Diseases of the Diseases of the microfibril/elastic fiber microfibril/elastic fiber

systemsystem

Juan Pablo Olano M.D.Juan Pablo Olano M.D.ProfessorProfessor

UTMB, 2012UTMB, 2012

Microfibril/elastic fiber systemMicrofibril/elastic fiber system Extracellular matrix of every organExtracellular matrix of every organ Abundant in organs subject to mechanical stressAbundant in organs subject to mechanical stress Elastin: Core protein. Fibrillin directs deposition of Elastin: Core protein. Fibrillin directs deposition of

tropoelastin during developmenttropoelastin during development Microfibrils: Unbranching chains sheathing the Microfibrils: Unbranching chains sheathing the

elastin core. Fibrillin 1 and 2. Fibrillin 3 recently elastin core. Fibrillin 1 and 2. Fibrillin 3 recently described. 2 and 3 preferentially expressed in described. 2 and 3 preferentially expressed in embryonic development.embryonic development.

Microfibrils can be present without elastinMicrofibrils can be present without elastin• Biomechanical anchors in basement membranes and Biomechanical anchors in basement membranes and

areas of repeated mechanical stress.areas of repeated mechanical stress.

Microfibril (non-fibrillin) associated Microfibril (non-fibrillin) associated proteinsproteins

MAGP-1MAGP-1 MAGP-2MAGP-2 MFAP3-4MFAP3-4 AAAP-40AAAP-40 FibulinFibulin BMPBMP Proteoglycans (perlecan, decorin, Proteoglycans (perlecan, decorin,

versican)versican)

Genetic disorders of the elastic Genetic disorders of the elastic fiber systemfiber system

Elastin geneElastin gene• Supravalvular aortic stenosisSupravalvular aortic stenosis• Autosomal dominant cutis laxaAutosomal dominant cutis laxa

FBN1, TGFFBN1, TGFββR1 and TGFR1 and TGFββ2:2:• Marfan’s syndrome and related disorders:Marfan’s syndrome and related disorders:

Neonatal Marfan syndromeNeonatal Marfan syndrome Isolated ectopia lentisIsolated ectopia lentis Loeys-Dietz syndromeLoeys-Dietz syndrome Familial and non-syndromic thoracic aortic aneurysms and Familial and non-syndromic thoracic aortic aneurysms and

dissections.dissections. Shprintzen-Goldberg craniosynostosis syndromeShprintzen-Goldberg craniosynostosis syndrome Weill-Marchesani syndromeWeill-Marchesani syndrome

FBN2FBN2• Congenital contractural arachnodactyly (Beals Congenital contractural arachnodactyly (Beals

syndrome)syndrome)

Fibrillin 1Fibrillin 1 Multi-domain proteinMulti-domain protein

• EGF-like motif with a conserved calcium EGF-like motif with a conserved calcium binding sequence.binding sequence.

• Latent TGFLatent TGFββ binding protein motif. binding protein motif. • Fib motifFib motif• Mutations present in all three domains.Mutations present in all three domains.• nMFS associated with mutations in nMFS associated with mutations in

exons 24-32. exons 24-32. • No other correlations existNo other correlations exist

TGF-TGF-ββ Cell proliferation, differentiationCell proliferation, differentiation ApoptosisApoptosis ECM formationECM formation TGF-TGF-ββ1 abundant in ECM. Cysteine rich.1 abundant in ECM. Cysteine rich. Secreted as homodimeric proproteinSecreted as homodimeric proprotein

• Dimeric propeptide or Latency associated Dimeric propeptide or Latency associated polypeptide (LAP) and growth factorpolypeptide (LAP) and growth factor

• LAP is bound to Latent TGF LAP is bound to Latent TGF ββ binding proteins binding proteins (LTBP) forming large latent complex or LLC(LTBP) forming large latent complex or LLC

LTBP play an important role in folding, secreting and LTBP play an important role in folding, secreting and targeting TGF targeting TGF ββ in ECM. Also cysteine rich. in ECM. Also cysteine rich.

LTBP-1 interacts with fibrillin-1 (stabilizer).LTBP-1 interacts with fibrillin-1 (stabilizer).

Marfan’s syndromeMarfan’s syndrome Autosomal dominant inherited disease that Autosomal dominant inherited disease that

affects the microfibril/elastic fiber system affects the microfibril/elastic fiber system and involves several organ systems and involves several organ systems including the heart, aorta, skeleton and including the heart, aorta, skeleton and the eye. Clinical presentation is extremely the eye. Clinical presentation is extremely pleiotropic. pleiotropic.

Incidence: 2-3/10,000 populationIncidence: 2-3/10,000 population MutationsMutations

• 1/3: Shortened molecules and decay1/3: Shortened molecules and decay• 2/3: Binding domains: Protein-protein 2/3: Binding domains: Protein-protein

interations, calcium binding domains. interations, calcium binding domains.

