A 5-year-old boy is brought to the physician because of behavioral problems. His mother says that he has frequent angry outbursts and gets into fights with his classmates. He constantly complains of feeling hungry, even after eating a full meal. He has no siblings, and both of his parents are healthy. He is at the 25th percentile for height and is above the 95th percentile for weight. Physical examination shows central obesity, undescended testes, almond-shaped eyes, and a thin upper lip. Which of the following genetic changes is most likely associated with this patient's condition?

Loss of paternal gene expression on chromosome 15

Mitotic nondisjunction of chromosome 21

Mutation of FBN-1 gene on chromosome 15

Microdeletion of long arm of chromosome 7

Deletion of Phe508 on chromosome 7

A 1-week-old baby is brought to the pediatrician’s office for a routine checkup. On examination, she is observed to have microcephaly with a prominent occiput. She also has clenched fists and rocker-bottom feet with prominent calcanei. A cardiac murmur is evident on auscultation. Based on the clinical findings, a diagnosis of nondisjunction of chromosome 18 is suspected. The pediatrician orders a karyotype for confirmation. He goes on to explain to the mother that her child will face severe growth difficulties. Even if her daughter progresses beyond a few months, she will not be able to reach developmental milestones at the appropriate age. In addition to the above, which of the following is most likely a consequence of this genetic disturbance?

Death within the first year of life

A 6-year-old male presents to the pediatrician with seizures. His mother reports that the patient has had two seizures lasting about 30 seconds each over the last three days. She reports that the patient has previously had seizures a few times per year since he was 12 months of age. The patient’s past medical history is otherwise notable for intellectual disability. He rolled over at 14 months of age and walked at 24 months of age. The patient’s mother denies any family history of epilepsy or other neurologic diseases. The patient is in the 3rd percentile for height and the 15th percentile for weight. On physical exam, he has a happy demeanor with frequent smiling. The patient has strabismus and an ataxic gait accompanied by flapping of the hands. He responds intermittently to questions with one-word answers. This patient is most likely to have which of the following genetic abnormalities?

Paternal uniparental disomy of chromosome 15

Chromosomal macrodeletion on chromosome 5

Maternal uniparental disomy of chromosome 15

Imprinting defect on chromosome 11

Chromosomal disorders for USMLE Step 3: High-Yield Pediatrics Lessons

Autosomal Trisomies - Three's a Crowd

Most common aneuploidies, caused by meiotic nondisjunction.

Karyotype of Trisomy 21 (Down Syndrome)

Feature	Trisomy 21 (Down Syndrome)	Trisomy 18 (Edwards Syndrome)	Trisomy 13 (Patau Syndrome)
Incidence	1 in 700	1 in 8000	1 in 10,000
Facies	Flat facies, upslanting eyes, Brushfield spots	Micrognathia, low-set ears, prominent occiput	Cleft liP/Palate, microphthalmia, holoprosencephaly
Hands/Feet	Single palmar (simian) crease, sandal gap	Clenched fist (overlapping fingers), rocker-bottom feet	Polydactyly, rocker-bottom feet
Cardiac	Endocardial cushion defect (AVSD)	VSD	VSD, PDA
Prognosis	IQ ~50, 50% survive to >50 years	Median survival < 1 year	Median survival < 1 year

⭐ Exam Favourite: While Down Syndrome is associated with advanced maternal age, most babies with Down Syndrome are born to younger mothers because of higher birth rates in that group.

Sex Chromosomes - X's and Y's

Feature	Turner Syndrome (45,X)	Klinefelter Syndrome (47,XXY)
Karyotype	45,X (most common mosaicism)	47,XXY
Phenotype	Female, short stature, webbed neck (pterygium colli), shield chest, low posterior hairline.	Male, tall stature, gynecomastia, small, firm testes, long limbs (eunuchoid habitus).
Hormones	↓ Estrogen, ↑↑ FSH, LH (hypergonadotropic hypogonadism). Streak gonads.	↓ Testosterone, ↑ Estradiol, ↑ FSH, LH (hypergonadotropic hypogonadism).
Associations	Coarctation of aorta (15-30%), bicuspid aortic valve (30%), horseshoe kidney, cystic hygroma.	Learning disabilities, metabolic syndrome, ↑ risk of breast cancer & autoimmune disease.

⭐ The most common cause of primary amenorrhea is gonadal dysgenesis, and Turner Syndrome is a key cause. Intelligence is usually normal.

📌 Mnemonic (Klinefelter): Kings are TALL, have MAN-BOOBS (gynecomastia), and are STERILE.

Microdeletions - A Little Bit Missing

Detected by FISH or microarray, these involve loss of a small chromosomal segment.

Syndrome	Deletion	Key Features
Cri-du-chat	5p	High-pitched, cat-like cry; microcephaly; VSD.
DiGeorge	22q11.2	Thymic/parathyroid aplasia, conotruncal cardiac defects, abnormal facies.
Williams	7q11.23	"Elfin" facies, hypercalcemia, supravalvular aortic stenosis, "cocktail party" personality.
Prader-Willi	Paternal 15q	Neonatal hypotonia, failure to thrive; later hyperphagia & obesity.
Angelman	Maternal 15q	"Happy puppet" ataxia, inappropriate laughter, seizures, severe ID.

⭐ Prader-Willi and Angelman syndromes are key examples of genomic imprinting; the phenotype depends on the parental origin of the deleted chromosome 15q.

📌 CATCH-22 for DiGeorge: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, chromosome 22.

High-Yield Points - ⚡ Biggest Takeaways

Down syndrome (Trisomy 21): Most common chromosomal disorder, linked to advanced maternal age.

Edwards syndrome (Trisomy 18): Key signs are clenched hands and rocker-bottom feet.

Patau syndrome (Trisomy 13): Presents with severe midline defects like holoprosencephaly.

Turner syndrome (45, XO): Look for webbed neck, coarctation of the aorta, and streak gonads.

Klinefelter syndrome (47, XXY): Most common cause of male hypogonadism; presents with gynecomastia.

Fragile X (CGG repeat): Most common inherited cause of intellectual disability; features macroorchidism.

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