CHAPTER 11: Genetics

GENETIC APPROACH TO EVALUATION OF COMMON PROBLEMS

AN INFANT WITH DYSMORPHIC FEATURES OF MULTIPLE ANOMALIES

Major anomalies are structural defects that require surgery or ongoing medical care (e.g., cleft palate, cardiac defects, hypospadias). Minor anomalies are unusual morphologic features that are of no serious medical or cosmetic consequence to the patient (e.g., single palmar crease, low-set ears, clinodactyly).

EPIDEMIOLOGY

• Major anomalies are detected in 3% of newborns, but up to 7% of children will have a defect identified by the age of 5 years

• Minor anomalies are found in 15% of children

• Only 1% of children have three or more anomalies, 90% of whom also have at least one major anomaly

• A child with multiple minor anomalies should be evaluated for the presence of a major anomaly

IMPACT

• Birth defects are the second leading cause of death in the first month of life (second only to prematurity)

ETIOLOGY

• Chromosome rearrangements: 5–10%

• Single gene defects: 10–15%

• Environmental (nongenetic) factors: 10%

• Polygenic/multifactorial causes: 35–40%

• Unknown: 30%

DIAGNOSTIC CONSIDERATIONS

• Age of parents:

  • ✓ Advanced maternal age is associated with increased rate of Trisomy 21, and other chromosomal disorders (Table 11-1)

  • ✓ Advanced paternal age is associated with increased rate of de novo autosomal dominant single gene disorders

• Multiple pregnancy losses:

  • ✓ Can indicate a balanced translocation or X-linked disorder that is lethal in males

  • ✓ If available, genetic testing from these fetuses should be reviewed

• Family history:

  • ✓ Identification of family members with similar birth defects, pregnancy losses, infertility, and whether the child resembles his or her family members

  • ✓ Ethnicity should be elicited to determine the rarity of physical features (e.g., synophrys, hypertrophy and fusion of the eyebrows, is common in children of Middle Eastern descent, epicanthal folds are common in children of Asian descent) and to identify genetic conditions prevalent in certain ethnic groups

  • ✓ Presence of consanguinity increases likelihood of autosomal recessive disorder in offspring

• Medication/drug exposure during pregnancy:

  • ✓ Many medications (e.g., anticonvulsants, warfarin, retinoic acid) and other substances (e.g., alcohol) are associated with an increased rate of birth defects

• Maternal medical conditions during pregnancy:

  • ✓ Risk due to medical condition itself (e.g., maternal diabetes associated with an increased risk of many birth defects including cardiac defects, duplicated great toe) or because of exposure to teratogenic medications (e.g., anticonvulsants, warfarin, retinoic acid)

• Genetic screening or diagnostic testing during pregnancy:

  • ✓ Results of genetic screening (offered to all women) and diagnostic genetic testing (often done following abnormal screening or identification of anomalies) may not be recorded in the infant’s chart, and these records should be requested

  • ✓ Prenatal testing may have lower sensitivity than postnatal testing, and may need to be repeated

  • ✓ Prenatal karyotypes are often limited to FISH for 13, 18, ...