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 minor 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.

• Assisted reproductive technology:

  • ✓ Rate of birth defects is higher in infants conceived using assisted reproductive technology (8.3%) and is highest in infants conceived via intracytoplasmic sperm injection (9.9%).

  • ✓ Preimplantation genetic testing during in vitro fertilization does not rule out mosaic disorders or types of genetic disorders that were not evaluated.

  • ✓ Higher risk of growth restriction and/or placental dysfunction when the mother is not genetically related to the infant (e.g., egg donor, embryo donor, surrogate gestation)

  • ✓ Ovarian hyperstimluation (e.g., clomiphene [Clomid], in vitro fertilization) increases the risk of methylation defects (e.g. Beckwith-Wiedemann syndrome is 18 times more likely in an infant conceived via in vitro fertilization)

  • ✓ Records should be reviewed to determine what types of carrier screening and preimplantation genetic testing and/or screening were completed

• 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.

  • ✓ Maternal immunization status prior to pregnancy and titers if possible, with special attention to ...