Osteopetrosis

Abstract

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.

Figure 1

ADO: lateral spine radiograph, age 4 years. Note sclerosis of vertebral endplates (arrows) resulting in 'sandwich vertebrae' appearance.

Figure 2

Pycnodysostosis: Hand radiograph, age 3 years. Note acro-osteolysis in the distal phalanx of thumb and index fingers (arrows) and generalised increased bone density.

Figure 3

Pycnodysostosis: Lateral skull radiograph, age 3 years. Note loss of the mandibular angle (arrow) and increased thickness of vault.

Figure 4

Current model of the pathogenesis of osteopetrotic conditions in relation to normal osteoclast function, modified from Del Fattore et al [77] (ER: endoplasmic reticulum, ARO: autosomal recessive osteopetrosis, RTA: renal tubular acidosis).

Figure 5

ADO: Radiograph of left femur, age 4 years. Note Erlenmeyer flask deformity of distal femur (arrows) and generalised increased bone density.

Figure 6

Severe ARO: Right hand radiograph, age 2 weeks. Note metaphyseal lucent bands in the distal ulna and radius (arrows) and short tubular bones.