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

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.

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.

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.

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.

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

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

Birth Defects annually (2001 WHO data) Congenital heart disease 1,040,835 Neural tube defects 323,904 Down syndrome 217,293

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

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

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

History Prenatal history

History Birth history

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

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

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

Bone lengths Rhizomelic shortening Proportionate dwarfism Upper:lower segment

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

Isolated findings vs. syndromic findings

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

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

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

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

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%

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

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

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

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

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%

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

Treatment and Prognosis Support Evaluation Medical management Surgical intervention Genetic counseling