Osteopetrosis

At a glance

Heterogenous genetic disorder of bone metabolism characterized by deficient osteoclast function with defective bone resorption and increased bone mass. Depending on the mode of inheritance, its course can be either uniformly fatal with pancytopenia, recurrent pathologic fractures, blindness, and other neurologic symptoms, or it can exist in a much milder form with later manifestation and favorable prognosis.

Synonyms

Albers-Schönberg Disease; Autosomal Dominant Marble Bones; Osteosclerosis Fragilis Generalisata; Osteopetrosis Renal Tubular Acidosis; Osteopetrosis Resulting from Carbonic Anhydrase II Deficiency; Malignant Osteopetrosis; Autosomal Recessive Marble Bones; Autosomal Recessive Albers-Schönberg Disease.

History

First described by German radiologist and gynecologist Heinrich E Albers-Schönberg in 1903.

Incidence

1:100,000 to 500,000 live births for the autosomal dominant form and 1:200,000 live births for the autosomal recessive form.

Genetic inheritance

Exists in both autosomal recessive form (infantile or malignant osteopetrosis) and autosomal dominant form (benign osteopetrosis). The frequency of the two forms is about equal. The intermediate autosomal recessive and the X-linked are extremely rare.

Pathophysiology

The autosomal recessive form has two different subsets based on bone morphology: Osteoclast-rich and osteoclast poor. The responsible mutations have been identified for the osteoclast-rich as TCIRG1, CLCN7, OSTM1, SNX10, and PLEKHM1. These genes encode proteins that are critically involved in the acidification of resorption lacunae. Mutations in TNFSF11 and TNFRSF11A prevented osteoclastogenesis and lead to the osteoclast-poor subset. For the autosomal dominant form, the gene has been mapped to 16p13.3 (chloride channel 7 gene). The increased skeletal mass is the result of defective bone resorption, which is caused by failure of the (morphologically and numerically normal) osteoclasts to resorb the calcified cartilage during bone development. In addition, bone formation and enchondral ossification continue. This combination results in the typical dense radiologic appearance of the sclerotic bones. The microscopic finding of persistent primary spongiosa, which consists of calcified cartilage bars within the sclerotic bone, is considered pathognomonic. This process can occupy the majority of the medullary cavity and thereby affect bone marrow function and lead to extramedullary hematopoiesis with hepatosplenomegaly. The increased fragility of the bones is caused by a deficient remodeling of the architecture of the bone. Therefore, an inability to replace the woven bone by lamellar and mechanically more competent bone results.

Diagnosis

Based on radiographic findings and laboratory investigations revealing low serum calcium with secondary hyperparathyroidism and elevated serum phosphate and alkaline phosphatase concentrations.

Clinical aspects

Different forms of osteopetrosis have been described.

• Autosomal Recessive or Malignant or Infantile Osteopetrosis: Symptoms may be present in fetal life (with risk of stillbirth and spontaneous abortion) or manifest in early infancy. Initial presenting symptoms are failure to thrive with ...