# Clinical Cases: Genetic Disorders

## 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:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| TSH | 12.5 mU/L | <10 mU/L (newborn) |
| Free T4 | 0.9 ng/dL | 0.9-2.3 ng/dL |
| Hemoglobin | 18.2 g/dL | 14-24 g/dL |
| WBC | 22,000/μL | 9,000-30,000/μL |

**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

2. **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)

3. **Pathophysiology:**
   - Extra copy of chromosome 21 genes
   - Gene dosage imbalance affects multiple organ systems
   - Overexpression of genes including APP (Alzheimer's precursor)

4. **Associated Conditions:**
   - Increased risk of acute leukemia (10-20x)
   - Early-onset Alzheimer disease (by age 40)
   - Hypothyroidism
   - Atlantoaxial instability
   - Obstructive sleep apnea

### Clinical Image
![Down Syndrome - Karyotype](case_01_image.jpg)

*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

2. **Developmental:**
   - Early intervention services
   - Physical therapy for hypotonia
   - Speech therapy
   - Special education support

3. **Medical surveillance:**
   - Thyroid function annually
   - Hearing evaluation every 6 months until age 3
   - Ophthalmology evaluation
   - Atlantoaxial screening before contact sports
   - Celiac disease screening

4. **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)

---

## Case 2: Sickle Cell Disease - Autosomal Recessive Hemoglobinopathy

### Patient Demographics
- **Age:** 8 years old
- **Sex:** Male
- **Ethnicity:** African American

### Chief Complaint
"My legs and back hurt really bad and won't stop"

### History of Present Illness
An 8-year-old boy with known sickle cell disease (HbSS) presents to the emergency department with severe pain in his lower back and bilateral legs that began 12 hours ago. He rates the pain as 10/10 and describes it as constant and throbbing. He recently had a cold and has been less active due to fatigue. His parents have given him oral oxycodone at home without relief. He has had 3 previous pain crises in the past year, each requiring hospitalization. He is up to date on vaccinations including pneumococcal and meningococcal vaccines.

### Physical Examination
- **Vital Signs:** BP 102/68 mmHg, HR 112 bpm, RR 24/min, Temp 38.2°C (100.8°F), SpO2 95% on room air
- **General:** Ill-appearing boy in obvious distress, crying from pain
- **HEENT:** Icteric sclerae
- **Cardiovascular:** Tachycardic, 2/6 systolic flow murmur
- **Lungs:** Clear to auscultation
- **Abdomen:** Mild splenomegaly (unusual for his age - suggests early disease)
- **Musculoskeletal:** Tenderness to palpation of lumbar spine and bilateral femurs, no swelling or erythema
- **Neurologic:** Alert, no focal deficits

### Diagnostic Workup

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| Hemoglobin | 7.2 g/dL | 11-16 g/dL |
| MCV | 88 fL | 80-100 fL |
| Reticulocyte count | 12% | 0.5-2% |
| WBC | 18,400/μL | 4,500-11,000/μL |
| Total bilirubin | 4.8 mg/dL | 0.1-1.2 mg/dL |
| LDH | 680 U/L | 140-280 U/L |
| Haptoglobin | <10 mg/dL | 30-200 mg/dL |

**Peripheral Blood Smear:**
- Sickle cells (drepanocytes)
- Target cells
- Howell-Jolly bodies (functional asplenia)
- Polychromasia (reticulocytosis)

**Hemoglobin Electrophoresis (prior):**
- HbS: 85%
- HbA: 0%
- HbA2: 3%
- HbF: 12%

**Imaging:**
- **Chest X-ray:** No infiltrates (ruled out acute chest syndrome)

### Pathology Correlation
This case demonstrates **autosomal recessive inheritance** and hemoglobin sickling:

1. **Genetic Basis:**
   - Point mutation in beta-globin gene (chromosome 11)
   - GAG → GTG codon change (glutamic acid → valine at position 6)
   - Both alleles must be affected (homozygous HbSS) for disease
   - Heterozygotes (HbAS = sickle trait) are typically asymptomatic

2. **Pathophysiology of Sickling:**
   - Deoxygenated HbS polymerizes into rigid fibers
   - RBCs deform into sickle shape
   - Rigid cells obstruct microvasculature (vaso-occlusion)
   - Repeated sickling damages RBC membrane → hemolysis

3. **Vaso-Occlusive Crisis:**
   - Triggers: Infection, dehydration, hypoxia, cold, stress
   - Sickling causes microvascular occlusion
   - Tissue ischemia and infarction cause pain
   - Common sites: Bones, chest, abdomen, CNS

4. **Chronic Complications:**
   - Functional asplenia (autosplenectomy) → infection risk
   - Howell-Jolly bodies indicate splenic dysfunction
   - Aplastic crisis (parvovirus B19)
   - Stroke, avascular necrosis, priapism

### Clinical Image
![Sickle Cell Disease - Blood Smear](case_02_image.jpg)

*Peripheral blood smear demonstrating sickle cell disease. Multiple sickle cells (drepanocytes) are visible with their characteristic elongated, crescent shape. The sickling occurs when deoxygenated hemoglobin S polymerizes into rigid fibers that distort the red blood cell membrane. Target cells and polychromasia from reticulocytosis are also present.*

