Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva

Bravenboer, Nathalie; Micha, Dimitra; Triffit, James; Bullock, Alex N.; Ravazollo, Roberto; Bocciardi, Renata; Rocco, Maja Di; Netelenbos, J.C.; Dijke, Peter ten; Sánchez‐Duffhues, Gonzalo; Kaplan, F S; Shore, Eileen M.; Pignolo, Robert J.; Seemann, Petra; Ventura, Francesc; Beaujat, Genevieve; Eekhoff, Elisabeth M. W.; Pals, Gerard

doi:10.1038/ejhg.2014.274

Cited by 19 publications

(12 citation statements)

References 18 publications

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“…Clinical therapy is now limited to anti‐inflammatory drugs, radiation, or surgical excision of the already formed bone, which is associated with a higher recurrence rate (Dey et al , ; Eisenstein et al , ). In addition to trauma‐induced HO, fibrodysplasia ossificans progressiva (FOP) is a devastating congenital autosomal dominant disorder also involving HO (Bravenboer et al , ). Ectopic bones form progressively through endochondral ossification, mostly in episodic flare‐ups associated with trauma and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

et al. 2019

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Heterotopic ossification (HO) is the pathological formation of ectopic endochondral bone within soft tissues. HO occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). FOP patients carry a conserved mutation in ACVR1 that becomes neomorphic for activin A responses. Here, we demonstrate the efficacy of BYL719, a PI3Kα inhibitor, in preventing HO in mice. We found that PI3Kα inhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibition of PI3Kα also impairs skeletogenic responsiveness to BMPs and the acquired response to activin A of the Acvr1R206H allele. Further, the efficacy of PI3Kα inhibitors was evaluated in transgenic mice expressing Acvr1Q207D. Mice treated daily or intermittently with BYL719 did not show ectopic bone or cartilage formation. Furthermore, the intermittent treatment with BYL719 was not associated with any substantial side effects. Therefore, this work provides evidence supporting PI3Kα inhibition as a therapeutic strategy for HO.

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Section: Introductionmentioning

confidence: 99%

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

et al. 2019

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“…Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder causing progressive heterotopic ossification (HO) of muscles, tendons, and ligaments . The activating R206H mutation of the bone morphogenetic protein (BMP) type 1 receptor ACVR1 accounts for most of the classical FOP cases .…”

Section: Introductionmentioning

confidence: 99%

Flare‐Up After Maxillofacial Surgery in a Patient With Fibrodysplasia Ossificans Progressiva: An [¹⁸F]‐NaF PET/CT Study and a Systematic Review

et al. 2017

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons, and ligaments, which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable impact on her quality of life (QOL). The entire trismus history of this FOP patient is presented. [18F]‐NaF position emission tomography/computed tomography (PET/CT) scans were introduced as an imaging method for heterotopic bone formation activity. To place our findings into context, a systematic review on jaw surgery in FOP was performed. After falling down the stairs, a 9‐year‐old patient developed mobility impairment of her left‐sided jaw. During the following 13 years bone scintigraphy showed persistent activity of the disease leading to progressive left‐sided zygomatico‐mandibular fusion by HO, resulting in complete trismus. Within 1 month after HO removal on the left side and a matching right coronoidectomy, [18F]‐NaF PET/CT demonstrated a substantial flare‐up activity followed by new HO in both masseter and temporalis muscles. Despite recurrent HO and trismus her QOL increased due to a stable increased interincisal opening of 5.5 mm. Although systematic review reveals a 100% risk of HO recurrence after jaw surgery, information on improved QOL is scarce. In conclusion, surgery in FOP may be beneficial for QOL despite new HO formation. Assessment of disease activity using [18F]‐NaF PET/CT is possible before HO is evident on CT and may serve as a new and quantitative marker of the disease. © 2017 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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“…Fibrodysplasia ossificans progressiva (FOP) is a very rare autosomal inherited disorder caused by a mutation in the ACVR1/ALK2 gene (103). FOP is a clinical diagnosis, confirmed by genetic testing.…”

Section: Fibrodysplasia Ossificans Progressivamentioning

confidence: 99%

A Clinical Perspective on Advanced Developments in Bone Biopsy Assessment in Rare Bone Disorders

et al. 2020

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Introduction: Bone biopsies have been obtained for many centuries and are one of the oldest known medical procedures in history. Despite the introduction of new noninvasive radiographic imaging techniques and genetic analyses, bone biopsies are still valuable in the diagnosis of bone diseases. Advanced techniques for the assessment of bone quality in bone biopsies, which have emerged during the last decades, allows in-depth tissue analyses beyond structural changes visible in bone histology. In this review, we give an overview of the application and advantages of the advanced techniques for the analysis of bone biopsies in the clinical setting of various rare metabolic bone diseases. Method: A systematic literature search on rare metabolic bone diseases and analyzing techniques of bone biopsies was performed in PubMed up to 2019 week 34. Results: Advanced techniques for the analysis of bone biopsies were described for rare metabolic bone disorders including Paget's disease of bone, osteogenesis imperfecta, fibrous dysplasia, Fibrodysplasia ossificans progressiva, PLS3 X-linked osteoporosis, Loeys-Diets syndrome, osteopetrosis, Erdheim-Chester disease, and Cherubism. A variety of advanced available analytical techniques were identified that may help to provide additional detail on cellular, structural, and compositional characteristics in rare bone diseases complementing classical histopathology. Discussion: To date, these techniques have only been used in research and not in daily clinical practice. Clinical application of bone quality assessment techniques depends upon several aspects such as availability of the technique in hospitals, the existence of reference data, and a cooperative network of researchers and clinicians. The evaluation of rare metabolic bone disorders requires a repertoire of different methods, owing to their distinct bone tissue characteristics. The broader use of bone material obtained from biopsies could provide much more information about pathophysiology or treatment options and establish bone biopsies as a valuable tool in rare metabolic bone diseases.

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Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva

Cited by 19 publications

References 18 publications

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

Flare‐Up After Maxillofacial Surgery in a Patient With Fibrodysplasia Ossificans Progressiva: An [¹⁸F]‐NaF PET/CT Study and a Systematic Review

A Clinical Perspective on Advanced Developments in Bone Biopsy Assessment in Rare Bone Disorders

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Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva

Cited by 19 publications

References 18 publications

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

Flare‐Up After Maxillofacial Surgery in a Patient With Fibrodysplasia Ossificans Progressiva: An [18F]‐NaF PET/CT Study and a Systematic Review

A Clinical Perspective on Advanced Developments in Bone Biopsy Assessment in Rare Bone Disorders

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Flare‐Up After Maxillofacial Surgery in a Patient With Fibrodysplasia Ossificans Progressiva: An [¹⁸F]‐NaF PET/CT Study and a Systematic Review