Costello Syndrome Family Network Conference

Orlando, Florida July 31-August 2, 2013

THE HEART of

COSTELLO SYNDROME

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FIRST, THANKS TO YOU

Angela E. Lin, MD, FAAP, FACMG

lin.angela@mgh.harvard.edu

Clinical Professor of Pediatrics

Harvard Medical School

Genetics Unit, MassGeneral Hospital for Children

MA DPH, Birth Defects Research & Prevention

Co-Director,

Professional Advisory Committee

Costello Syndrome Family Network 3

Kathryn Chatfield, MD

kathryn.chatfield@ucdenver.edu

Instructor of Pediatrics

University of Colorado School of Medicine

Director of Cardiac Genetics Clinic

Children’s Hospital Colorado

New member of the Costello PAC

Dr. Lin:

• Trained in pediatric cardiology (UCLA

1983-85), board certified, not practicing

and genetics.

• Longterm research interest in the

“heart of syndromes”.

• “Your cardiologist knows more about

your heart though I know more about

the heart of Costello”

• Role in the CSFN:

- “clearinghouse” for families with heart

problems

- Research collaborator with Dr. Gripp

in the natural history study, ending role.

- Doctor availability (who, where, what)

- Advocate for care

* Avoid management of specific cases

at the meeting

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Dr. Chatfield:

• Trained in peds/genetics (CHOP,

2006-10), and ped cardiology

(Children’s Hospital Colorado/UCD

2010-2013), boarding in clinical

genetics and pediatric cardiology.

• Research interest in inherited forms of

cardiomyopathy, how the heart uses

energy

• “Your cardiologist knows more about

your heart though I know more about

genetic syndromes unfamiliar to most

cardiologists (Rasopathies)” - Will become the research collaborator

with Dr. Gripp in the natural history

study

- Doctor availability (who, where, what),

advocate for care

- Discuss therapy with your physicians

who can call her

* Avoid management of specific cases

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TYPES OF HEART PROBLEMS: In general

(1) Structure: Congenital heart defects

(2) Muscle: Cardiomyopathy (thick, thin)

(3) Rhythm: Arrhythmia (fast, slow, irregular))

(4) Blood vessel: Aorta

(5) Atherosclerosis (coronary arteries)

(6) Pericarditis (sac surrounding the heart)

GOALS FOR THIS TALK

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REVIEW (Dr. L) Structure of the normal heart

INDIVIDUAL (Dr. L)

1. Congenital heart defects

2. Cardiomyopathy (HCM)

3. Tachycardia

4. Aorta

TREATMENT (Dr. C) HCM: Outflow obstruction and CHF, medical

management, myectomy

Arrhythmias: Medications, Devices

Transplantation: Costello and Rasopathy, in

general

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NEWBIES? PROS?

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THE HEART IS LIKE A HOUSE

UPSTAIRS

Right Atrium Left Atrium

Dividing wall = Atrial Septum

SWINGING

DOORS

Tricuspid Valve

Mitral Valve

DOWNSTAIRS

Right Ventricle

Left Ventricle

Dividing Wall = Ventricular Septum

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AORTA

arch

SUPERIOR

VENA CAVA

RIGHT PULMONARY

ARTERY

LEFT

PULM ONARY

ARTERY

INFERIOR

VENA CAVA

AORTA

descending

LEFT

PULMONARY

VEINS RIGHT

PULMONARY

VEINS

Left

Ventricle Aortic

Valve

Mitral

Valve

Left

Atrium

Right

Atrium

Tricuspid

Valve

Right

Ventricle

PULM ONARY

ARTERY

PLUMBING: BLOOD VESSELS

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PIPES GOING IN

From the body Superior vena cava

Inferior vena cava

From the lungs 4 pulmonary veins

INTERIOR

PLUMBING

Coronary arteries

PIPES GOING OUT

To the lungs

Pulmonary artery

To the body

Aorta

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ELECTRICAL WIRING: CONDUCTION SYSTEM

Sinus node

AV node

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TYPES OF HEART PROBLEMS

(1) Congenital heart defects

(2) Hypertrophic cardiomyopathy

(3) Arrhythmia (tachycardia)

(4) Vascular problems (blood vessel)

(1) CONGENITAL HEART DEFECT (CHD)

CARDIOVASCULAR MALFORMATION (CVM)

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• Heart structure is abnormal

• Occurs error early in development (first 10 weeks)

• Usually present at birth, early childhood.

