Autosomal trisomies: Pathology review

Chapters:

Watch video only

Case Study0:00–1:46

A 1 day old newborn boy, named Nikolas, is brought to the emergency department due to frequent vomiting of a "greenish liquid” immediately after meals.
Physical examination shows a flat nasal bridge, small mouth with a protruding tongue, and a single palmar crease on each hand.
A plain abdominal x-ray reveals a double bubble appearance on the upper abdomen, with no gas seen distally. The infant was born at home to a 41 year old mother who received no prenatal care and is unable to provide any medical history.
Some days later, a 39 year old mother gives birth to a female baby, named Taylor, through emergency cesarean section at 36 weeks of gestation.
Taylor is found to have a punched out lesion on the left side of her scalp, where skin is missing. On further examination, her head is smaller compared to infants of the same age and gender, and she has an extra finger on her right hand.
The mother lives in a remote area and was not able to receive any prenatal care. Finally, 37 year old Annita visits the prenatal clinic at 16 weeks of gestation for the quadruple screen test.
Results show a low level of maternal serum alpha-fetoprotein or AFP for short, low human chorionic gonadotropin or hCG, low unconjugated estriol, and normal inhibin A.
She has not undergone any first trimester screening.Based on the initial presentation, all cases seem to have some form of autosomal trisomy.

Genetics1:46–4:07

This is where the baby ends up with three copies of an autosomal chromosome instead of two. For your exams, remember that, in most cases, this results from a process called nondisjunction.
This typically occurs during meiosis 1, where a chromosome pair in the egg or sperm cell doesn’t split apart. So the child of this individual could receive 2 chromosomes from that parent and 1 more from the other parent.
The resulting zygote will have three autosomal chromosomes or an autosomal trisomy.Another topic examiners love to focus on is Robertsonian translocation, which means that a piece of one chromosome translocates over to another chromosome.
The result is a hybrid chromosome with both long arms and one hybrid with both short arms. The one with the short arms is typically lost by the end of meiosis.
Having both long arms leads to “balanced carriers”, since most of the genes are still there. Now, the translocation can also be unbalanced, if one normal chromosome ends up with the short arm, and the other normal chromosome with the long arm.
And since the long arms carry most of the genetic material, cells with the long arm will basically have one extra chromosome, which, when combined with the other parent’s again, will result in trisomy, while cells with the short arm are basically missing a chromosome and can result in monosomy.
Finally, another high- yield mechanism is mosaicism. This occurs due to mutations that occur during embryonic development where one person has two or more different genotypes.
For example, these individuals may have some cells in their body with the 46 chromosomes, and others with 47 chromosomes, so a trisomy.Okay, now, the most common autosomal trisomies are trisomies 21, 18, and 13.
So, first, let’s go over trisomy 21, also known as Down syndrome. For your exams, you definitely need to remember that this is the most common chromosomal disorder in live births, affecting about 1 in every 700 infants born alive.

Trisomy 214:07–5:37

Another high- yield fact is that about 95% of cases result from nondisjunction. In 90% of these, the extra chromosome 21 originates from the mother.
In such cases, a major risk factor is advanced maternal age. In fact, for mothers younger than 20 years old, trisomy 21 happens in about one out of 1500 births.
On the other hand, for mothers older than 45 years old, this can happen in about one in 25 births. Now, another 4% of all trisomy 21 cases arise from an unbalanced Robertsonian translocation involving chromosome 21 with any other chromosome.
For your test, keep in mind that most often it’s chromosome 14. Finally, about 1% of individuals with Down syndrome are mosaic, meaning some of their cells have 46 chromosomes, and others have 47 chromosomes, with an extra chromosome 21.
Now, Down syndrome causes some classic physical characteristics, the most important of which are a flat facial profile, excessive skin at the back of the neck, epicanthal folds, upward- slanting palpebral fissures, a small nose and mouth, a large tongue and low-set ears, as well as a single transverse palmar crease, clinodactyly or curving of the fifth finger, and a big gap between the first two toes.

