Osteopetrosis, autosomal dominant 1 (OPTA1)

LRP5 related high bone density phenotypes

Hyperostosis corticalis generalisata, benign form of worth, with torus palatinus or endosteal hyperostosis (MIM 144750) is an autosomal dominant disorder caused by mutations in the LDL receptor-related protein 5 (LRP5) gene. The main findings include cortical thickening of the long bones and progressive enlargement of the mandible with decreased gonial angle and the development of torus palatinus. The long bones are not altered in shape but are resistant to fractures. The torus palatinus may lead to malocclusion and tooth loss. The skeleton is usually normal in childhood and the patients are of normal height and proportion. During adolescence the face begins to flatten and the mandibular and palate changes occur. Increased density of the calvarium may be evident on radiographs.

Osteopetrosis, autosomal dominant 1 (OPTA1; MIM 607634) is characterized by diffuse osteosclerosis with pronounced involvement of cranial bones. The cranial vault may be enlarged and a conductive hearing loss may be present. OPTA1 is not associated with an increased fracture rate. OPTA1 is caused by gain of function mutations in the gene encoding the LDL receptor-related protein 5 (LRP5). See also osteopetrosis, autosomal dominant 2 (OPTA2; MIM 166600) caused by mutations in the CLCN7 gene.

Van Buchem disease, type 2 (VBCH2; MIM 607636) is an autosomal dominant, high bone density disorder caused by mutations in the LDL receptor-related protein 5 (LRP5) gene. Clinical features include an enlarged mandible, increased calvarial thickness, cranial osteosclerosis and thickened cortices of long bones. The clinical findings in VBCH2 are similar to those in hyperostosis corticalis generalisata. It has been suggested that these high bone density disorders represent a continuum. The detection of a shared LRP5 mutation in patients with VBCH2 and hyperostosis corticalis generalisata indicates that this is indeed the case. It should be noted that an autosomal recessive variant of Van Buchem disease is recognized. Patients with autosomal recessive Van Buchem disease are more severely affected and present with facial nerve palsies.