Osteopetrosis

Two main forms of osteopetrosis have been delineated: a severe autosomal recessive form (OMIM 259700) with an incidence of ∼1/250,000 births and a mild autosomal dominant form (OMIM 166600) with an incidence of ∼1/20,000 births. Disturbances of osteoclast function due to mutations in a gene encoding an osteoclast-specific subunit of the vacuolar proton pump (TCIRG1) are found in most patients with the recessive form. Mutations of the gene encoding the chloride channel protein, CLCN7, are observed in the dominant form of osteopetrosis. Both types of mutations lead to disturbances of acidification needed for normal osteoclast function.

The severe form is usually detected in infancy or earlier because of macrocephaly, hepatosplenomegaly, deafness, blindness, and severe anemia. Radiographs reveal diffuse bone sclerosis. Later films show the characteristic bone-within-bone appearance (Fig. 690-1). With time, infants typically fail to thrive and show psychomotor delay and worsening of cranial neuropathies and anemia. Dental problems, osteomyelitis of the mandible, and pathologic fractures are common. The most severely affected patients die during infancy; less severely affected patients rarely survive beyond the 2nd decade. Those who survive beyond infancy usually have learning disorders but might have normal intelligence despite hearing and vision loss.

Figure 690-1 Lateral radiograph showing bone-in-bone appearance that is characteristic of osteopetrosis.

Pyknodysostosis

An autosomal recessive bone dysplasia, pyknodysostosis (OMIM 265800) manifests in early childhood with short limbs, characteristic facies, an open anterior fontanel, a large skull with frontal and occipital bossing, and dental abnormalities. The hands and feet are short and broad, and the nails may be dysplastic. The sclerae may be blue. Minimal trauma often leads to fractures. Treatment is symptomatic and focused mainly on the management of dental problems and fractures. The prognosis is generally good, and patients typically reach heights of 130-150 cm.

Skeletal radiographs show a generalized increase in bone density. In contrast to many disorders in this group, the metaphyses are normal. Other changes include wide sutures and wormian bones in the skull, a small mandible, and hypoplasia of the distal phalanges (Fig. 690-2).

Figure 690-2 Right hand radiograph, age 2 wk. Note metaphyseal lucent bands in the distal ulna and radius (arrows) and short tubular bones.

(From Stark Z, Savarirayan R: Osteopetrosis, Orphanet J Rare Dis 4:5, 2009.)

Several mutations have been found in the gene encoding cathepsin K, a cysteine protease that is highly expressed in osteoclasts. The mutations predict loss of enzyme function, suggesting that there is an inability of osteoclasts to degrade bone matrix and remodel bones.