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Transcript
Diseases of the
microfibril/elastic fiber
system
Juan Pablo Olano M.D.
Associate Professor
Director, Residency Training Program
Member, Center for Biodefense and Emerging
Infectious Diseases
UTMB, 2010
Microfibril/elastic fiber system
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Extracellular matrix of every organ
Abundant in organs subject to mechanical stress
Elastin: Core protein. Fibrillin directs deposition
of tropoelastin during development
Microfibrils: Unbranching chains sheathing the
elastin core. Fibrillin 1 and 2. Fibrillin 3 recently
described. 2 and 3 preferentially expressed in
embryonic development.
Microfibrils can be present without elastin
• Biomechanical anchors in basement membranes and
areas of repeated mechanical stress.
Microfibril (non-fibrillin) associated
proteins
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MAGP-1
MAGP-2
MFAP3-4
AAAP-40
Fibulin
BMP
Proteoglycans (perlecan, decorin,
versican)
Genetic disorders of the elastic
fiber system

Elastin gene
• Supravalvular aortic stenosis
• Autosomal dominant cutis laxa

FBN1, TGFβR1 and TGFβ2:
• Marfan’s syndrome and related disorders:
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Neonatal Marfan syndrome
Isolated ectopia lentis
Loeys-Dietz syndrome
Familial and non-syndromic thoracic aortic aneurysms and
dissections.
Shprintzen-Goldberg craniosynostosis syndrome
Weill-Marchesani syndrome
FBN2
• Congenital contractural arachnodactyly (Beals
syndrome)
Fibrillin 1

Multi-domain protein
• EGF-like motif with a conserved calcium
binding sequence.
• Latent TGFβ binding protein motif.
• Fib motif
• Mutations present in all three domains.
• nMFS associated with mutations in
exons 24-32.
• No other correlations exist
TGF-β
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Cell proliferation, differentiation
Apoptosis
ECM formation
TGF-β1 abundant in ECM. Cysteine rich.
Secreted as homodimeric proprotein
• Dimeric propeptide or Latency associated
polypeptide (LAP) and growth factor
• LAP is bound to Latent TGF β binding proteins
(LTBP) forming large latent complex or LLC
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LTBP play an important role in folding, secreting and
targeting TGF β in ECM. Also cysteine rich.
LTBP-1 interacts with fibrillin-1 (stabilizer).
Marfan’s syndrome

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Autosomal dominant inherited disease that
affects the microfibril/elastic fiber system
and involves several organ systems
including the heart, aorta, skeleton and
the eye. Clinical presentation is extremely
pleiotropic.
Incidence: 2-3/10,000 population
Mutations
• 1/3: Shortened molecules and decay
• 2/3: Binding domains: Protein-protein
interations, calcium binding domains.
Genetics
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1991: Mutations in FBN1. High
penetrance.
25% of cases are the index case:
New mutations in the egg or sperm
of parents.
>600 mutations described (most
missense).
Fibrillin: 350 kDa glycoprotein. 230
kb. 65 exonsChromosome 15q21
Genetics

MFS type 2 (MFS locus 2):
• TGFβR1 and TGFβR2
• Described in 1993 in a French cohort
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Caused by TGFβR2
Cardiovascular and skeletal findings. Not ocular.
Difficult to differentiate from Loeys-Dietz syndrome
Loeys-Dietz syndrome
• Described in 2005
• Aortic aneurysms, hypertelorism, bifid uvula,
cleft palate, arterial tortuosity.
• TGFβR1 and 2.
Genetics

Familial thoracic aortic aneurysms and
dissections
• Described in 2005
• FBN1, TGFβR1 and 2.
• Overlap with Loeys-Dietz syndrome (arterial
tortuosity).

Shprintzen-Goldberg syndrome
• Craniosynostosis, marfanoid skeletal
abnormalities and developmental delay.
• FBN1 and TGFβR1
Genetics

TGFβR1 and 2 are associated with
severe vascular manifestations
• Aneurysms at early age and distant
aneurysms
Other related disorders
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MASS phenotype and familial mitral
valve prolapse: Myopia, minimal
aortic dilation, subtle skeletal
changes, skin stria.
Familial tall stature
Contractural arachnodactyly
Marfan Syndrome:Clinical
manifestations

Cardiovascular
• Dilation of ascending aorta
• Dissection of aorta (30-45% deaths in
Marfan’s syndrome).
• Mitral valve prolapse (more frequent
than aortic lesions).
• Dilation of pulmonary artery

Pulmonary system:
• Blebs, spontaneous pneumothorax
Clinical manifestations (cont)

Skeletal system
• Pectus excavatum/carinatum
• Hypermobility
• Scoliosis
• Reduced upper/lower extremity ratios
• Pes planus
• Long tapering fingers and toes
• Dolichocephaly
Clinical manifestations (cont)

Ocular
• Ectopia lentis
• Flat cornea
• Hypoplastic iris
• Increased axial length of ocular globe
Clinical manifestations (cont)
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Integumentary system:
• Skin striae.
• Hernias
Marfan Syndrome. Hemopericardium
Marfan Syndrome. Aortic tear
Marfan Syndrome. Aortic tear
Marfan Syndrome. Aortic dissection
Marfan Syndrome. “Floppy” Mitral Valve
Thanks for your attention