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Fibrodysplasia ossificans Progressiva (FOP) Samantha He Medical Genetics 12/31/09.

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Presentation on theme: "Fibrodysplasia ossificans Progressiva (FOP) Samantha He Medical Genetics 12/31/09."— Presentation transcript:

1 Fibrodysplasia ossificans Progressiva (FOP) Samantha He Medical Genetics 12/31/09

2 A baffling and rare disease John Ferke of Saint Bartholomew’s Hospital, 1741: ‘ …They arise from all over the vertebrae of the neck and reach down to the sacrum; they likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of corals do, they make as it were, a fixed bony pair of bodice.’

3 General overview of FOP Soft connective tissue that progressively turn into bone Occurrence: 1 /2,000,000 ▫Regardless of gender and ethnicity 700 confirmed cases in the world, 285 known cases in U.S Misdiagnosis rate around 60%~80% ▫Cancer ▫Juvenile Firbromatosis Median age of survival: 45 years No cure

4 (Kaplan et al. 2008)

5 Genetics of FOP Discovered in 2006 Heritable in typical autosomal dominant pattern Low reproductive fitness Complete penetrance Phenotype: Heterotopic Ossificans (HO) ▫Heterotopic = misplaced Heterozygous point mutation on Activin Receptor IA (ACVR1) gene ▫Novel mutations cause atypical FOP

6 Cytogenic Location (“ACVR1,” n.d., Where is ACVR1 located, figure 1) 2q23-q24

7 (Feldman et al. 2000)

8 ACVR1 Also known as Activin receptor-like kinase-2 (ALK2) Gene ▫Codes for Activin receptor type 1 protein ACVR1 protein function ▫Controls and regulates growth of bones, muscles and ossification recruit and phosphorylate signaling molecules (Smad) ▫Signaled by bone morphogenic protein (BMP) ▫Effects growth and differentiation of cells Mutation: ▫Ligand dependent over responsiveness ▫Ligand independent leakiness

9 How AVCR1 works (Kaplan et al. 2008)

10 AVCR1 schematic diagram Typical mutation on AVCR1 Missense mutation at codon 206 of GS region (Shore et al. 2008)

11 ACVR1 schematic diagram Atypical mutations noted in FOP patients (Petrie et al. 2009) R = Arginine I = Isoleucine G= Glycine H= Histidine E=Glutamic Acid

12 Histological insight on FOP Transgenic mice enables researchers to study progressive growth of heterotrophic bone (Kan et al. 2004)

13 Phase I Local proliferation of fibroblast-like near muscle cells (Kan et al. 2004)

14 Phase II de novo blood vessels in connective tissue near dense fibromatic region (Kan et al. 2004)

15 Phase III Inner cells of new growth shows chondrocyte like morphology (Kan et al. 2004)

16 Phase IV Multifocal, central, and hypertrophic chondrocytes surrounded by high proliferating fibroblast like cells (Kan et al. 2004)

17 Clinical Features of FOP Malformed great toes in newborns HO mimics embryonic development ▫Axial  appendicular ▫Crainal  caudual ▫Proximal  distal Episodic HO ▫flare ups of tumor like swellings, soft tissue lesions transformed into bone  Skeletal muscle, tendons, joints, soft connective tissue, aponeuroses, fascia, ligaments ▫Smooth muscle and cardiac muscles are spared

18 Clinical Features of FOP Injury induced HO ▫Due to inflammatory response of cell proliferation Complications ▫Thoracic insufficiency syndrome ▫Heart failure ▫Severe weight loss

19 Clinical data (Lee. et al 2009)

20 Big toe malformation



23 Treatment Lifestyle changes ▫Injury prevention Caution involving medical procedures ▫Surgery is to be avoided ▫Intramuscular injections (includes local anesthesia) Drugs ▫Anti-inflammatory  Cortical steroids  only for major joints, jaws/mandible  Non steroidal anti inflammatory drugs ▫Anti-angiogenic ▫Aminobiphosphates – inhibits mineralization ▫Muscle relaxtant

24 Future Treatment? ACVR1/ALK2 signal transduction inhibitor ▫Monoclonal antibody against ACVR1/ALK2  Blocks receptor at cell surface (Kaplan et al. 2007)

25 (Yu et al. 2008) LDN-193189 inhibits activation of BMP signaling effectors (Smads)

26 FOP pregnancy High risk to both mother and child Complications for mother ▫Flare-ups during pregnancy and management ▫Breathing problems ▫Childbirth complications Complications for child ▫50% chance of inheriting FOP ▫Fetal distress because of poor blood supply ▫Premature

27 Differential diagnosis Progressive Osseous Heteroplasia (POH) ▫Genetic condition of progressive ossification ▫Differs from FOP  Does not have flare ups  Bones grows in skin and fat tissue ▫Bone growth spreads like a web  from skin down to subcutaneous tissue and muscles ▫Clinical sign: rice grain like particles under the skin ▫Differentiated from FOP during research ▫Mutation is on a different gene

28 Other mysteries of FOP Variable age of onset ▫Generally within 1-5 th year ▫Other cases: teens-late teens, adults Episodic HO that’s unpredictable ▫HO can stop for as long as 9 years or more Triggers of flare ups ▫Some major injury will not trigger HO, but sometimes even walking will trigger HO

29 End Quote “Doctors work in the light, but researchers work in the dark. As researchers, our job is to find the switch that can light up people’s lives for generations to come”

30 References Kan, L.X., Hu, M., Gomes, W.A., Kessler, J.A. (2004) Transgenic mice overexpressing BMP4 Develop Fibrodysplasia Ossificans Progressiva (FOP) Like Phenotype. Am J Pathol 165 (4): 1107-1115 Kaplan, F.S., Le Merrer, M., Glaser, D.L., Pignolo, R.J., Goldsby, R.E., et al. (2008) Fibrodysplasia Ossificans Progressiva. Best Pract Res Clin Rheumatol 22(1): 191-205. Kaplan, F.S., Xu, M.Q., Glaser, D.L., Collins, F., Connor, M., et al. (2008) Early Diagnosis of Fibrodysplasia Ossificans Progressiva. Pediatrics 121 (5): 1295-1300 Lee, D.Y., Cho, T.J., Lee, H.R., Park, M.S., Chung, C.Y., Choi, I.H. (2009) ACVR1 Gene Mutation in Sporadic Korean Patients with Fibrodysplasia Ossificans Progressiva. J Korean Med Sci 24: 433-7. doi: 10.3346/jkms.2009.24.3.433

31 References Petrie, K.A., Lee, W.H., Bullock, A.N., Pointon, J.J., Smith, R., et al. (2009) Novel Mutations in ACVR1 Results in Atypical Features in Two Fibrodysplasia Ossificans Progressiva Patients. PLoS ONE 4(3): e5005. doi: 10.1371/ Shore, E.M., Kaplan, F.S. (2008) Insights from a Rare Genetic Disorder of Extra-skeletal Bone Formation, Fibrodisplasia Ossificans Progressiva. Bone 43(3): 427-433. doi: 10.1016/j.bone.2008.05.013. Yu, P.B., Deng, D.Y., Lai, C.S., Hong, C.C., Cuny, G.D., et al. (2008) BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14: 1363-1369. ACVR1. (December, 21, 2009). Retrieved December 29, 2009, from Genetics Home Reference. Website:

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