Osteopoikilosis/ Buschke-Ollendorff syndrome (BOS)

(OMIM phenotype number #166700)

Buschke-Ollendorff syndrome is an autosomal dominant connective tissue disorder, characterized by multiple subcutaneous nevi or nodules (elastin-rich, elastoma, or collagen-rich, dermatofibrosis lenticularis disseminata, on histologic examination). Affected individuals also have osteopoikilosis. Osteopoikilosis is a disorder of endochondral ossification involving the secondary spongiosa. This disease literally means "spotted bones", which are osteosclerotic foci occurring in the epimetaphyseal region of long bones, such as wrist, foot, ankle, pelvis, and scapula. X rays show numerous small round or oval foci of osteosclerosis, as an incidental radiological finding. They may mimic metastatic lesions, but radionuclide accumulation is not increased on bone scans. Most reported cases of Buschke-Ollendorff syndrome and Osteopoikilosis are benign. The disease can be  asymptomatic, or associated with skin manifestations. In some patients, melorheostosis can be present, characterized by asymmetric linear hyperostosis of the cortex of long bones, reminiscent of dripping candle wax, often associated with joint contractures, sclerodermatous skin lesion, muscle atrophy, hemangiomas, and limphedema. Inactivating mutations in the LEMD3 gene have been described. LEMD is a protein binding the inner nuclear membrane, which antagonizes TGF-β and bone morphogenic protein (BMP) signalling, resulting in focal deposits of compact lamellar bone in the spongiosa that have the appearance of an enostosis, or bone island. Multiple enostoses are laid down at the ends of short tubular bones, in the tarsal, carpal, and pelvic bones, and in the meta-epiphyseal regions of long bones.

Gene

LEMD3 gene, 12q14.3 (OMIM gene/locus number *607844)

Phenotype

Asymptomatic, disseminated connective tissue nevi with both elastic-type nevi (juvenile elastoma) and collagen type nevi (dermatofibrosis lenticularis disseminate), subcutaneous nontender firm nodules, subcutaneous connective tissue nevi, osteosclerotic foci in epimetaphyseal regions of long bones (wrist, foot, ankle, pelvis, and scapula), stiff joints, melorheostosis, typically affect diaphyses (less common).

Image

Fig. Anteroposterior radiograph of the left shoulder showing multiple osteopoikilosis lesions, best visible in the left humerus

Reproduced by permission from Macmillan Publishers Ltd: Nat Genet 2004 Nov;36:1213-8, copyright 2004.

References

  1. Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004 Nov;36(11):1213-8.
  2. De Vernejoul MC, Kornak U. Heritable sclerosing bone disorders: presentation and new molecular mechanisms. Ann N Y Acad Sci. 2010 Mar;1192:269-77.
  3. 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.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Nov;26(11):2717-8.
  5. http://www.omim.org