Osteopetrose

Zusammenfassung

Unter der Diagnose Osteopetrose wird eine heterogene Gruppe von seltenen monogenetischen Knochenerkrankungen zusammengefasst, die sich durch eine reduzierte Osteoklasten-Aktivität, eine gesteigerte Knochenmasse und eine gesteigerte Knochenbrüchigkeit auszeichnet. Die Osteopetrosen werden verursacht durch Mutationen in verschiedenen Genen, die in der Osteoklastogenese oder Osteoklasten-Funktion involviert sind. Durch den Verlust der Knochenresorption werden Knochenumbau und -neubildung beeinträchtigt, wodurch sich die Qualität und Architektur des Knochengewebes verschlechtert. Häufige klinische Zeichen sind Osteosklerose, Knochendeformitäten, hämatologische Insuffizienzen durch Verengung der Knochenmarkräume, Sehstörungen durch Verengung der Foramina nervi optici und andere neurologische Störungen. Bis auf eine X-chromosomale Form sind alle infantilen schweren Osteopetrosen autosomal rezessiv vererbt. Die rezessiven Formen verlaufen gewöhnlich ohne Behandlung tödlich im Säuglings- oder Kindesalter, wobei allerdings selten mildere klinische Verläufe als sog. Intermediäre Osteopetrose vorkommen. Die dominante Form ist assoziiert mit Mutationen im CLCN7-Gen und verläuft in der Regel milder. Die meisten schweren Osteopetrosen können durch eine allogene hämatopoetische Stammzelltransplantation (HSZT) behandelt werden, sofern sie Osteoklasten-autonome Ursachen haben und nicht mit einer primären neurologischen Komponente verbunden sind.

Summary

The diagnosis osteopetrosis comprises a heterogenous group of rare monogenetic bone diseases with the common features of reduced osteoclast activity, increased bone mass and high bone fragility. Osteopetroses are caused by mutation in a variety of genes involved in osteoclastogenesis or osteoclast function. Loss of bone resorption prevents bone remodeling and impaired bone quality causing pathological fractures. The clinical manifestation is rather heterogenous, but common clinical signs are increased bone density in X-rays, bone deformities, haematological insufficiencies due to narrowed bone marrow cavities, visual impairment due to the compression of nervi optici and other neurological symptoms. The diseases are autosomal, with only one extremely rare form which show X-chromosomal inheritance. Recessive osteopetroses are usually lethal in infancy or early childhood, with rarely occurring milder forms clinically named intermediate osteopetroses. Dominant osteopetrosis is caused by mutations in the CLCN7 gene and usually shows a benign clinical course with rare exceptions clinically resembling intermediate osteopetrosis with a reduced quality of life and sometimes also reduced life expectancy. Severe osteopetroses caused by osteoclast autonomous defects can be treated by hematopoietic stem cell transplantation (HSCT). Patients should be treated by this invasive procedure as soon as possible to prevent severe disabilities and sequelae. Also some patients with intermediate osteopetroses may be candidates for HSCT but neither Osteopetrosis due to deficiency of the pro-osteoclastogenic cytokine RANKL nor neurodegenerative osteopetroses caused by all mutation in OSTM1 and about half of the mutation in CLCN7 are suitable for HSCT. Novel therapeutic strategies are necessary to treat these forms.

Schlüsselwörter

Stammzelltransplantation - Anämie - Thrombozytopenie - Osteoklasten - Blindheit

Keywords

Stem cell transplantation - anaemia - thrombocytopenia - osteoclasts - blindness

• Literatur

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