Fibrodysplasia ossificans Progressiva (FOP) Samantha HeMedical Genetics 12/31/09

A baffling and rare diseaseJohn 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.’

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

(Kaplan et al. 2008)

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

Cytogenic Location

(“ACVR1,” n.d., Where is ACVR1 located, figure 1)

• 2q23-q24

(Feldman et al. 2000)

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

How AVCR1 works

(Kaplan et al. 2008)

AVCR1 schematic diagram

•Typical mutation on AVCR1•Missense mutation at codon 206 of GS

region

(Shore et al. 2008)

ACVR1 schematic diagram• Atypical mutations

noted in FOP patients

(Petrie et al. 2009)

R = Arginine I = Isoleucine G= Glycine H= Histidine E=Glutamic Acid

Histological insight on FOP • Transgenic mice enables researchers to study

progressive growth of heterotrophic bone

(Kan et al. 2004)

Phase I • Local proliferation of

fibroblast-like near muscle cells

(Kan et al. 2004)

Phase II •de novo blood vessels in connective tissue

near dense fibromatic region

(Kan et al. 2004)

Phase III•Inner cells of new

growth shows chondrocyte like morphology

(Kan et al. 2004)

Phase IV•Multifocal,

central, and hypertrophic chondrocytes surrounded by high proliferating fibroblast like cells

(Kan et al. 2004)

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

Clinical Features of FOP•Injury induced HO

▫Due to inflammatory response of cell proliferation

•Complications ▫Thoracic insufficiency syndrome ▫Heart failure ▫Severe weight loss

Clinical data

(Lee. et al 2009)

Big toe malformation

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

Future Treatment?

•ACVR1/ALK2 signal transduction inhibitor ▫Monoclonal

antibody against ACVR1/ALK2 Blocks receptor

at cell surface

(Kaplan et al. 2007)

(Yu et al. 2008)

• LDN-193189 inhibits activation of BMP signaling effectors (Smads)

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

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

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

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”

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

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/journal.phone.005005

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: http://ghr.nlm.nih.gov/gene=acvr1