Pathology · Year 2 · from Pathology

Case 1: Down Syndrome - Chromosomal Aneuploidy

Patient Demographics

• Age: Newborn (2 days old)
• Sex: Male
• Mother's age: 42 years old

Chief Complaint

"The baby looks different and has a heart murmur"

History of Present Illness

A male infant was born at 38 weeks gestation to a 42-year-old G3P2 mother via vaginal delivery. Birth weight was 2.8 kg (10th percentile). The pregnancy was uncomplicated, and the mother declined prenatal genetic testing due to personal beliefs. At the initial newborn examination, the pediatrician noted distinctive facial features and detected a heart murmur. The infant has been feeding poorly and appears hypotonic. APGAR scores were 7 at 1 minute and 8 at 5 minutes.

Physical Examination

• Vital Signs: HR 142 bpm, RR 48/min, Temp 36.8°C, SpO2 94% on room air
• General: Hypotonic infant with characteristic facial features
• Head/Face:
• Flat facial profile
• Upslanting palpebral fissures
• Epicanthal folds
• Small, low-set ears
• Protruding tongue (relative macroglossia)
• Flat nasal bridge
• Brachycephaly (flat occiput)
• Cardiovascular: 3/6 holosystolic murmur at left lower sternal border, no cyanosis
• Hands: Short, broad hands with single transverse palmar crease (simian crease), clinodactyly of 5th finger
• Feet: Wide gap between 1st and 2nd toes (sandal gap deformity)
• Neurologic: Generalized hypotonia, decreased Moro reflex

Diagnostic Workup

Laboratory Studies:

Karyotype:

• 47,XY,+21 (Trisomy 21 - nondisjunction type)

Imaging:

• Echocardiogram: Complete atrioventricular canal defect (AVCD) with primum ASD, inlet VSD, and common AV valve
• Abdominal ultrasound: Normal (no duodenal atresia)

Additional Screening:

• Hearing screen: Refer for audiology follow-up
• Ophthalmology: Brushfield spots on iris

Pathology Correlation

This case demonstrates chromosomal aneuploidy (trisomy 21):

1. Mechanism of Nondisjunction:

• Failure of chromosome 21 to separate during meiosis
• Maternal age is the strongest risk factor (1 in 25 at age 45)
• 95% of cases result from meiotic nondisjunction
• 3-4% from Robertsonian translocation (familial)
• 1-2% from mosaicism

1. Phenotypic Features:

• Characteristic facial features (flat profile, epicanthal folds)
• Hypotonia
• Intellectual disability (IQ typically 25-50)
• Congenital heart defects (40-50%) - AVCD is most characteristic
• GI abnormalities (duodenal atresia)

1. Pathophysiology:

• Extra copy of chromosome 21 genes
• Gene dosage imbalance affects multiple organ systems
• Overexpression of genes including APP (Alzheimer's precursor)

1. Associated Conditions:

• Increased risk of acute leukemia (10-20x)
• Early-onset Alzheimer disease (by age 40)
• Hypothyroidism
• Atlantoaxial instability
• Obstructive sleep apnea

Clinical Image

Karyotype demonstrating trisomy 21 (Down syndrome). Note the three copies of chromosome 21 (circled), resulting from nondisjunction during meiosis. The total chromosome count is 47 instead of the normal 46. This chromosomal abnormality is the most common genetic cause of intellectual disability.

Image Source: Wikimedia Commons - "Down Syndrome Karyotype" License: Public Domain (NIH) URL: https://commons.wikimedia.org/wiki/File:Down_Syndrome_karyotype.png

Diagnosis

Down Syndrome (Trisomy 21) with complete atrioventricular canal defect

Treatment and Management

1. Cardiac:

• Cardiology follow-up
• Surgical repair of AVCD typically at 3-6 months of age
• Endocarditis prophylaxis

1. Developmental:

• Early intervention services
• Physical therapy for hypotonia
• Speech therapy
• Special education support

1. Medical surveillance:

• Thyroid function annually
• Hearing evaluation every 6 months until age 3
• Ophthalmology evaluation
• Atlantoaxial screening before contact sports
• Celiac disease screening

1. Family support:

• Genetic counseling for parents
• Support group referral
• Discussion of recurrence risk

Teaching Points

1. Nondisjunction during meiosis produces aneuploidy (abnormal chromosome number)
2. Maternal age is the strongest risk factor for trisomy 21 (1/700 overall, 1/25 at age 45)
3. Complete AVCD (endocardial cushion defect) is the most characteristic cardiac malformation
4. Karyotype is the gold standard for diagnosis (identifies trisomy vs translocation)
5. Patients with Down syndrome have increased risk of acute leukemia and early-onset Alzheimer disease
6. Prenatal screening (cell-free fetal DNA, quad screen) can identify high-risk pregnancies
7. Life expectancy has improved dramatically with cardiac surgery and medical care (>60 years)

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