Osteopetrosis

Synonyms: marble bone disease, Albers-Schönberg's disease

What is osteopetrosis?¹

Osteopetrosis, or marble bone disease, was first described in 1904 by the German radiologist Albers Schönberg as a heritable disorder characterised by increased bone density (‘bone within bone’ appearance. The impaired equilibrium of bone formation and remodelling leads to structural brittleness, predisposition to fractures, skeletal deformities and dental abnormalities.

The disease is caused by defective osteoclast differentiation or function, but is clinically and genetically heterogeneous, ranging in severity from benign to lethal in early childhood. Based on the pattern of inheritance, osteopetroses have been categorised into:

• Autosomal recessive osteopetrosis (also known as infantile malignant osteopetrosis).²

• Autosomal dominant osteopetrosis, which is an adult-onset more benign form.³

How common is osteopetrosis? (Epidemiology)

Osteopetrosis has an estimated incidence of 1 in 250,000 newborns in the autosomal recessive form and 1 in 20,000 in the autosomal dominant form.⁴

Genetics

Autosomal recessive osteopetrosis²

Autosomal recessive osteopetrosis is primarily caused by homozygous or compound heterozygous mutation in the TCIRG1 subunit of the vacuolar proton pump on chromosome 11q13. Other forms of autosomal recessive infantile malignant osteopetrosis include:

• Mutations in the CLCN7 gene on chromosome 16p13, and mutations in the OSTM1 gene on chromosome 6q21.

• A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14.

• An intermediate form is caused by mutation in the PLEKHM1 gene on chromosome 17q21.

• A severe osteoclast-poor form associated with hypogammaglobulinaemia is caused by mutation in the TNFRSF11A gene on chromosome 18q22.

• Another form is caused by mutation in the SNX10 gene on chromosome 7p15.

• A form of autosomal recessive osteopetrosis associated with renal tubular acidosis is caused by mutation in the CA2 gene on chromosome 8q21.

• Another form is caused by mutation in the SLC4A2 gene on chromosome 7q36.

Autosomal recessive osteopetrosis

• Autosomal dominant osteopetrosis-1 is caused by heterozygous mutation in the LRP5 gene on chromosome 11q13.⁵

• Autosomal dominant osteopetrosis-2 (accounts for 70% of cases of autosomal dominant osteopetrosis) is caused by heterozygous mutation in the CLCN7 gene on chromosome 16p13.³

Presentation

Severe (autosomal recessive) osteopetrosis¹

• Severe symptoms, including growth retardation, skull abnormalities (macrocephaly, frontal bossing, choanal stenosis), hydrocephalus, hypocalcaemia (defective calcium mobilisation activity of osteoclasts) and abnormal tooth eruption.

• Nerve compression may cause blindness and deafness.
  The abnormal bone density causes an expansion of skeletal tissue into marrow cavities at the expense of the bone marrow, leading to severe anaemia, bleeding, frequent infections and hepatosplenomegaly due to increased extramedullary haematopoiesis. The limited bone marrow also causes the circulation of high numbers of haematopoietic stem and progenitor cells.

• The increased susceptibility to infections leads to the development of dental caries and facial osteomyelitis, especially after dental surgery.

Mild osteopetrosis

• This ranges from asymptomatic and discovered incidentally on X-ray to multiple fractures of both the long bones and the small bones of the hands and feet, with mild anaemia.

• Patients may present with osteoarthritis or osteomyelitis.⁶

• Rarely, a more severe form produces nerve compression with deafness and blindness.

Differential diagnosis

• Myelofibrosis.

• Renal glomerular osteodystrophy.

• Inherited hypophosphataemia.

• Fluorosis in adults.

• Hypoparathyroidism.

• Pseudohypoparathyroidism.

• Lead toxicity.

Investigations

• Diagnosis is made by X-rays which are usually diagnostic:⁷
  

  • Generalised osteosclerosis; bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in the iliac wings and near the ends of long bones.

  • Bones may be club-like or appear like a bone within bone.

  • The entire skull is thickened and dense, especially at the base.

  • Sinuses are small.

  • Vertebrae are very radiodense and may show alternating bands (rugger-jersey sign).

  • There may be evidence of fractures or osteomyelitis.

  • Severe osteopetrosis:
    

    • Characteristic changes ('Erlenmeyer flask deformity' of the metaphyses) on X-ray.

  • Mild osteopetrosis:
    

    • X-ray shows generalised increase in bone density and clubbing of metaphyses.

    • In vertebral bodies, alternating lucent and dense bands cause a sandwich-like appearance.

• CT scans may occasionally be required and the use of MRI tends to be limited to imaging of the marrow in the severe, recessive disease, which is usually fatal without marrow transplantation.⁷

• In severe osteopetrosis, the plasma calcium is reduced, and acid phosphatase and calcitriol are raised.

• Genetic testing, which allows for disease confirmation, appropriate management, and assessment of prognosis, as well as for genetic counselling and prenatal diagnosis.⁴

Associated diseases

Deficiency of carbonic anhydrase can cause petrosis associated with renal tubular acidosis, cerebral calcification, growth failure and severe learning difficulties.

Osteopetrosis treatment and management

Autosomal recessive osteopetrosis¹

Because osteoclasts originate from haematopoietic precursors, haematopoietic stem cell transplantation (HSCT) is the therapy of choice, resulting in improved bone remodelling and reversal of pancytopenia and extramedullary haematopoiesis.

• However, HSCT is effective only in cases of intrinsic osteoclast defects and is not recommended for osteopetrosis caused by absent osteoclasts due to mutation in TNFSF11.

• In cases of CNS involvement, such as in osteopetrosis caused by mutations in CLCN7 and OSTM1, which are associated with primary neuropathy, HSCT is proven to be ineffective and contraindicated.

• Intermediate osteopetrosis, comprising both severe dominant forms with an early onset and recessive ones without CNS involvement, have a better prognosis and are candidates for HSCT.

• For this reason, extensive neurological evaluation by CT or MRI and electroencephalography are required, especially in patients carrying unknown mutations in the CLCN7 gene.

In intermediate- and late-onset forms, HSCT may pose greater risks than benefits. When HSCT is not indicated or adequate donors are lacking, patients are empirically treated and receive conservative care based on multi-disciplinary approaches, according to clinical manifestations. These interventions may include calcium and vitamin D supplementation, corticosteroids, antimicrobial therapy, orthopaedic surgery, neurosurgery, transfusions and pain management.

Autosomal dominant osteopetrosis

Adult osteopetrosis requires no treatment unless complications arise which do require treatment. No specific medical treatment exists for the adult type. Management is mainly focused on correcting complications and improving the quality of life. The gene defects have not yet been identified.⁸ Management of complications includes treatment of fractures, and joint replacements.⁶

Complications

Autosomal recessive osteopetrosis causes severe morbidity, including:¹

• Bone marrow failure, with severe anaemia, bleeding and infections.

• Growth restriction and failure to thrive.

Prognosis

• Without treatment, autosomal recessive osteopetrosis is lethal in 70% of cases. Death is usually within the first decade of life due to severe anaemia, bleeding or infection.¹

• Adults with osteopetrosis are usually asymptomatic and have good long-term survival rates.