recognizing genetically triggered aortopathy in...
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Recognizing Genetically Triggered Aortopathy in your practice and the implication it may have
Sherene Shalhub MD MPHAssociate Professor of Surgery
Director, Multidisciplinary Vascular Genetics ClinicDivision of Vascular Surgery, University of Washington
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DISCLOSURESherene Shalhub, MD, MPH
• No relevant financial relationship reported
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The eye doesn’t seen what the mind doesn’t knowPatient’s mother
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Recognizing Genetically Triggered Aortopathyin your practice
• The genetic landscape from a vascular surgeons' perspective
• The red flags that should make you take pause
• General management principles
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Connective Tissues Disorders
The landscape of genetically triggered aortopathies
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Connective Tissues Disorders
The landscape of genetically triggered aortopathies
Heritable Thoracic Aortic Disease (H-TAD) Genes
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Marfan
Loeys Dietz
Vascular Ehlers-Danlos
syndrome
ACTA2
MYH11
MYLK
PRKG1
TGF-βsignaling pathway
Aortic smooth
muscle cellsCollagen
The landscape of genetically triggered aortopathies
Heritable Thoracic Aortic Disease Genes
Hypermobility Spectrum disorders
Other Ehlers-Danlos syndrome subtypes
Connective Tissues Disorders
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Marfan
Loeys Dietz
Vascular Ehlers-Danlos
syndrome
ACTA2
MYH11
MYLK
PRKG1
TGF-βsignaling pathway
Aortic smooth
muscle cellsCollagen
The landscape of genetically triggered aortopathies
Heritable Thoracic Aortic Disease Genes
Syndromic and non-
syndromic
Hypermobility Spectrum disorders
Other Ehlers-Danlos syndrome subtypes
Connective Tissues Disorders
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Other Ehlers-Danlos syndrome subtypes
Hypermobility Spectrum disorders Marfan Vascular
Ehlers-Danlos
syndrome
ACTA2
MYH11
MYLK
PRKG1
TGF-βsignaling pathway
Aortic smooth
muscle cellsCollagen
The landscape of genetically triggered aortopathies
Heritable Thoracic Aortic Disease Genes
1:5,000
1:50,000
Connective Tissues Disorders
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Non-syndromic familial thoracic aneurysms and dissections (FTAAD)
have a pathogenic variant in an H-TAD gene
First or second degree relative with aortic aneurysms/dissections/sudden deaths10-30%
30%
De-Novo mutations50%
The landscape of genetically triggered aortopathies
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The red flags that should make you take pause
History Elements
Physical Exam findings
Imaging findings
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Cardiology
Family history
Age
UW experience in acute TBAD (2000-16)
N=227 Family history is obtainable
1 in 4 were genetically triggeredSyndromic: 8% (41+11 years)Familial: 15% (55+11 years)
History Elements
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History Elements
• Skin: easy bruising
• HEENT: lens dislocation, sleeps with eyes open
• Neuro: early stroke, intracranial aneurysms
• Pulm: spontaneous pneumothorax/hemothorax
• Cardiac: early coronary artery disease, coronary aneurysms, history of patent ductus arteriosus
• GI: prior intestinal perforation
• Heme: spontaneous retroperitoneal hematoma
• Musculoskeletal: scoliosis, pectus, club feet
• Hernias, poor wound healing
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History Elements: Marfan syndrome/TGFb Pathway
• Skin: easy bruising
• HEENT: lens dislocation, sleeps with eyes open
• Neuro: early stroke, intracranial aneurysms
• Pulm: spontaneous pneumothorax/hemothorax
• Cardiac: early coronary artery disease, coronary aneurysms, history of patent ductus arteriosus
• GI: prior intestinal perforation
• Heme: spontaneous retroperitoneal hematoma
• Musculoskeletal: scoliosis, pectus, club feet
• Hernias, poor wound healing
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History Elements: Vascular Ehlers-Danlos Syndrome
• Skin: easy bruising
• HEENT: lens dislocation, sleeps with eyes open
• Neuro: early stroke, intracranial aneurysms
• Pulm: spontaneous pneumothorax/hemothorax
• Cardiac: early coronary artery disease, coronary aneurysms, history of patent ductus arteriosus
• GI: prior intestinal perforation
• Heme: spontaneous retroperitoneal hematoma
• Musculoskeletal: scoliosis, pectus, club feet
• Hernias, poor wound healing
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Shalhub et al, J Vasc Surg, July 2014
Physical Exam Findings
