Congenital Heart Disease

Question 1

What are congenital heart defects?

Answer 1

structural abnormalities of the heart present at birth, regardless of the age of diagnosis

Does not include:

• patent ductus arteriosus in premature infants
• functional defects (i.e. dilated cardiomyopathies)
• inherited arrhythmias

occurence is 10X higher in stillborn births

Question 2

Environmental components of CHDs

Answer 2

maternal infections (i.e. rubella)
Maternal diseases (ie diabetes, PKU)
Teratogenic substances (alcohol, dilantin)

Question 3

Genetic component of CHDs

Answer 3

5-8% of CHD due to gross chromosomal defects

• 99% of trisomy 18 has CHD
• Trisomy 21
• Turner syndrome

Single-gene defects account for 3% of CHD

Question 4

DiGeorge syndrome/ 22q11.2 deletion syndrome

features

Answer 4

Cardiac: conotruncal defects
- cardiac lesions may include interrupted aortic arch, truncus arteriosus, tetralogy of fallot
Immunologic: thymic aplasia or hypoplasia
Hypocalcemia: parathyroid absence or hypoplasia
Dysmorphism: hypertelorism, short philtrum, cupid’s bow mouth, ear anomalies

Question 5

Velocardiofacial syndrome features

Answer 5

Cardiac: VSD, ToF, right aortic arch
Cleft palate: overt of submucosal
Developmental delay: mild-to-moderate, especially speech
Dysmorphism: prominent nose, abnormal ears, abundant hair, tapered fingers

Question 6

Genetic testing for Digeorge and velocardiofacial syndromes

Answer 6

FISH (not used much anymore), MLPA, aCGH
source: peripheral blood, amniocytes, CVS

Utility: detects 85-90% of cases

Takes 2 weeks

10% of cases are inherited
Flanked by low copy repeats

Question 7

Hidden risks for VCF/DG syndromes

Answer 7

Genetic risk: parents with mild phenotypes
Medical risk: speech/language delay, palatal surgery, hypocalcemia, late-onset psychiatric disorders
Cardiac risk: risk of blood transfusions and open chests, worse surgical outcomes

Question 8

Noonan syndrome features

Answer 8

short stature
facial dysmorphism
cardiovascular disease
- pulmonic stenosis
- HCM
- septal defects
- aortic coarctation

skeletal

• pectus carinatum/excavatum
• vertebral
• cubitus valgus

Webbed/short neck
Cryptorchidism
Bleeding diathesis
Neurodevelopmental delays

Question 9

Noonan syndrome genetics

Answer 9

autosomal dominant, with a high percentage of sporadic cases. VERY RARELY can be AR

Most common non-chromosomal syndrome with heart defects
Genetically heterogeneous

gene: PTPN11

Question 10

PTPN11

Answer 10

Gene candidate for Noonan syndrome
encodes SHP-2, a protein tyrosine phosphatase with a role in signal transduction and development
SHP-2 has role in Ras-Raf pathway, mutation leaves active site open for constitutive activity

increased prevalence of pulmonic stenosis and ASD

Question 11

Noonan syndrome related phenotypes

Answer 11

Noonan syndrome with multiple lentigines - RAF1 mutation, phosphatase activity has loss of function

Noonan-like with loose anagen hair (GOF)

Cardiofaciocutaneous syndrome - KRAS, BRAF, MEK1, MEK2 (GOF)

Costello syndrome - HRAS mutation (GOF)

Question 12

KRAS

Answer 12

Candidate for Noonan syndrome and cardiofaciocutaneous syndrome

Severe with ectodermal involvement and IDD

Question 13

SOS1 and SOS2

Answer 13

Candidates for Noonan syndrome
Normal stature and development
ectodermal involvement

Question 14

RAF1

Answer 14

Noonan syndrome with multiple lentigines

Hypertrophic cardiomyopathy

Question 15

SHOC2

Answer 15

Noonan syndrome

Loose anagen hair, tan skin, raspy voice

Question 16

Hidden risks of Noonan syndrome

Answer 16

Genetics: parents with mild phenotypes
Medical risk: 
- developmental delay
- complications of bleeding diathesis
- utility of GH treatment
- Leukemia

Cardiac risk: occult hypertrophic cardiomyopathy