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Pregnancy History for the Mother of the Affected Person
• Were there any problems in the pregnancy (e.g., premature rupture of membranes, placental problems)?
• Was the pregnancy full term? Premature?
• What was the fetal presentation at delivery (e.g. breech, vertex)?
• What was the mode of delivery (e.g., a C-section may be an indication of breech presentation or fetal distress)?
• Did the mother have any infections or illnesses during the pregnancy? If so, obtain information about timing during pregnancy.
• Does the mother have any medical problems such as diabetes, cardiovascular disease, or epilepsy?
• Did she take any medications (particularly for seizures) during the pregnancy? If so, obtain specific information about the medication, dosage, and timing.
• Did the mother drink alcohol or use tobacco products? If so, obtain information about usage and timing in pregnancy.
• Did the mother use street drugs (particularly cocaine)? If so, obtain information about usage and timing in pregnancy.
• What were the results of any prenatal testing (such as ultrasound, maternal serum marker testing, amniocentesis, or chorionic villus sampling)?
Family History Questions
• Does anyone have a history of pregnancy losses such as miscarriages or stillbirths?
• Have other babies been born with birth anomalies? If so, describe the defects.
• Does anyone in the family have:
Mental retardation? (If yes, see Table 4.12)
A neurological condition? If yes, explain and note the age of onset of symptoms (see Table 4.14)
Muscle weakness? If yes, explain and note the age of onset of symptoms.
Hearing loss? If yes, note the severity and age of onset (see Table 4.7)
• Are the parents of the affected individual blood relatives? If so, what is their exact relationship (i.e., the mother’s father and the father’s father are brothers, therefore the child’s parents are first cousins)?
4.2 PHYSICAL BIRTH ANOMALIES AND VARIANTS
ment for reproductive planning should be offered a genetic evaluation, preferably prior to conception.
Cleft lip and palate has been associated with several teratogens in pregnancy including alcohol abuse. The prescription drugs hydantoin, trimethadione, aminop-terin, and methotrexate are associated with CL/P. Hyperthermia in the mother (early in pregnancy) and maternal PKU are associated with cleft palate. Amniotic bands can cause a disruption in fetal development resulting in cleft lip. Maternal tobacco use in pregnancy may increase the risk of orofacial clefting through a gene-environ-ment interaction in children with certain alleles of TGF-alpha (transforming growth factor alpha) (Shaw et al., 1996). Some studies suggest that vitamin supplementation with folic acid may help to prevent orofacial clefting (Czeizel et al., 1996; To-larova and Harris, 1995).
A syndrome commonly associated with cleft lip is Van der Woude syndrome, an autosomal dominant syndrome with reduced penetrance and extremely variable expression such that the clinical manifestations vary from pits in the lower lips to severe cleft lip. Parents of a child with a seemingly isolated cleft lip should be examined for lip pits. If one of the parents has lip pits, than the couple’s chance to have another child with a cleft lip is about 26% (not everyone who inherits the gene alteration has clefting). This compares to an approximately 4% recurrence risk if the parents have a normal examination and there is no other family history of clefting (Robinson and Linden, 1993; Tewfik and der Kaloustian, 1997).
Velocardiofacial (DiGeorge) syndrome is an autosomal dominant syndrome characterized by cleft palate, cardiac anomalies (conotruncal), frequent infections, typical facies, and learning disabilities. Velocardiofacial syndrome (VCFS) may be the most common cleft palate syndrome. Shprintzen and colleagues (1985) reported that VCFS accounts for 8.1% of children with palatal clefts.
Most isolated instances of CL/P or cleft palate follow a multifactorial model of causation. Risk of recurrence for the healthy parents of an affected child are gleaned from empirical risk tables, and range from 3-7% for CL/P to 2-5% for cleft palate. A parent with an apparently isolated CL/P has a 2-4% chance to have a child with CL/P, and a parent with cleft palate has a 2-5% chance to have a child with a cleft palate.
Congenital Heart Defects
Congenital heart defects (CHD) are the most common form of birth anomaly, affecting more than 1/200 newborns worldwide (Burn and Goodship, 1997). Between 20% and 45% of infants with a CHD have other noncardiac abnormalities. A specific genetic cause is identified in about one in five children with a cardiac malformation. Usually CHDs occur sporadically, with about 10% occurring as part of a syndrome (Seashore and Wappner, 1996). Congenital heart malformations are associated with close to 200 syndromes. Burn and Goodship (1997) provide a comprehensive list of the syndromes associated with cardiac malformation as well as a listing by major features (e.g., dysmorphic features and mental retardation, limb reduction defects, polydactyly, skeletal defects, ear and eye anomalies, genitourinary