Carbonic anhydrase II deficiency.

Carbonic anhydrase (CA) isoenzyme II deficiency--formerly called the syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification--is an autosomal recessive "inborn error of metabolism" that has disclosed important insight concerning osteoclast function. Nearly 50 cases have been described, predominantly from the Middle East and Mediterranean region. It is discovered late in infancy or early in childhood through developmental delay, short stature, fracture, weakness, cranial nerve compression, dental malocclusion, and/or mental subnormality. Typical radiographic features of osteopetrosis are present, and histopathologic study of the iliac crest reveals unresorbed calcified primary spongiosa. The radiographic findings are unusual, however, in that cerebral calcification appears by early childhood and the osteosclerosis and skeletal modeling defects may gradually resolve by adulthood. Patients are usually not anemic. A hyperchloremic metabolic acidosis, sometimes with hypokalemia, is caused by renal tubular acidosis that may be a proximal, distal, or combined type. Several different mutations within the CA II gene have been identified. There is no established medical therapy, and the long-term outcome remains to be characterized. Prenatal diagnosis has not been reported. Delineation of CA II deficiency establishes an important role in humans for CA II. The pathogenesis of the mental subnormality and cerebral calcification is poorly understood; however, CA II deficiency provides significant insight concerning CA II in renal regulation of acid/base homeostasis and osteoclast-mediated bone resorption.