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Osteologie 2018; 27(04): 215-221
DOI: 10.1055/s-0038-1676925
Seltene Knochenerkrankungen – Rare bone diseases
Georg Thieme Verlag KG Stuttgart · New York

Fibrodysplasia Ossificans Progressiva – FOP

Fibrodysplasia Ossificans Progressiva – FOP
L. Seefried
1   Klinische Studieneinheit, Orthopädische Klinik König-Ludwig-Haus, Universität Würzburg
,
R. Morhart
2   Abtlg. für Kinder- und Jugendmedizin am Klinikum Garmisch- Partenkirchen
,
O. Semler
3   Klinik für Kinder- und Jugendmedizin, Uniklinik Köln
› Author Affiliations
Further Information

Publication History

received: 23 October 2018

accepted: 06 November 2018

Publication Date:
10 January 2019 (online)

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Zusammenfassung

Bei der Fibrodysplasia ossificans progressiva (FOP) besteht aufgrund einer aktivierenden Mutation im Gen für den Activin A Rezeptor Typ 1 (ACVR1 / ALK2), eine Prädisposition zu heterotoper Knochenbildung in Weichgeweben, insbesondere der Muskulatur. Die Prävalenz der Erkrankung wird in einer Größenordnung von 1 pro 1–2 Mio. angegeben. Klinisch kommt es intrauterin zu Fehlbildungen, z. B. zu einem bds. Hallux valgus, der bei der überwiegenden Mehrheit der Patienten bereits bei Geburt besteht. Postnatal kommt es meist in den ersten Lebensjahren beginnend im Schulter-/ Nackenbereich episodenartig bereits nach kleineren Verletzungen zu schmerzhaften Weichteilreaktionen, sogenannten flareups die nachfolgend im Sinne einer enchondralen Ossifikation verknöchern. Die Akkumulation dieser irreversiblen Verknöcherungen im Weichgewebe bedingt eine zunehmende Einschränkung der Beweglichkeit bis hin zur kompletten Einsteifung des Körpers. Letztlich kommt es durch die fortschreitende Rigidität des Thorax zu einer respiratorischen Insuffizienz und kardialer Dekompensation.

Therapeutisch steht im Vordergrund die Vermeidung von Traumata als Auslöser für die Entstehung extraossären Knochengewebes, insbesondere auch der Verzicht auf unnötige iatrogene Schädigungen durch Operationen, Biopsien und intramuskuläre Injektionen. Supportiv sind eine adäquate Hilfsmittelversorgung, psychologische Unterstützung und eine analgetische Versorgung erforderlich. Im Falle eines Traumas werden kurzfristig hochdosiert Glucocorticoide empfohlen, um das Risiko und Ausmaß der flare-ups und nachfolgender Verknöcherungen zu reduzieren. Ergänzend können NSAR hilfreich sein. Derzeit werden unterschiedliche neue Therapieansätze entwickelt. Am weitesten fortgeschritten ist dabei der Retinolsäure Rezeptor Gamma (RARg) Agonist Palovarotene, der durch Interferenz mit der ALK2 vermittelten Signalkaskade einen zentralen Punkt im Pathomechanismus der Erkrankung adressiert.

Summary

Fibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation in the Activin- Rezeptor 1 (ACVR1 / ALK2) Gene on Chromosome 2q23–24. Associated increased activity of the receptor predisposes to the development of heterotopic ossifications in the connective tissue, particularly in the muscles. The prevalence of the disorder is estimated to range between 1 in 1–2 Mio persons. At the time of birth, the only hallmark of the disease is a characteristic malformation of the great toe. During childhood, affected patients episodically develop painful soft tissue reactions, so-called flare-ups, marked by inflammation and swelling upon minor trauma. Subsequently these lesions form bone structures within the soft tissues by means of endochondral ossification. Typically, first lesions occur in the proximal, cranial, dorsal regions of the body, i. e. around the shoulder and the neck. Ossifications are irreversible and accumulate over time in the soft tissues, thereby progressively limiting patients’ mobility. Increasing limitations of chest expansion eventually compromise respiratory capacity, promote the risk for pneumonia and right-sided heart failure.

Therapeutic approaches focus on preventing additional trauma and interventions that might trigger additional heterotopic ossification, including avoidance of iatrogenic interventions like operations, biopsies and intramuscular injections. Supportive care comprises psychologic counseling, provision with appropriate technical tools as well as analgesic treatment, preferentially using NSAIDs. In case of a trauma, short term treatment with high doses of glucocorticoids is recommended in order to reduce the risk and extension of flare-ups and subsequent ossifications. Currently various novel therapeutic approaches are being evaluated. Among these, the retinoic acid receptor gamma (RARg) agonist Palovarotene is most advance in development. By binding to RARg, Palovarotene directly targets and interferes with the ALK2 induced signaling cascade considered a central aspect of the pathomechanism of the disease.

Schlüsselwörter

Fibrodysplasia ossificans progressiva - Myositis ossificans progressiva - Heterotope Ossifikationen - kongenitaler Hallux valgus - Flare-up

Keywords

Fibrodysplasia ossificans progressiva - myositis ossificans progressiva - heterotopic ossifications - kongenital hallux valgus - flare-up
 

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