbolo, P., Grubb, J., Strisciuglio, P., Sly, W. S. Carbonic anhydrase II deficiency: diagnosis and carrier detection using differential enzyme inhibition and inactivation. Am. J. Hum. Genet. 38: 125-136, 1986. [PubMed: 3080873]
Vainsel, M., Fondu, P., Cadranel, S., Rocmans, C., Gepts, W. Osteopetrosis associated with proximal and distal tubular acidosis. Acta Paediat. Scand. 61: 429-434, 1972. [PubMed: 5041390] [Full Text: https://doi.org/10.1111/j.1651-2227.1972.tb15859.x]
Venta, P. J., Welty, R. J., Johnson, T. H., Tashian, R. E. Human carbonic anhydrase II deficiency syndrome in a Belgium family appears to be caused by a destabilizing amino acid substitution (107his-to-tyr). (Abstract) Am. J. Hum. Genet. 47 (suppl.): A168, 1990.
Venta, P. J., Welty, R. J., Johnson, T. M., Sly, W. S., Tashian, R. E. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107his-to-tyr): complete structure of the normal human CA II gene. Am. J. Hum. Genet. 49: 1082-1090, 1991. [PubMed: 1928091]
Whyte, M. P., Murphy, W. A., Fallon, M. D., Sly, W. S., Teitelbaum, S. L., McAlister, W. H., Avioli, L. V. Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. Am. J. Med. 69: 64-74, 1980. [PubMed: 7386510] [Full Text: https://doi.org/10.1016/0002-9343(80)90501-x]