1. Pediatric Genetics Cases
Leah W. Burke, MD
May 10, 2021

2. Goals
• Use cases to inform the decision making
needed for a genetics referral
• Understand the components of a genetic
evaluation
• Become familiar with three syndromes in
which the presenting symptom can be a heart
murmur

3. Congenital Heart Defects and
Syndromes

4. Case 1: Coralie
• You are seeing a 7 month old in clinic to
address her growth issues and colic issues
• You hear a heart murmur that you have not
heard before
• You also notice that her development is
slower than her brother’s
• She is sent for a genetic and cardiac evaluation

5. REMEMBER THE RULE OF “TWO/TOO” (when asking questions)
• TOO tall
• TOO short
• TOO early
• TOO many
• TOO young
• TOO different
• TWO tumors
• TWO generations
• TWO in the family
• TWO birth defects

7. Williams Syndrome
• Heart defect
–Supravalvular aortic stenosis
–Stenosis of other arteries
–Thought to be due to a defect in
the elastin gene

8. Williams Syndrome
• Facial features
– Periorbital puffiness
– Wide mouth & thick lips
– Stellate irides

10. Williams Syndrome
• Neurosensory
–Hyperacusis
–Musical abilities
–Intellectual disability
–Relative sparing of language
–Cocktail party personality

12. www.gemssforschools.org

14. Williams Syndrome
• Heart defect
– Supravalvular aortic stenosis
– Stenosis of other arteries
• Facial features
– Periorbital puffiness
– Wide mouth & thick lips
– Stellate irides
• Neurosensory
– Hyperacusis
– Musical abilities
– Intellectual disability
– Relative sparing of language
– Cocktail party personality
• Short stature
• Kidney abnormalities
• Hoarse voice
• Hypercalcemia
• Continuous gene deletion of
7q11.2, including the elastin
gene (ELN)

15. Case 2: Olivia
• You are seeing a newborn for the first time in
the nursery
• You hear a heart murmur
• You have her evaluated by the cardiologist

17. Noonan Syndrome
• Cardiac defects
– Pulmonary valve stenosis
– Dysplastic (abnormal) pulmonary valve
– Hypertrophic cardiomyopathy may be present in
early infancy or even develop prenatally

18. Noonan syndrome
Facial features
• Eyes
–Ptosis
–Downslanting palpebral fissures
• Ears
–Low-set
–Posteriorly rotated

20. Facial landmarks

21. Innercanthal/Innerpupillary
Measurement
Hypotelorism Normal Hypertelorism

22. Innercanthal/Innerpupillary
Measurement
Hypotelorism Normal Hypertelorism

23. Ear

25. Noonan syndrome
• Congenital heart defect
• Characteristic facies – ptosis, downslanting palpebral fissures,
low-set and rotated ears
• Short stature
• Broad or webbed neck
• Unusual chest shape with superior pectus carinatum, inferior
pectus excavatum
• Apparently low-set nipples
• Developmental delay of variable degree
• Cryptorchidism
• Coagulation defects

27. Genetics in Noonan Syndrome

28. Case 3: Kirsten
• You are seeing a 3 year old in your office for
her well child check-up
• You hear a heart murmur on examination
• She has some speech delays and has very
nasal sounding speech

30. 22q Deletion Syndrome
• Other names
– Velocardiofacial syndrome
– DiGeorge Syndrome
– Shprintzen Syndrome
– CATCH 22 – not used by most physicians because
of the negative reaction by families
• Estimated prevalence is 1 in 2000 to 1 in 4000

31. 22q Deletion Syndrome
• Congenital heart defects are found in 74%
• Major cause of mortality (>90% of all deaths)
• Conotruncal (area of the outflow tracts)
cardiac defects are the most common
– Some like interrupted aortic arch are rarely seen
other than in 22q deletion
– 20% of individuals with Tetraology of Fallot (TOF)
have 22q deletion

32. Craniofacial Features
• Short palpebral fissures
• Wide nasal bridge with narrow alae nasae
• Small mouth
• Cleft palate or cleft lip and palate or
dysfunctional palate
• Structurally and/or functionally asymmetric
face
• Asymmetric crying facies

33. Facial landmarks

37. 22q Deletion syndrome
• Cardiac defects
• Endocrine
– Thymic hypoplasia
leading to T-cell
abnormalities
– Parathyroid hypoplasia
• Neurologic/psychologic
– Learning problems
– ADHD
– Autism spectrum disorder
– Psychiatric illness as
adolescents/adults
• Speech
– Cleft palate
– Velopharyngeal
insufficiency (VPI)
– Hypernasal Speech
problems
• Characteristic facial
features

38. Early Cognitive and Behavioral Phenotype
• Delayed early motor development
• Delayed language
• Autism/autism spectrum disorders – 20%
• Decreased cognitive scores in toddlers

39. General Cognitive Ability
• In general individuals with 22q Deletion have IQ scores
that are lower than their unaffected siblings or other
family members
• 66% have a non-verbal learning disability (Verbal IQ >
performance IQ)
– VerbaI IQ averages 75-80
– Performance (non-verbal) IQ averages 70-75
• IQ appears to be lower in familial cases than in de novo
cases
• Some evidence that IQ scores are lower in boys than in
girls

40. Attention Deficit Disorders
• The most frequent behavioral observation
• 30-50% meet criteria for ADHD
• Reductions in volumes of the frontal lobe and
dorsolateral prefrontal cortex in 22q deletion
may explain part of the prevalence
• Medications such as methylphenidate have
been proven useful

41. Psychiatric Issues
• 20% will have a psychiatric diagnosis
• Schizophrenia and bipolar disease are the
most common
• Anxiety disorders are very common

42. Motor Abilities
• Hypotonia in infancy is common and may
be significant
• Impact on both fine and gross motor
• In school may present with difficulties in
writing, using scissors, etc
• Fine motor skills may be impacted by both
the hypotonia and the visual-spatial
difficulties

43. Genes in 22q Deletion
• TBX-1 was the first gene to be implicated
• Other genes have followed

44. 22q Deletion Syndrome and
Newborn Screening