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

DISCLOSURESherene Shalhub, MD, MPH

• No relevant financial relationship reported

The eye doesn’t seen what the mind doesn’t knowPatient’s mother

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

Connective Tissues Disorders

The landscape of genetically triggered aortopathies

Connective Tissues Disorders

The landscape of genetically triggered aortopathies

Heritable Thoracic Aortic Disease (H-TAD) Genes

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

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

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

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

The red flags that should make you take pause

History Elements

Physical Exam findings

Imaging findings

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

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

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

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

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

Physical Exam Findings

Ecotpia lentis(Marfan Syndrome)

Arched palate(Marfan Syndrome)

Bifid uvula(Loeys Dietz Syndrome)

Physical Exam Findings

Skin: Visible veins, soft velvety skin (vEDS)

Musculoskeletal Findings

Scoliosis Pectus Deformity

Thumb Sign Wrist Sign

Imaging Findings: Ascending Aorta

Aortic root and ascending aortic dilation/aneurysms

Loeys-Dietz syndrome

(TGFBR1) Familial Marfan syndrome

Imaging Findings: Arterial Tortuosity

Marfan Syndrome LDS4 (TGFB2) vEDS (COl3A1)

Imaging Findings: Unusual Arterial aneurysms and dissections

LDS3 (SMAD3)

vEDS (COL3A1) Marfan Syndrome (HI)

Acute TBAD with rupture in a 56 year old man (No family history)

Imaging Findings: Radiologic Phenotype

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

Odertic

Shalhub, Genetic considerations in patients with aortic

disease Endovascular Aortic Repair, Oderich ed, 2017

Marfan

Syndrome

Loeys Dietz

Syndrome

Vascular Ehlers-Danlos

Syndrome

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

Mosaic for Platelet derived growth

factor receptor-b (PDGFRb)

The clinical imperative of accurate diagnosisand management principles

• Knowing the diagnosis improves outcomes

• Operative planning/techniques

Ascending aorta dimensions for

prophylactic root/ascending thoracic aortic

repair

Acute (N=12)

Chronic (N=10)

Retrograde dissection 25% 0Reintervention 50% 40%Stent graft explantation

17% 20%

August 2018

Fluoroquinolones

Avelox

(moxifloxacin)

Baxdela

(delafloxacin)

Cipro (ciprofloxacin)

Factive

(gemifloxacin)

Levaquin

(levofloxacin)

Generic ofloxacin

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

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%)

• 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

Shalhub@uw.edu