Physical Characteristics5:37–6:20

Another physical clue might be brushfield spots or small spots at the periphery of the iris. Having an extra chromosome 21 also has an effect on almost every organ system in the body.
About half of individuals with Down syndrome have cardiovascular complications. The most common ones are endocardial cushion defects, also known as atrioventricular septal defects, or AVSDs, which may involve the valves between the atria and the ventricles, as well as walls between the right and left atria and right and left ventricles.

Organ Complications6:20–11:18

Less commonly, Down syndrome can present ventricular septal defects, or VSDs, as well as atrial septal defects or ASDs. For your test, pay attention to auscultation clues.
With atrioventricular septal defects, heart murmurs can vary according to the exact type of the defect. With ventricular septal defects, a harsh holosystolic murmur is heard over the left sternal border.
Finally, atrial septal defects have a characteristic fixed split S2 heart sound, meaning that it’s split to the same degree during inspiration and expiration.Now, for gastrointestinal complications, remember that the most common one is duodenal atresia.
This is a failure to canalize, resulting in a blind pouch and intestinal obstruction. If the obstruction is before the major duodenal papilla, which is where bile and pancreatic juices are emptied into the duodenum, the infant will typically present with non-bilious vomiting.
On the other hand, if the obstruction is distal, they’ll have bilious vomiting. This often occurs just hours after birth.
A very high yield sign on radiography is the double bubble sign, where both the stomach and duodenum are filled with air, while no air can pass and be found distal to the obstruction.
Next, hematologic consequences mainly involve an increased risk of developing childhood leukemia, so both acute lymphoblastic leukemia or ALL for short, as well as acute myeloblastic leukemia or AML.
In a test question, this can show up as a child with recurrent respiratory tract infections, anemia and leukopenia on blood tests, and more than 20% blast cells in a bone marrow biopsy.
Regarding the urogenital system, males with Down syndrome often have decreased fertility or even sterility.Moving on to neurological complications, remember that trisomy 21 is the most common genetic cause of intellectual disability.
In addition, it is associated with early- onset Alzheimer disease, which often progresses by the age of 40. The major player here is amyloid precursor protein, or APP, which normally helps the neuron grow and repair.
Now, it turns out that the gene responsible for producing APP is located on chromosome 21. This means that people with Down syndrome have an extra APP gene, which can potentially increase the amount of amyloid plaque buildup.
Ultimately, these amyloid plaques can get between the neurons and impair their function.Finally, individuals with Down syndrome often present atlantoaxial instability, which is when the posterior transverse ligaments are “lax” or floppy.
These ligaments are responsible for holding together the first cervical vertebra, also known as C1 or atlas, and the second cervical vertebra, also known as C2 or axis.
Atlantoaxial instability results in decreased stability of the cervical spine, which can go on to compress the cervical nerve roots or spinal cord.
So, suspect atlantoaxial instability in someone with Down syndrome, present with motor symptoms, like weakness in the arms or legs, or torticollis, meaning the head tilting to one side.
To prevent that from happening, cervical spine precautions must be taken, like avoiding excessive neck extension or flexion and neurologic evaluation before participation in sports.Okay, now for diagnosis of Down syndrome, the first approach involves prenatal screening tests.
During the first trimester, most commonly between the 11th and 13th week of pregnancy, a combined test can be performed, combining a blood test with ultrasound.

Diagnosis & Screening11:18–13:36

The blood test involves beta human chorionic gonadotropin or β-hCG, which is typically elevated, and pregnancy-associated plasma protein A or PAPP-A, which is typically low, when compared to unaffected pregnancies.
Upon ultrasound, fetuses with Down syndrome exhibit increased nuchal translucency due to the build up of fluid in the neck area, as well as an absent or hypoplastic nasal bone, and shortened middle phalanges of the fifth digits.Then, in the second trimester, usually between weeks 15 and 18, a quadruple screening test can be done, where alpha-fetoprotein or AFP and unconjugated estriol or uE3, are on average lower, while β-hCG and inhibin A are both typically elevated compared to unaffected pregnancies.
For your test, a-fetoprotein levels are key, since elevated levels are often seen in multiple gestations, open neural tube defects, and abdominal wall defects.Now, if any of these screening tests come back abnormal, a karyotype analysis can be recommended to visualize each chromosome.
Remember that that’s the only actual way to confirm the diagnosis of Down syndrome. Karyotype analysis can be done before birth via chorionic-villus sampling between 9 and 11 weeks of gestation, or amniocentesis between 15 and 20 weeks of gestation, or at any time after birth with a simple blood test.Okay, now, let’s switch gears and talk about another trisomy, this time affecting chromosome 18, called Trisomy 18, also known as Edwards syndrome.
For your exams, remember that this is the second most common chromosomal disorder in live births, affecting about 1 in every 8,000 infants born alive.
Just like Down syndrome, the majority of the cases result from meiotic nondisjunction. And the most important risk factor is advanced maternal age.

