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Fibrodysplasia ossificans Progressiva (FOP)

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Presentation on theme: "Fibrodysplasia ossificans Progressiva (FOP)"— Presentation transcript:

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

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 ACVR1 is a receptor  to BMP molecule (the signal)

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

7 This diagram demonstrates heritability in typical Autosomal dominant pattern
An affected child will have an affected parent and so on until the source of mutation is found Each pregnancy is an individual event so families will seem to have different ratios but the chances for any child is still 50/50 (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 Ossification of cartilage occurs normally from birth to maturity

9 How AVCR1 works (Kaplan et al. 2008)
ACVR1 receptor normally inactive until binding of extracellular BMP (Bone morphogenetic protein) Extra cellular BMP binding at GS domain (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) GS= glycine-serine rich domain 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) Inner cells of new growth shows chondrocyte like morphology

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

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 TIS= loss of chest wall mobility

19 Clinical data (Lee. et al 2009)

20 Big toe malformation Pictures might make you uncomfortable



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

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 GNAs1 is present in almost every cell

28 Other mysteries of FOP Variable age of onset
Generally within 1-5th 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): 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): 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): 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: doi: /jkms

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: / Shore, E.M., Kaplan, F.S. (2008) Insights from a Rare Genetic Disorder of Extra-skeletal Bone Formation, Fibrodisplasia Ossificans Progressiva. Bone 43(3): doi: /j.bone 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: ACVR1 . (December, 21, 2009). Retrieved December 29, 2009, from Genetics Home Reference. Website:

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