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Autosomal trisomies: Pathology review





Population genetics
Genetic disorders
Down syndrome (Trisomy 21)
Edwards syndrome (Trisomy 18)
Patau syndrome (Trisomy 13)
Fragile X syndrome
Huntington disease
Myotonic dystrophy
Friedreich ataxia
Turner syndrome
Klinefelter syndrome
Prader-Willi syndrome
Angelman syndrome
Beckwith-Wiedemann syndrome
Cri du chat syndrome
Williams syndrome
Alagille syndrome (NORD)
Polycystic kidney disease
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary spherocytosis
Huntington disease
Li-Fraumeni syndrome
Marfan syndrome
Multiple endocrine neoplasia
Myotonic dystrophy
Treacher Collins syndrome
Tuberous sclerosis
von Hippel-Lindau disease
Polycystic kidney disease
Cystic fibrosis
Friedreich ataxia
Gaucher disease (NORD)
Glycogen storage disease type I
Glycogen storage disease type II (NORD)
Glycogen storage disease type III
Glycogen storage disease type IV
Glycogen storage disease type V
Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)
Krabbe disease
Niemann-Pick disease types A and B (NORD)
Niemann-Pick disease type C
Primary ciliary dyskinesia
Phenylketonuria (NORD)
Sickle cell disease (NORD)
Tay-Sachs disease (NORD)
Wilson disease
Fragile X syndrome
Alport syndrome
X-linked agammaglobulinemia
Fabry disease (NORD)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)
Lesch-Nyhan syndrome
Muscular dystrophy
Ornithine transcarbamylase deficiency
Wiskott-Aldrich syndrome
Mitochondrial myopathy
Autosomal trisomies: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
Miscellaneous genetic disorders: Pathology review

Autosomal trisomies: Pathology review


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USMLE® Step 1 style questions USMLE

12 questions

A 35-year-old primigravida comes to the office to discuss the results of abnormal laboratory tests. The patient is at 12 weeks gestation based on her last menstrual period. She has been taking prenatal vitamins consistently and has no active complaints. Past medical history is noncontributory. First trimester screening tests revealed reduced levels of β-hCG and pregnancy-associated plasma protein-A.  Ultrasound at that time demonstrated nuchal thickening. Chorionic villus sampling reveals a fetal karyotype of 47, XX, +13. The fetus is at the greatest risk of developing which of the following conditions?  


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. 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. 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. 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. 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.

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