1. Genetics in the NICU Approach to the Infant with Birth Defects
Robert Wallerstein, MD
Director, South Bay Regional Genetics Center
Santa Clara Valley Medical Center

2. Birth defects are defined as abnormalities of structure or function, that are present at birth.
Major birth defects are abnormalities that lead to developmental or physical disabilities or require medical or surgical treatment.

3. There are more than 7,000 different known birth defects, ranging from minor to serious, and although many can be treated or cured, they're the leading cause of death in the first year of life.
The most common type of major structural defects are heart defects, which affect 1 in 150 babies in the United States.
Other common structural defects include spina bifida, cleft palate, clubfoot, and congenital dislocated hip.

4. According to the March of Dimes, about 150,000 babies are born with birth defects each year in the United States.
The American College of Obstetricians and Gynecologists (ACOG) says that 3 out of every 100 babies born in the United States have some kind of major birth defect.
Birth defects can be caused by genetic, environmental, or unknown factors. For most birth defects, the cause is believed to be an interaction of a number of genetic and environmental factors.

5. Causes
Most babies with birth defects are born to two parents with no obvious health problems or risk factors.
A woman can do everything her doctor recommends to deliver a healthy child and still have a baby with a birth defect.
In fact, according to the March of Dimes, about 60% of birth defects have unknown causes. The rest are caused by environmental or genetic factors, or some combination of the two.

6. Worldwide Birth Defects
7.9 million children
6% of total births
3.3 million children under age of 5 die from birth defects annually
3.2 million survivors may be diables for life

7. Worldwide status 94% of serious birth defects
95% of birth defect related deaths
Occur in middle and low income countries due to:
Differences in maternal health
Consanguinity
nutrition

8. Birth Defects annually (2001 WHO data)
Congenital heart disease 1,040,835
Neural tube defects ,904
Down syndrome ,293

9. In the United States, fortification of food supply with folic acid:
Has resulted in a 1/3 decline of neural tube defects
$400 million dollars saved annually in healthcare costs

10. Evaluation 9 criteria for genetics referral Johns Hopkins Hospital
1. Known or suspected hereditary disorder
2. Major physical anomalies, unusual body proportion, short statire or dysmorphic features
3. Major organ involvement
4. Developmental delay
5. Complete or partial blindness or hearing loss

11. Evaluation 9 criteria for genetics referral Johns Hopkins Hospital
6. Deterioration of skills in a previously thriving child
7. Maternal exposure to drugs, alcohol or radiation during pregnancy
8. Strong family history of cancer (not in NICU)
9. Failure to thrive

12. History
Prenatal history

13. History
Birth history

14. History Family History 3 generation pedigree
For each family member-age, sex, medical status or cause of death
Specifically ask about family history of neonatal or childhood death, mental retardation, developmental delay, birth defects, seizures, known genetic disorders, ethnicity, consanguinity, infertility, miscarriages, and stillbirths

15. Dysmorphology Examination a quick guide
Eyes
Hypotelorism and hypertelorism
Philtrum
Long, short, or flat
Ears
Ear pitsor tags
Low set or posteriorly rotated

16. Jaw Hands and Feet micrognathia retrognathia Abnormal hand creases
5th finger clinodactyly
Syndactyly
Polydactyly

17. Bone lengths Rhizomelic shortening Proportionate dwarfism
Upper:lower segment

18. Classification Definitions
Syndrome-a set of symptoms occurring together from a single cause
Malformation-a deformity in the shape or structure of a part
Deformation -a major difference in the shape of body part caused by an outside force

19. Isolated findings vs. syndromic findings

20. Laboratory tools Imaging studies Brain MRI Echocardiography
Abdominal ultrasonography
Skeletal survey
Ophthalmologic examination

21. Genetic Diagnostic tests
Chromosomes
FISH
Chromosome micro array (CGH)
DNA analysis
Biochemical analysis

22. Indication for chromosome studies
Two major or
one major and two minor malformations
(include small for gestational age and developmental delay as major)
Features of a specific chromosome syndrome
At risk for a familial chromosome aberration
Ambiguous genitalia

23. Trisomy 21
Incidence 1:660
Features: Presence of 6 of 10 cardinal features
Hypotonia
Poor Moro reflex
Hyperextensibility
Excess skin on the back of the neck
Flat facies
Slanted palpebral fissures
Anomalous auricles
Pelvic dysplasia
Dysplasia of midphalanx of 5th finger
Single transverse palmar crease

24. Trisomy 21 Natural history: Cardiac defects 50% GI atresias 12%
Mental retardation 100%
Leukemia 1%
Thyroid disease 15%
Hearing loss 75%
Serous otitis media 50-70%
Eye disease 60%

25. Trisomy 18 Incidence: 1:3,000 with 3:1 female preponderance
Features:clenched hand with index finger overlapping third and fifth fuinger overlapping fourth, IUGR, decreased fetal activity,low-arch dermal ridge pattern, inguinal or umbilical hernia, cardiac defects, prominent occiput, low set ears, micrognathia, rocker bottom feet

26. Trisomy 18 Natural history: Apnea Severe failure to thrive
50% die by one week
90% by 1 year
Profound mental retardationin survivors

27. Trisomy 13 Incidence: 1:5,000 Features: Holoprosencephaly Polydactyly
Scalp skin defects
Seizures
Deafness
Microcephaly
Sloping forehead
Cleft lip and palate
Retinal anomalies
Microphthalmia
Abnormal ears
Single umbilical artery
Inguinal hernia
Omphalocele
Cardiac defects
Urinary tract malformation

28. Trisomy 13 44% die within 1 month >70% with 1 year
Profound mental reatrdation in survivors

29. 45,X Turner Syndrome Incidence: 1:5,000 Features:
Short female with broad chest
Wide spaced nipples
Webbed neck
Congenital lymphedema
Gonadal dysgenesis 90%
Renal anomalies 60%
Cardiac defects 20%
most commonly coarctation of the aorta
Hearing loss 50%

30. 45,X Natural history: Infertility Normal lifespan Mean IQ 90
Short stature

31. Treatment and Prognosis
Support
Evaluation
Medical management
Surgical intervention
Genetic counseling