Down, Edward, & Patau syndromes

The vast majority of the time (>95%), the syndrome is caused by meiotic nondisjunction of the maternal chromosome 21, leading to an ovum with two copies of chromosome 21 (the male sperm adds the third upon fertilization).

Roughly <5% of the time, Down syndrome is due to Robertsonian translocation.

Finally, about <1% of the time, Down syndrome is due to post-fertilization mitotic error, leading to mosaicism.

It is known that advanced maternal age is associated with increased risk of meiotic nondisjunction, but the USMLE wants you to know that it is age thirty-five, NOT forty, that is the threshold age for significance.

At age age 35, risk is 1/350.

At age 40, risk is 1/100.

At age 49, risk is 1/10.

Most common cause of mental retardation across the entire population is fetal alcohol syndrome (FAS), however over age 40 it is Down syndrome.

Firstly, an acrocentric chromosome is when the centromere that joins the short (p) and long (q) arms is located near one end, rather than close to the middle.

A Robertsonian translocation is when two chromosomes’ q-arms join together at a centromere, and the two p-arms are lost.

In Down syndrome, this occurs between chromosomes 14 and 21. This is written as t(14q;21q).

If a child has Down syndrome, one of the parents, instead of having two separate copies of chromosome 21, has one of his or her chromosome 21s attached to one of his or her chromosome 14s.

The total amount of genetic material in the parent is normal (balanced), so he or she doesn’t have any pathology, but if the abnormal chromosome 14 is passed to the offspring, a trisomy can occur.

Mosaicism occurs when only a fraction of the individual’s cells contain the trisomy, and the other fraction is normal.

The mechanism for this cannot possibly happen during meiosis, because if it did, all of the child’s cells would contain the trisomy.

So if they ever mention a case of a mosaic Down syndrome patient, the answer is always post-fertilization mitotic error.

The above underlined point is exceedingly HY!

Outward manifestations of Down syndrome:

Epicanthal folds (down-turning of medial canthus of eyes)

Slanted palpebral fissures (refers to the elliptical space between the eye’s lateral and medial canthi)

Flat facies (lack of anterior projection of profile, often with a very flat nose).

Brushfield spots (small white spots found in the periphery of the iris). Bitot spots are a buildup of keratin on the cornea of the eye seen in vitamin A deficiency.

The hands often show a single palmar crease, also known as a Simian crease.

However it should be noted that the single palmar crease, whilst seen in ↑ frequency in Down syndrome, is NOT pathognomonic and can also be seen in the general population. For instance, if they mention a single palmar crease + elongated philtrum, the answer is FAS, not Down.

Rocket bottom feet and prominent occiput are seen in Edward syndrome.

Atrioventricular septal defect is the most common type (endocardial cushion defect).

There are classic endocardial cushion defects in the heart (often resulting in atrioventricular septal defect (AVSD), or ostium primum-type atrial septal defect).

Down patients also tend to have a cleft on the mitral valve (and sometimes the tricuspid valve), which increases the risk of mitral and tricuspid regurgitation.

Increased risk of pulmonary hypertension and pulmonary artery malformations.

Pulmonic stenosis is seen classically in Tetralogy of Fallot (DiGeorge syndrome).

If they ever ask you about the mechanism of cardiac defects in Down syndrome, the answer is failure of neural crest cell migration, since the heart’s endocardial cushions develop from neural crest.

Gastrointestinally, there is increased risk of tracheoesophageal fistula, duodenal atresia, and Hirschsprung disease.

Hematologically, there is increased risk of ALL and AML.

Down syndrome is associated with hypothyroidism (↑TSH).

There may also be recurrent otitis media + hearing impairment due to eustachian tube dysfunction.

One of the most heavily tested clinical features of Down syndrome is that it leads to early Alzheimer disease (i.e., 30s-40s). This is because one of the genes for β-amyloid production is on chromosome 21.

First trimester triple screen (11-13 weeks):

• ↑ nuchal translucency   |   ↓ PAPP-A   |    ↑ beta-hCG
• Nasal bone hypoplastic or absent on ultrasound

Second trimester quad screen (16-18 weeks):

• ↓ AFP   |   ↓ estriol   |   ↑ β-hCG   |   ↑ inhibin A

Prenatal testing

• • Chorionic villus sampling (CVS)
    • Can be performed at ~10-12 weeks.
    • A sample of placental tissue is retrieved via an ultrasound-guided needle, either transcervically or -abdominally.
    • If adequate sample is obtained, there is a near 100% diagnostic accuracy for Down syndrome (and many other disorders).
    • Risk of iatrogenic abortion (fetal demise) has been ubiquitously reported in the literature as on the magnitude of ~1%.
  • Amniocentesis
    • Generally performed ~14-16 weeks.
    • Ultrasound-guided needle is inserted transabdominally into the amniotic sac to retrieve free-floating fetal DNA.
    • Adequate sample yields near 100% diagnostic accuracy.
    • Iatrogenic abortion (fetal demise) can occur ~0.5% of the time, but the literature varies as far as the range. It is definitive, however, that amniocentesis carries lower risk than CVS.
  • Cell-free DNA
    • Can be performed ~10 weeks gestation.
    • Also referred to as NIPD (non-invasive prenatal diagnosis)
    • Test involves nothing more than merely drawing maternal venous blood and analyzing free-floating fetal DNA that normally crosses the placenta in trace amounts.
    • Newest test (as compared to CVS and amniocentesis), but also most expensive, and many clinics and regions don’t offer it.
    • Accuracy is near 100%, and risk of iatrogenic abortion is near zero.

Classic characteristics are low-set ears, micrognathia, prominent occiput, clenched hands, and rocker bottom feet.

Other typical features (although not pathognomonic) are omphalocele, Meckel diverticulum, and gut malrotation.

In contrast to Down syndrome, AFP, estriol, β-hCG and inhibin A are all down.

If you get a question mentioning low-set ears, flattened facies and clubbed feet, this is a classic external presentation for Potter sequence (renal agenesis + pulmonary hypoplasia) secondary to oligohydramnios, NOT Edward syndrome.

Low-set ears + rocker bottom feet + prominent occiput +/- omphalocele = Edward syndrome

Low-set ears + clubbed feet + flattened facies = Potter sequence

Patau syndrome (trisomy 13)

• Presents classically with holoprosencephaly, cleft lip/palate, polydactyly, and omphalocele.
• AFP, estriol, β-hCG and inhibin A are often all normal, however these values are practically never addressed in USMLE questions because they vary.
• USMLE questions on Patau syndrome tend to focus on the above bold findings (notably holoprosencephaly).

If you get a question on holoprosencephaly, the top three DDx tested on Step1 are severe fetal alcohol syndrome (most common cause), Patau syndrome, and homeobox gene mutation.

If you get a question mentioning cleft lip/palate, the top three USMLE Step1-tested associations are DiGeorge syndrome, Patau syndrome, and vitamin A teratogenicity (i.e., maternal use of isotretinoin).