GeneticsGenetics 1991: Mutations in FBN1. High 1991: Mutations in FBN1. High

penetrance.penetrance. 25% of cases are the index case: 25% of cases are the index case:

New mutations in the egg or sperm New mutations in the egg or sperm of parents. of parents.

>600 mutations described (most >600 mutations described (most missense).missense).

Fibrillin: 350 kDa glycoprotein. 230 Fibrillin: 350 kDa glycoprotein. 230 kb. 65 exons. Chromosome 15q21kb. 65 exons. Chromosome 15q21

GeneticsGenetics MFS type 2 (MFS locus 2):MFS type 2 (MFS locus 2):

• TGFTGFββR1 and TGFR1 and TGFββR2R2• Described in 1993 in a French cohortDescribed in 1993 in a French cohort

Caused by TGFCaused by TGFββR2R2 Cardiovascular and skeletal findings. Not ocular.Cardiovascular and skeletal findings. Not ocular. Difficult to differentiate from Loeys-Dietz syndromeDifficult to differentiate from Loeys-Dietz syndrome

Loeys-Dietz syndromeLoeys-Dietz syndrome• Described in 2005Described in 2005• Aortic aneurysms, hypertelorism, bifid uvula, Aortic aneurysms, hypertelorism, bifid uvula,

cleft palate, arterial tortuosity.cleft palate, arterial tortuosity.• TGFTGFββR1 and 2.R1 and 2.

GeneticsGenetics Familial thoracic aortic aneurysms and Familial thoracic aortic aneurysms and

dissectionsdissections• Described in 2005Described in 2005• FBN1, TGFFBN1, TGFββR1 and 2.R1 and 2.• Overlap with Loeys-Dietz syndrome (arterial Overlap with Loeys-Dietz syndrome (arterial

tortuosity).tortuosity). Shprintzen-Goldberg syndromeShprintzen-Goldberg syndrome

• Craniosynostosis, marfanoid skeletal Craniosynostosis, marfanoid skeletal abnormalities and developmental delay. abnormalities and developmental delay.

• FBN1 and TGFFBN1 and TGFββR1R1

GeneticsGenetics TGFTGFββR1 and 2 are associated with R1 and 2 are associated with

severe vascular manifestationssevere vascular manifestations• Aneurysms at early age and distant Aneurysms at early age and distant

aneurysmsaneurysms

Other related disordersOther related disorders MASS phenotype and familial mitral MASS phenotype and familial mitral

valve prolapse: Myopia, minimal valve prolapse: Myopia, minimal aortic dilation, subtle skeletal aortic dilation, subtle skeletal changes, skin stria. changes, skin stria.

Familial tall statureFamilial tall stature Contractural arachnodactylyContractural arachnodactyly

Marfan Syndrome:Clinical Marfan Syndrome:Clinical manifestationsmanifestations

CardiovascularCardiovascular• Dilation of ascending aortaDilation of ascending aorta• Dissection of aorta (30-45% deaths in Dissection of aorta (30-45% deaths in

Marfan’s syndrome).Marfan’s syndrome).• Mitral valve prolapse (more frequent Mitral valve prolapse (more frequent

than aortic lesions).than aortic lesions).• Dilation of pulmonary arteryDilation of pulmonary artery

Pulmonary system:Pulmonary system:• Blebs, spontaneous pneumothoraxBlebs, spontaneous pneumothorax

Clinical manifestations (cont)Clinical manifestations (cont) Skeletal systemSkeletal system

• Pectus excavatum/carinatumPectus excavatum/carinatum• HypermobilityHypermobility• ScoliosisScoliosis• Reduced upper/lower extremity ratiosReduced upper/lower extremity ratios• Pes planusPes planus• Long tapering fingers and toesLong tapering fingers and toes• DolichocephalyDolichocephaly

Clinical manifestations (cont)Clinical manifestations (cont) OcularOcular

• Ectopia lentisEctopia lentis• Flat corneaFlat cornea• Hypoplastic irisHypoplastic iris• Increased axial length of ocular globeIncreased axial length of ocular globe

Clinical manifestations (cont)Clinical manifestations (cont) Integumentary system:Integumentary system:

• Skin striae.Skin striae.• HerniasHernias

Marfan Syndrome. HemopericardiumMarfan Syndrome. Hemopericardium

Marfan Syndrome. Aortic tearMarfan Syndrome. Aortic tear

Marfan Syndrome. Aortic tearMarfan Syndrome. Aortic tear

Marfan Syndrome. Aortic dissection Marfan Syndrome. Aortic dissection

Marfan Syndrome. “Floppy” Mitral ValveMarfan Syndrome. “Floppy” Mitral Valve

Thanks for your attentionThanks for your attention