Characteristic facial features in vascular Ehlers-Danlos syndrome: thin lips and philtrum, small chin, thin nose, large eyes, attached ear lobes
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Physical Exam Findings
Ecotpia lentis(Marfan Syndrome)
Arched palate(Marfan Syndrome)
Bifid uvula(Loeys Dietz Syndrome)
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Physical Exam Findings
Skin: Visible veins, soft velvety skin (vEDS)
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Musculoskeletal Findings
Scoliosis Pectus Deformity
Thumb Sign Wrist Sign
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Imaging Findings: Ascending Aorta
Aortic root and ascending aortic dilation/aneurysms
Loeys-Dietz syndrome
(TGFBR1) Familial Marfan syndrome
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Imaging Findings: Arterial Tortuosity
Marfan Syndrome LDS4 (TGFB2) vEDS (COl3A1)
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Imaging Findings: Unusual Arterial aneurysms and dissections
LDS3 (SMAD3)
vEDS (COL3A1) Marfan Syndrome (HI)
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Acute TBAD with rupture in a 56 year old man (No family history)
Imaging Findings: Radiologic Phenotype
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Early-onset varicose
veins: 15%Thin, translucent
skin: 49%
Tendon or
muscle rupture:
9%
Clubfoot: 9%
Characteristic facial
appearance: 31%
Small joints hypermobility: 41%
PTX/HTX: 14%
Physical findings in Vascular Ehlers-Danlos syndrome (N=86)
Easy
bruising:
64%
Journal of Vascular Surgery, 2019, in press
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Odertic
Shalhub, Genetic considerations in patients with aortic
disease Endovascular Aortic Repair, Oderich ed, 2017
Marfan
Syndrome
Loeys Dietz
Syndrome
Vascular Ehlers-Danlos
Syndrome
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Diagnostic testing centers (CDL, CTGT, Invitae, Prevention, Ambry,
Baylor, GeneDx)
Referral to Medical Genetics
• Pre-testing counseling
• 4-6 weeks turn around time
• Results Interpretation
• Not all variants are pathogenic
UW experience
• Pathogenic variant: 36%
• Variant of unknown significance: 12%
September 2018
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Mosaic for Platelet derived growth
factor receptor-b (PDGFRb)
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The clinical imperative of accurate diagnosisand management principles
• Knowing the diagnosis improves outcomes
• Operative planning/techniques
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Ascending aorta dimensions for
prophylactic root/ascending thoracic aortic
repair
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Acute (N=12)
Chronic (N=10)
Retrograde dissection 25% 0Reintervention 50% 40%Stent graft explantation
17% 20%
August 2018
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Fluoroquinolones
Avelox
(moxifloxacin)
Baxdela
(delafloxacin)
Cipro (ciprofloxacin)
Factive
(gemifloxacin)
Levaquin
(levofloxacin)
Generic ofloxacin
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Blood Pressure Control cannot be overstated!
Unchanged TBAD over 4 years with excellent hypertension control
(PRKG1(c.530G>A,p.Arg177Gln) Shalhub et al, JVS, March 2019
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Male, 31 ControlDeath or iliac artery rupture within 4 monthsof enrollment. Underwent open abdominal aortic repair then died from type A dissection
Male, 28 Control Hypogastric artery rupture
Female, 51
Control Spontaneous cerebral hematoma
Female, 38
ControlSpontaneous hematoma of psoas muscle with blood suffusion
Male, 25 Control Carotid dissection
Male, 28 Control Death or aortic dissection
Female, 24
Control Carotid dissection
Female, 34
Control Carotid-cavernous sinus fistula
Female, 31
Control Carotid-cavernous sinus fistula
Female, 42
Control Primitive iliac artery dissection
Male, 45 Control Sudden death after acute lumbar pain
Male, 19 CeliprololSudden death after acute chest pain radiatingto the right arm
Male, 19 Celiprolol Hemoptysis (recurrent)
Lancet, 2010
Accurate diagnosis is important for research design
87 individuals screened (2003-2006)
53 randomized(33 with confirmed
mutation)
Celiprolol group 13 with confirmed
mutation
Control group 20 with confirmed
mutation
1 death (8%) 3 deaths (15%)
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• The key to diagnosis is recognition
• Accurate diagnosis is an imperative
• Management principles: Holistic care
– Aggressive risk factor modification: Medication plan and lifestyle recommendations
– Surgical planning
– Precision medicine approach
– Don’t forget the family
• The future: Molecular vascular surgery
– understanding how the genotype affects the phenotype, natural history, and management outcomes
Management of Genetically Triggered Aortopathy and Arteriopathy