Trisomy 21, the cause of Down syndrome (DS), is the most common chromosomal abnormality and most common genetic cause of intellectual disability.  Risk factors include advanced maternal age (≥35) and a parent with a Robertsonian translocation.

DS can be screened and diagnosed prenatally.  One common option for screening during the second trimester is the quadruple screen at 15-19 weeks gestation.  Low maternal serum alpha-fetoprotein (AFP) and unconjugated estriol levels are associated with DS and correlate with decreased fetal levels (possibly due to suboptimal fetal tissue function).  In addition, increased β-hCG and inhibin A are secreted by the placenta, possibly due to compensatory placental hyperfunction.  The diagnosis is confirmed by karyotyping fetal cells in the amniotic fluid (amniocentesis).

Most patients with DS have trisomy 21 from meiotic nondisjunction—specifically, failure of chromosome 21 to divide during meiosis.  Chromosome 21 nondisjunction occurs during oogenesis and is significantly associated with advanced maternal age; it is not seen in spermatogenesis or in postzygotic mitotic errors.  DS can also result from an unbalanced Robertsonian translocation, during which the entire long arm of one chromosome 21 is translocated to the long arm of an acrocentric chromosome (ie, chromosome 14).  These individuals have 46 chromosomes; however, one chromosome 14 is comprised of the long arms of both chromosomes 14 and 21.

(Choices A, B, and D)  AFP is produced in both the yolk sac and developing fetal liver; fetal defects that disrupt the abdominal wall or neural tube allow AFP to concentrate in the amniotic fluid, thereby raising maternal serum levels.  Gastroschisis, an abdominal wall defect lateral to the umbilicus with herniation of uncovered bowel, and myelomeningocele, a type of neural tube defect, are two conditions associated with an elevated maternal AFP.  Amniotic bands, loose strands of amnion that constrict and disrupt developing fetal structures, can affect the abdominal wall or neural tube development in severe cases and lead to elevated AFP levels.

(Choice C)  Multiple gestation will cause all of the quadruple screen analytes to be abnormally high due to increased fetal tissue and placental mass associated with ≥2 fetuses.

Educational objective:
Down syndrome is the most common chromosomal anomaly.  It is associated with low levels of maternal serum alpha-fetoprotein (AFP) and estriol, while β-hCG and inhibin A levels are increased.  Elevated AFP levels are seen in multiple gestation, open neural tube defects, and abdominal wall defects.