Autosomal recessive osteopetrosis

Last revised by Daniel J Bell on 15 Oct 2021

Infantile autosomal recessive osteopetrosis is a subtype of osteopetrosis, a bone disease of dysfunctional osteoclasts that results in the overgrowth of bone. It is a more severe form that tends to present earlier. Hence, it is referred to as "infantile" and "malignant" compared to its autosomal dominant mate.

The natural history of the condition means that by the age of 6 years, 70% of the affected will die 5. Most of the remainder have a very poor quality of life with death resulting by the age of ~10 years.

Presentation in this, the more severe form of osteopetrosis, maybe at birth. Indeed, children may be stillborn.

Those who survive childbirth present with general failure to thrive, bone marrow failure or characteristic facies. Clinical features include:

  • failure to thrive
  • cranial nerve entrapment (see below)
  • snuffling (nasal sinus architecture abnormalities)
  • hypercalcemia 4
  • pancytopenia (anemia, leukopenia and/or thrombocytopenia)
  • hepatosplenomegaly (extramedullary haemopoiesis)
  • intracerebral hemorrhage (thrombocytopenia)
  • lymphadenopathy
  • premature senile facies
  • dental caries

One of the commonest presentations is with ocular disturbance: failure to establish fixation, nystagmus or strabismus 4. The cause of these symptoms is compression of the cranial nerve roots because of foraminal overgrowth and hence, symptoms tend not to regress despite treatment. Other cranial nerves and foramina may be affected:

Both forms of osteopetrosis (autosomal recessive and autosomal dominant) are congenital abnormalities with localized chromosomal defects. In autosomal recessive osteopetrosis, the defect is located on chromosome 11q13.

There are defective osteoclast function and overgrowth of bone: which become thick, dense and sclerotic. However, their increased size does not improve their strength. Instead, their disordered architecture results in weak and brittle bones that result in multiple fractures with poor healing.

Patients generally have a weak and dense skeleton which may have multiple healed fractures. Metaphyseal splaying may also be apparent 5.

  • bone in bone appearance
  • mandible: characteristic triangular opacity representing calcification within the secondary condylar cartilage ossification center 2
  • defective dentition with incomplete enamel formation and/or caries
  • paranasal sinuses: poorly pneumatized (ethmoid sinuses least severely affected)
  • hypertelorism 2
  • calvaria: high-attenuation inner table, a broad, low-attenuation diploic space, and a less high-attenuation outer table
  • "hair-on-end" appearance: areas of increased hematopoietic activity 2
  • sclerotic bone demonstrated low signal intensity on both T1 and T2-weighted MR images; areas containing marrow have intermediate signal intensity

Not infrequently, children are stillborn and few survive beyond mid-life. Death is secondary to bone marrow failure with recurrent infection, massive hemorrhage or transformation to leukemia and its sequelae.

The only curative approach is allogeneic bone marrow transplantation. There are encouraging signs that the use of high dose, highly T-lymphocyte depleted, parental marrow or peripheral blood stem cell transplants can improve outcome for those lacking a family donor 4.

The prognosis for those who are not treated is poor, especially in children who have early visual and hematologic impairment 5.

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Cases and figures

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