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Q1: What are the radiological and biochemical features and the diagnosis of this case?
The computed tomogram shows extensive cerebral calcification (fig 1; see p358), and the radiograph shows the dense osteosclerosis (fig 2; see p358) that is characteristic of osteopetrosis. Biochemical investigations show hypokalaemia, hyperchloraemia, low bicarbonate levels, and a low arterial pH in association with a high urinary pH, indicating distal renal tubular acidosis. The diagnosis is carbonic anhydrase II (CA II) deficiency syndrome, which is characterised by the triad of osteopetrosis, intracranial calcification, and renal tubular acidosis.1 Intracranial calcification and renal tubular acidosis distinguish CA II deficiency from classical varieties of osteopetrosis. Also, severe anaemia, a common finding in classical osteopetrosis, is absent or very mild in CA II deficiency.1
CA II deficiency is a rare autosomal recessive disorder attributed to mutations of the CA II isoenzyme gene (chromosome 8).1,2 CA II is the most catalytically active as well as the most widely distributed isoenzyme of the CA series. CA II is important for acid-base regulation as well as bone resorption.3 The latter function is mediated by its effects on osteoclast function: it enables H+ pump activity, which helps the osteoclast in secreting acid that helps to dissolve bone mineral as well as digest bone matrix. Therefore, in CA II deficiency, bone resorption is markedly affected, leading to osteopetrosis. The raised serum acid phosphatase levels are attributed to defective osteoclast activity. A similar deficiency in acid excretion by the kidney may explain renal tubular acidosis. The reason for cerebral calcification is presently unclear. Children usually present with mental subnormality, short stature, and involvement of lower cranial nerves (due to sclerosis of skull base). As this is an inherited condition, family members also need to be investigated if molecular studies are readily available.
Q2: What are the radiological features of this disorder?
Skeletal radiography in CA II deficiency reveals findings indistinguishable from classical osteopetrosis—that is, a generalised increase in bone density; hence the term “marble bone disease”. Skull radiographs typically show a thick dense cranium with basal osteosclerosis and under-pneumatisation of the paranasal and mastoid sinuses. Another well described radiological feature of osteopetrosis is the appearance of alternating dense and lucent bands in the long bones and skull, which occurs due to a fluctuating skeletal growth.1 However, in CA II deficiency, osteosclerosis can spontaneously diminish. Cerebral calcification involving the cortex and the basal ganglia on computed tomography may appear at about 2–5 years of age.1
CA II deficiency is an atypical variant of classical osteopetrosis and is characterised by renal tubular acidosis and cerebral calcification.
Radiological features of osteopetrosis include uniformly dense, sclerotic bones; alternating dark and lucent bands have also been described.
Children with CA II deficiency syndrome present with growth failure, asymptomatic cerebral calcification, and osteopetrosis.
The disorder is compatible with long life.
Bone marrow transplantation may improve osteopetrosis, but does not reverse acidosis; hence alkali supplementation is required.
Q3: What are the treatment options and prognosis of this disorder?
Bicarbonate supplementation is the mainstay of treatment, but the long term outcome of therapy is not known. Bone marrow transplantation may improve the skeletal disorder,4 but not the renal defect.1 A low calcium, high phosphate diet may be useful in this disorder. CA II deficiency is reportedly compatible with long life.
Carbonic anhydrase II deficiency syndrome.