Trisomy 1813:36–14:31

Apart from nondisjunction, a few cases result from unbalanced Robertsonian translocation involving chromosome 18, plus any other chromosome, typically chromosome 14.
Finally, about 1% of individuals are mosaic. Now, there is a long list of physical characteristics of Edwards syndrome, but the most important to memorize for your exam are microcephaly, which means small head, a prominent occiput, low-set ears, cleft lip and palate, which are openings in the upper lip or roof of the mouth, micrognathia, or abnormally small jaw, clenched hands with overlapping fingers, and rocker-bottom feet, which is when the soles of the feet are rounded and smooth like the bottom of a rocking chair.Now, most fetuses with Edwards syndrome die before birth, and those that survive pregnancy, usually die within a few weeks to months after birth due to complications.

Physical Characteristics14:31–15:10

Babies with Edwards syndrome typically develop severe intellectual disability and failure to thrive. Most will have a congenital heart defect, like a ventricular or atrial septal defect.

Organ Complications15:10–17:16

Now, gastrointestinal complications are especially high yield. One of them is omphalocele, which is when some of the bowels herniate out protrude through the umbilicus into the umbilical cord.
It’s important to differentiate that from gastroschisis, in which the abdominal organs protrude through a separate hole on the right side of the umbilicus.
Another difference is that, in gastroschisis, the abdominal contents can be directly seen since they are not covered by any peritoneal layer, whereas, in omphalocele, they are contained in a bubble or peritoneal sac.
Another common gastrointestinal complication is esophageal atresia, where the esophagus ends in a blind-ended pouch instead of continuing to the stomach.
Since the atresia prevents the baby from swallowing anything, like amniotic fluid, there will be polyhydramnios before birth.
Other high- yield complications include breathing problems due to pulmonary hypoplasia, frequent infections, and kidney malformations like horseshoe kidneys, where the two kidneys fuse together during fetal development, resulting in one horseshoe-shaped kidney.
Finally, babies with Edwards syndrome have increased risk of developing Wilms tumor, or nephroblastoma, which is a type of kidney tumor, as well as hepatoblastoma, which is a type of liver tumor.Okay, now, remember that examiners love screening tests!
So during the first trimester, βHCG and PAPP-A are typically decreased compared to unaffected pregnancies. On an ultrasound, look for an increased nuchal translucency.
During the second trimester, AFP and uE3 are also decreased. But another serum marker, inhibin A, is typically normal or slightly decreased.

Screening & Diagnosis17:16–18:08

Diagnosis can be confirmed with karyotyping before birth via chorionic-villus sampling between 9 and 11 weeks of gestation, or amniocentesis between 15 and 20 weeks of gestation, or at any time after birth with a blood test.Alright, the third most common autosomal trisomy is trisomy 13, also known as Patau syndrome.
This affects about 1 in 15,000 infants born alive. Just like the other two, it most commonly arises from meiotic nondisjunction, with advanced maternal age being the number one risk factor.
The next most common cause is unbalanced Robertsonian translocation between chromosome 13 and usually, chromosome 14. And finally, 1% of individuals are mosaic.

Trisomy 1318:08–18:50

The most classic physical characteristics of Patau syndrome are cutis aplasia, or scalp lesions with the absence of skin; microphthalmia, or small eyes; polydactyly, or having one or more extra fingers or toes; cleft lip and palate; and rocker bottom feet.
More severe defects include cyclopia, or having a single eye at the center of the forehead. For your exams, remember that this can occur as a result of the holoprosencephaly.