May be detected as fetus or adult

• Severity:

As mild as a tiny pinhole VSD

To a more severe forms which can be lethal

(most of these do not occur in Costello syndrome)

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Holes in the dividing wall (septum)

Atrial septal defect (ASD) Ventricular septal defect (VSD)

TYPES OF CHDs

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CHDs: Plumbing problem with pipes

(not seen in Costello syndrome, seen in Noonan syndrome)

Coarctation (narrow aorta) Tetralogy of Fallot (TOF)

• Tight valve

Pulmonary stenosis

Tricuspid stenosis

Mitral stenosis

Aortic stenosis

• Leaky valve

Tricuspid regurgitation

Pulmonary regurgitation

Mitral regurgitation

Aortic regurgitation

• Dysplasia

• Prolapse

CHDs: Valve problems

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• Abnormal heart muscle.

Structure OK, walls too thick.

• Hypertrophic = thick

Symmetric (both sides),

Asymmetric (one side)

Concentric (all around),

Obstructive (gradient)

Non-obstructive (no gradient)

Subaortic (under aorta)

• Dilated cardiomyopathy = thin wall

(2) HYPERTROPHIC CARDIOMYOPATHY

Aorta

Left

Atrium

Left

Ventricle

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Fast, regular heart beat = Tachycardia

Atrial tachycardia

Supraventricular tachycardia (SVT)

Paroxysmal tachycardia (PAT)

• Firing from many places

Chaotic atrial rhythm (CAR)

Chaotic atrial tachycardia (CAT)

Multifocal atrial tachycardia (MAT)

• Firing from one abnormal place

Ectopic atrial tachycardia (EAT)

(Technical term = Non-reentrant tachycardia)

(3) ARRHYTHMIAS: Atrial

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ATRIAL TACHYCARDIA: SVT, PAT

Common in the general population

Adults and children

Heart rate very fast (200-300), regular

CHAOTIC ATRIAL RHYTHM /TACHYCARDIA (CAR, CAT)

MULTIFOCAL ATRIAL TACHYCARDIA (MAT)

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Serious, difficult to treat

In people without Costello syndrome:

Infants: Usually no cause; often after heart surgery

Adults: With chronic lung disease

Short tracings from NICU may be misinterpreted

A full ECG or Holter is necessary

Most pediatric cardiologists were not aware

Costello syndrome is the most identifiable

cause of CAT/CAR, MAT, EAT

Now, also seen in Noonan and CFC (less common)

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Other Fast Rhythms (continued)

Fast, irregular

• Atrial Fibrillation

• Atrial Flutter

Atrial extra beats

• Premature atrial beats (PABs)

(3) ARRHYTHMIAS: Atrial

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VENTRICLES

• Ventricular tachycardia

• Premature ventricular beats (PVB)

UNCLEAR

• Wide QRS complex

CONDUCTION SYSTEM

• Heart block

• Prolonged QT interval

(3) ARRHYTHMIAS: Rare

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VASCULOPATHY

• Large vessels:

Aortic root dilation

• Small vessels:

Coronary artery “dysplasia” Hypertension

(4) BLOOD VESSEL PROBLEMS

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Am J Med Genet 2011; 155:486

• Lin et al., AJMG 2002. Clinical diagnosis only

• Lin et al., AJMG, 2011. Mutation confirmation

61 new + 85 literature patients = 146 total *83 total in study

• Costello syndrome compared with other rasopathy syndromes

• Natural history, outcome, guidelines

• Postponed: Arrhythmia treatment, Growth hormone

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COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61) ABNORMALITY FREQ FINDING

