Osteopetrosis, Autosomal recessive 2 (OPTB2)

(OMIM #259710)

Osteopetrosis, Autosomal recessive 2 is a genetic disease characterized by increased bone mass and density due to a failure in bone resorption. It is part of the group of autosomal recessive osteopetrosis, also called malignant infantile osteopetrosis (see OPTB1). This disease is caused by loss-of-function mutations of TNFSF11 gene, causing lack of biologically active Receptor activator of nuclear factor-kappaB-ligand (RANKL) in the mesenchymal lineage, including osteoblasts and stromal cells, leading to osteoclast‐poor form of autosomal recessive osteopetrosis.

Gene

TNFSF11 gene, 13q14.11 (OMIM gene/locus number *602642), encoding RANKL, the master osteoclastogenic cytokine produced mainly by osteoblasts and stromal cells in bone.

Phenotype

Intermediate form, osteoclast-poor, multiple fractures, increased bone density (sclerosis) and generalized high bone mass, diaphyseal sclerosis, genu valgum, dental defects (deciduous teeth retention, tooth crown malformation, dental caries), osteomyelitis of the mandible, mandibular prognathism, cranial hyperostosis, facial paralysis due to cranial nerve VII compression, normal intelligence, optic atrophy, early blindness, anemia, thrombocytopenia, pancytopenia, extramedullary hematopoiesis, hepatosplenomegaly.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Other resource

Osteopetrosis Society (OPETS)

References
  1. Pangrazio A, Cassani B, Guerrini MM, et al. RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations. J Bone Miner Res. 2012 Feb;27(2):342-51.
  2. Sobacchi C, Frattini A, Guerrini MM, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007 Aug;39(8):960-2.
  3. de Vernejoul MC, Kornak U. Heritable sclerosing bone disorders: presentation and new molecular mechanisms. Ann N Y Acad Sci. 2010 Mar;1192:269-77.
  4. Ihde LL, Forrester DM, Gottsegen CJ, et al. Sclerosing bone dysplasias: review and differentiation from other causes of osteosclerosis. Radiographics. 2011 Nov-Dec;31(7):1865-82.
  5. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  6. http://www.omim.org