Physical Characteristics18:50–19:49

That’s because when the forebrain of the embryo fails to divide into the two brain hemispheres, the two orbits don’t divide into two cavities either, remaining in a single cavity.
Their nose might be also missing or replaced by a proboscis, which is an elongated organ like an elephant’s trunk.Now, just like with Edwards syndrome, most babies with Patau syndrome die before birth or shortly after due to complications.
One of them is holoprosencephaly, where there’s a failure of the prosencephalon, which is the forebrain of the embryo, to divide into two hemispheres.
Another common defect is meningomyelocele, which is a severe type of spina bifida where the spinal cord and the surrounding meninges protrude out of an opening in the bony vertebrae and are held together by a sack of skin that pouches out from the back.

Organ Complications19:49–20:56

Babies with Patau syndrome also experience developmental delays and will end up with a severe intellectual disability. Problems in other organ systems include gastrointestinal complications like an omphalocele, heart problems like septal defects, and renal problems like polycystic kidney disease, which is when the kidneys become filled with hundreds of cysts or fluid-filled sacs.OK, now when it comes to screening, during the first trimester, βHCG and PAPP-A are low, whereas ultrasound may show increased nuchal translucency.
During the second trimester, AFP, uE3, inhibin, and also HCG, are all normal, which can be misleading. Diagnosis is once again confirmed with karyotyping, either before or after birth.

Screening & Diagnosis20:56–21:30

All right, as a quick recap, in autosomal trisomies, there’s an extra copy of an autosomal chromosome.. The most common chromosomal abnormality in live births is trisomy 21 or Down syndrome.
This can affect almost all organ systems, causing duodenal atresia, atrioventricular septal defects, AML and ALL, male sterility, intellectual disability, early onset Alzheimer disease, and atlantoaxial instability.

Review21:30–24:10

Physical characteristics may include a single palmar crease in the hands, a gap between the first two toes, a flat facial profile, and epicanthal folds.
Next, there’s trisomy 18 or Edwards Syndrome, which also affects various organ systems, causing congenital heart defects, as well as kidney and gastrointestinal malformations.
Due to these fatal complications, affected babies usually die before birth. Those that survive will have dysmorphic features like microcephaly, low-set ears, cleft lip and palate, micrognathia, and rocker bottom feet.
Finally, in trisomy 13 or Patau syndrome, characteristic findings include intellectual disability, holoprosencephaly, cutis aplasia, polydactyly, cyclopia, and proboscis.
The affected babies usually die before birth. Now, on screening tests, during the first trimester, βHCG is high in trisomy 21 and low in trisomies 18 and 13; while PAPP-A is low in all three.
An ultrasound can also be performed to measure nuchal translucency. During the second trimester, the quadruple test will show an AFP and unconjugated estriol that are low in trisomies 21 and 18, and normal in trisomy 13; while βHCG is elevated in trisomy 21, decreased in trisomy 18, and normal in trisomy 13; and inhibin A is high in trisomy 21, decreased or normal in trisomy 18, and normal in trisomy 13.Okay, back to our cases.
Nikolas, the newborn infant, presented with bouts of bilious vomiting and a double- bubble sign on the abdominal x-ray, which suggests duodenal atresia.
This is the most common gastrointestinal complication of Down syndrome. Nikolas also presents a flat nasal bridge, small mouth with a large protruding tongue, and a single palmar crease on each hand, so diagnosis of Down syndrome is highly likely.

Summary24:10–25:26

On the other hand, Taylor was born prematurely with cutis aplasia, microcephaly, and polydactyly, which are characteristic for trisomy 13.
And Annita had a quadruple screen test during her second trimester, showing low AFP, βhCG, and unconjugated estriol, but normal inhibin A.
That’s a classic finding of trisomy 18. In all cases, the diagnosis was confirmed with karyotyping, which showed an extra chromosome 21, 13, or 18, depending on the disorder.
Keep in mind that all mothers had an advanced age, which increases the risk for autosomal trisomies. and Anita had a quadruple screen test during your second, trimester showing low AFP beta, HCG and unconjugated estradiol, but normal inhibin, a, That's a classic finding of Troy.
Show me 18 in all cases. The diagnosis was confirmed with karyotyping which showed an extra chromosome, 21, 13 or 18.
Depending on the disorder. Keep in mind, that all mothers had an advanced