Any CV

abnormality

85%

CHD 44%

PS valvar

Supravalvar

20% 3 pts

ASD2 7%

Other

Rare

MVP,

Aortic stenosis/Bicuspid aortic valve

Polyvalve dysplasia

VSD, Coarctation

Outcome 80% Resolved or stable

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COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61)

ABNORMALITY FREQ FINDING

HCM 61%

Global

Concentric LVH

Most common

Outcome 41% Stable or regressed

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COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61)

ABNORMALITY FREQ FINDING

Arrhythmia

MAT, EAT

Outcome

56%

25%

71%

Stable, self-limiting

Aorta dilation 7% Among all patients (no BAV)

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When in doubt, ask your cardiologist and/or geneticist to call us.

1. All Costello patients:

Cardiology consult at diagnosis of CS.

Repeat, even if there was a fetal echocardiogram

Echocardiogram

ECG

As needed : Holter (24 hour monitor)

2. Longterm studies have helped delineate outcome.

Timing and type of follow-up is based on age

and problem. Less “cookbook”, more customized.

CLINICAL GUIDELINES: UPDATED

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• Focus on

MEDICAL THERAPIES FOR:

- Hypertrophic Cardiomyopathy (HCM)

- Arrhythmias

INTERVENTIONAL/SURGICAL TREATMENT:

- Hypertrophic Cardiomyopathy (HCM)

- Arrhythmias

To be discussed another time or in person

TREATMENTS FOR

- Pulmonary valve stenosis

- Dilated aorta

MEDICAL TREATMENT OF HEART CONDITIONS

IN COSTELLO SYNDROME

Aorta

Left

Atrium

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• HCM in Costello treated much like

HCM in children without a

Rasopathy syndrome

• Difference: in Costello we often

need to manage HCM and

arrhythmias simultaneously

• Luckily some of the medications

we use treat both problems!

HYPERTROPHIC CARDIOMYOPATHY in CS:

MEDICAL TREATMENT

Aorta

Left

Atrium

Left

Ventricle

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• HCM causes two primary problems:

- the heart cannot relax easily to fill with blood-

relaxation is as important as squeeze!

- septal hypertrophy can prevent blood exiting to the

aorta and on to the body

- LVOTO “left ventricle outflow tract obstruction”

• Not enough blood in, not enough blood out

HCM IN CS: MEDICAL TREATMENT

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A few things that are important to avoid

• Dehydration- keep the tank full

• Avoid low blood pressure,

caution must be used with

medications used to lower blood

pressure

(“afterload reduction” can increase

outflow gradient and impair blood

flow to the heart muscle itself)

HCM IN CS: MEDICAL TREATMENT

Certain medications can prevent sudden death related

to HCM (a few studies provide evidence in kids)

(b)Beta-blockers

propranolol

metoprolol

bisoprolol

-indicated in patients with LVOTO

-in patients with “symptoms”

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HCM IN CS: MEDICATIONS (1)

Calcium channel blockers (verapamil)

- use in patients who remain symptomatic on, or

who do not tolerate b- blocker

- use with great caution in severe LVOTO,

or slow heart rate

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HCM IN CS: MEDICATIONS (2)

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• Disopyramide

- not commonly used

- always used in addition to b-blocker

- use in patients with atrial and ventricular arrhythmias

• Amiodarone

- also used to treat arrhythmias

- many serious side affects with long-term use-

potential thyroid, lung, liver toxicities

HCM IN CS: MEDICATIONS (3)

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Why do these medications help?

- Possibly by slowing the heart down, allowing the

heart time for filling

- Decreasing the gradient across the LVOT

- “Stabilize” the myocardium (heart muscle)- making

it less prone to dangerous arrhythmias.

What if they are not helping enough?

- Congestive heart failure (CHF) may develop: back-

up of fluid into lungs or into body (edema, ascites)

- CHF can be managed- diuretics such as Lasix

(furosemide) are mainstay.

