Fibrodysplasia ossificans Progressvia

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Transcript Fibrodysplasia ossificans Progressvia

Fibrodysplasia ossificans
Progressiva (FOP)
Samantha He
Medical Genetics
12/31/09
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.’
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
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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
• 2q23-q24
(“ACVR1,” n.d., Where is ACVR1 located, figure 1)
(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)
• LDN-193189
inhibits
activation of
BMP
signaling
effectors
(Smads)
(Yu et al. 2008)
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