Osteopetrosis, Autosomal Dominant 1

A number sign (#) is used with this entry because of evidence that autosomal dominant osteopetrosis-1 (OPTA1) is caused by heterozygous mutation in the LRP5 gene (603506) on chromosome 11q13.

Description

The osteopetroses are a heterogeneous group of genetic disorders characterized by increased bone density due to impaired bone resorption by osteoclasts. Autosomal dominant osteopetrosis-1 is characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate (summary by Van Hul et al., 2002).

Genetic Heterogeneity of Autosomal Dominant Osteopetrosis

Autosomal dominant osteopetrosis-2 (OPTA2; 166600) is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13. Autosomal dominant osteopetrosis-3 (OPTA3; 618107) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21.

Clinical Features

Andersen and Bollerslev (1987) suggested that autosomal dominant osteopetrosis has 2 distinct radiologic types. Both have universal osteosclerosis, but in type I, the most striking finding is pronounced sclerosis of the cranial vault while the spine is almost unaffected; in type II, the sclerosis of the skull is most pronounced at the base, the vertebrae always have endplate thickening, and in the pelvis, the iliac wings contain convex arcs of sclerotic bone. Age and sex distribution did not differ between the types and each 'bred true' within given families. Bollerslev and Mosekilde (1993) found that bone resorption appears to be defective and bone formation normal in both types of patients. The frequency of fractures is increased in type II patients and normal in type I patients, in whom biomechanical investigations have shown normal or even increased trabecular bone strength.

Bollerslev and Andersen (1988) distinguished type I and type II on the basis of review of the radiographs of 34 patients with autosomal dominant osteopetrosis. Serum phosphate was lower in type I compared to II (P less than 0.01), and serum acid phosphatase was markedly increased in type II (P less than 0.01), suggesting differences between the 2 types in bone mineral metabolism and structural functions of the osteoclasts. No endplate thickening of the spine and no endobones ('bone within a bone') in the pelvis are seen in type I. This type presents as a fully penetrant disorder, compared with type II where the penetrance has been estimated at 60 to 80% (Van Hul et al., 2002).

Mapping

By linkage analysis in 2 Danish families with type I autosomal dominant osteopetrosis, Van Hul et al. (2002) assigned the disease-causing gene to 11q12-q13. A summated maximum lod score of 6.54 was obtained with marker D11S1889, and key recombinants allowed delineation of a candidate region of 6.6 cM.

Molecular Genetics

Van Wesenbeeck et al. (2003) identified a mutation in the LRP5 gene in the Danish families with type I autosomal dominant osteopetrosis used by Van Hul et al. (2002) to map the phenotype to 11q12-q13 (see 603506.0018); they also identified other affected individuals with LRP5 mutations.

Janssens and Van Hul (2002) reviewed the process of bone remodeling and the genetic defects resulting in aberrant bone formation and resorption.