HYPERTROPHIC CARDIOMYOPATHY:

MEDICAL TREATMENT- HOW DOES IT WORK?

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• Arrhythmias are the specialty of electro-physiology (EP) cardiologists- we ask them for help!

• There is no standard medical regimen to treat atrial

arrhythmias in CS (or in general in kids) • Therapy is very individual and sometimes trials of medication

are needed to find the right drug (or combination of drugs)

ATRIAL ARRHYTHMIAS IN CS:

MEDICAL TREATMENT

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• Treatment for EAT/MAT/CAT/SVT-

Antiarrhythmic medications

Class I- affect sodium channels

disopyramide is a Class Ia antiarrythmic

flecainide is a Class Ic

Class II- b-blockers (propranolol)

Class III- potassium channel blockers

Amiodarone- has class I, II, III and IV properties

Sotalol- also has b-blocker activity

Class IV- calcium channel blockers (verapamil)

Some of these drugs may sound familiar….

ATRIAL ARRHYTHMIAS IN CS: MEDICATIONS

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• This is only a sampling of the medications that can

be used for atrial arrhythmias

• Treatment of childhood arrhythmias is sometimes

more of an art than a science

• A cardiologists who specializes in cardiomyopathy

and one who specializes in rhythm problems

make a good team when it comes to the care of a

patient with Costello syndrome

ATRIAL ARRHYTHMIAS IN CS: MEDICATIONS

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• Reserve for arrhythmias that do

not resolve with age

• Child must be big enough

(safety issue)

• Involves mapping the electrical

system with catheters, finding

a problem spot and treating

with

- cryoablation- freezing

- radiofrequency- burning

ATRIAL ARRHYTHMIAS IN CS:

ELETROPHYSIOLOGY STUDY AND ABLATION

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• An ICD may be indicated for an individual with HCM and a prior resuscitated cardiac arrest (secondary prevention) • There are criteria for adults with HCM to determine when an ICD is indicated for primary prevention. • Placement of an ICD in a child is not straightforward!

LIFE-THREATENING ARRHYTHMIAS IN CS: A WORD ABOUT

IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS (ICDs)

• Septal myectomy - Reserved for those with

symptoms despite maximal medical therapy

• Alcohol septal ablation - Injection of alcohol into

septal coronary arteries to induce infarction of the septum

- Usually only in adult sized patients

SEVERE HCM REFRACTORY TO MEDICAL TREAMENT:

SURGICAL OPTIONS

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• In infants and children with HCM and heart failure +/-

refractory arrhythmias, heart transplant may be only

option for survival

• We know of no patients with Costello syndrome who have

had a heart transplant (from literature and our

colleagues). Do you?

• Children with Noonan syndrome have received heart

transplants- outcomes largely unknown. Others are

known to have died while waiting for transplant

CARDIAC TRANSPLANTATION IN RASOPATHY

MY RESEARCH

Chatfield K et al., 2013, Poster presented at the Ras Symposium

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• We have collected data on a small group of patients with

Rasopathies who underwent heat transplants for

cardiomyopathies and arrhythmias

- 5/6 are surviving (4 Noonan, 1 LEOPARD).

- The “CS” patient who died after transplant is suspected to

have had CFC syndrome.

• Another child with CFC received a heart transplant for severe

HCM, developed hepatoblastoma 2 years after transplant and

died of complications of this cancer (Al-Rahawan et al., 2007)

• It is still unknown if heart transplant is an option in CS.

Individuals are always considered on a case-by-case basis.

CARDIAC TRANSPLANTATION IN RASOPATHY

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• We've learned a lot, more to learn especially as "the

kids" grow up

• We know you want more information about

treatment, what works, what doesn't- and we do, too.

• As important as who has a heart problem, what can

we learn about those who had no problems?

• Still unanswered officially: what is the impact of

growth hormone (we feel reassured overall).

IN CONCLUSION