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Autosomal recessive malignant osteopetrosis

Synonym(s) Infantile malignant osteopetrosis
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • Q78.2
  • C1318518
MeSH -
MedDRA -


Disease definition

Infantile malignant osteopetrosis is a rare congenital disorder of bone resorption characterised by generalised skeletal densification.


Incidence is estimated at 1/200 000 live births. Osteopetrosis has been reported in most ethnic groups, although, as the disease is very rare, it is more frequently seen in ethnic groups where consanguinity is common.

Clinical description

Bone marrow failure, fractures and visual impairment are the classical features of the disease, which begins in early infancy or in foetal life. It results from the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and to the clinical signs and symptoms of bone marrow failure. It is accompanied by hepatosplenomegaly due to compensatory extramedullary hematopoiesis. Impaired bone remodelling causes bony narrowing of the cranial nerve foramina, which results in cranial nerve (especially optic nerve) compression. Pathologically, there is a persistence of the primary spongiosa characterised by cores of calcified cartilage within bone. Abnormal remodelling of primary, woven bone to lamellar bone results in 'brittle' bone that is prone to fracture. A rare form of the disease is associated with severe central nervous system dysfunction.


The disease is heterogeneous. Over 50% of cases are due to mutations in the TCIRG1 gene and another 10% are due to mutations in the CLCN7 gene. A small number of patients have been described with mutations in the OSTM1 gene.

Diagnostic methods

The clinical and radiological features establish the diagnosis. A bone biopsy may be confirmatory but is not usually necessary.

Differential diagnosis

Infantile onset osteopetrosis should be distinguished from the much milder autosomal dominant adult disease and the carbonic anhydrase II deficiency syndrome, which is associated with renal tubular acidosis and less severe osteopetrosis.

Antenatal diagnosis

Prenatal diagnosis can be performed by ultrasound late in the second trimester although, if available, a molecular diagnosis is recommended as it can be performed earlier, through chorionic villus sampling at 11-13 weeks of gestation.

Genetic counseling

Transmission is autosomal recessive. Families should offered genetic counselling regarding the autosomal recessive nature of the disease.

Management and treatment

Patients may require blood transfusions, treatment for infections and management of their developmental and visual problems. Bone marrow transplant can alleviate many features of the disease but needs to be performed early to minimise optic nerve encroachment.


The prognosis is variable but improves if bone marrow transplant is performed early.

Expert reviewer(s)

  • Dr Callum WILSON

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