**Image Source:** Wikimedia Commons - "Sickle Cell"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Sickle_cell_01.jpg

### Diagnosis
**Vaso-Occlusive Crisis** in Sickle Cell Disease (HbSS)

### Treatment
1. **Acute pain management:**
   - IV opioids (morphine or hydromorphone PCA)
   - NSAIDs (ketorolac) if renal function normal
   - Hydration with IV fluids
   - Supplemental oxygen if hypoxic

2. **Supportive care:**
   - Monitor for acute chest syndrome
   - Incentive spirometry
   - Blood transfusion if severe anemia

3. **Disease-modifying therapy:**
   - Hydroxyurea (increases HbF, reduces sickling)
   - Folic acid supplementation
   - Pneumococcal and meningococcal vaccination
   - Consider chronic transfusion therapy if stroke risk

4. **Curative options:**
   - Hematopoietic stem cell transplant (only cure)
   - Gene therapy (investigational)

### Teaching Points
1. **Autosomal recessive disorders** require two mutant alleles for disease expression
2. Sickle cell disease results from a **single nucleotide substitution** (point mutation)
3. **Heterozygote advantage:** Sickle trait provides malaria protection, explaining high prevalence in endemic areas
4. **Vaso-occlusion** from sickled RBCs causes the hallmark painful crises
5. **Howell-Jolly bodies** indicate functional asplenia (autosplenectomy)
6. **Hydroxyurea** increases fetal hemoglobin (HbF), which inhibits HbS polymerization
7. Patients are at increased risk for infections with **encapsulated organisms** due to splenic dysfunction

---

## Case 3: Cystic Fibrosis - Autosomal Recessive Multi-System Disease

### Patient Demographics
- **Age:** 6 months old
- **Sex:** Female
- **Ethnicity:** Caucasian

### Chief Complaint
"My baby isn't gaining weight despite good feeding"

### History of Present Illness
A 6-month-old female infant is brought to the pediatrician for failure to thrive. Despite breastfeeding well and supplementing with formula, she has dropped from the 50th percentile at birth to below the 5th percentile for weight. Parents report she has frequent, bulky, foul-smelling stools that are difficult to flush. She has had two episodes of bronchiolitis in the past 3 months, each requiring nebulizer treatments. At birth, she passed meconium late (at 36 hours of life). Newborn screening was positive for elevated immunoreactive trypsinogen (IRT), but the family missed the follow-up appointment.

### Physical Examination
- **Vital Signs:** HR 130 bpm, RR 36/min, Temp 37.0°C, SpO2 96% on room air
- **Growth:** Weight <5th percentile, Length 25th percentile, Head circumference 50th percentile
- **General:** Thin infant with decreased subcutaneous fat
- **HEENT:** No nasal polyps
- **Lungs:** Mild scattered rhonchi bilaterally
- **Cardiovascular:** Normal
- **Abdomen:** Mildly distended, no hepatosplenomegaly
- **Skin:** Salty taste when kissed (per mother)
- **Extremities:** Mild digital clubbing

### Diagnostic Workup

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| Sweat chloride | 85 mEq/L | <30 mEq/L (normal) |
| Fecal elastase | <15 μg/g | >200 μg/g |
| Fat-soluble vitamins | Low A, D, E, K | Variable |
| Albumin | 2.8 g/dL | 3.5-5.5 g/dL |

**Genetic Testing:**
- Homozygous for deltaF508 mutation in CFTR gene
- Both parents confirmed carriers (heterozygous deltaF508)

**Imaging:**
- **Chest X-ray:** Hyperinflation, mild peribronchial thickening
- **Abdominal ultrasound:** Echogenic pancreas

**Pulmonary Function:** Deferred (too young)

**Sputum/Throat Culture:** Staphylococcus aureus

### Pathology Correlation
This case demonstrates **autosomal recessive inheritance** of cystic fibrosis:

1. **Genetic Basis:**
   - Mutations in CFTR gene (chromosome 7)
   - DeltaF508 is most common mutation (70% of alleles)
   - CFTR encodes a chloride channel
   - Both alleles must be mutated for disease (autosomal recessive)
   - Carrier frequency: 1/25 in Caucasians

2. **Pathophysiology:**
   - Defective chloride transport across epithelial cells
   - Thick, viscous secretions in multiple organs
   - **Lungs:** Mucus plugging, chronic infection, bronchiectasis
   - **Pancreas:** Duct obstruction, exocrine insufficiency
   - **GI:** Meconium ileus (newborn), distal intestinal obstruction
   - **Sweat glands:** Elevated chloride (basis for sweat test)

3. **Progressive Organ Damage:**
   - Chronic pulmonary infections (S. aureus early, P. aeruginosa later)
   - Bronchiectasis and respiratory failure
   - Pancreatic fibrosis and diabetes (CF-related)
   - Male infertility (absent vas deferens)

4. **DeltaF508 Mutation:**
   - Deletion of phenylalanine at position 508
   - Causes misfolding and degradation of CFTR protein
   - Most common severe mutation

### Clinical Image
![Cystic Fibrosis - Pancreatic Pathology](case_03_image.jpg)

*Gross pathology of pancreas in cystic fibrosis demonstrating extensive fibrosis and atrophy replacing normal pancreatic tissue. The obstruction of pancreatic ducts by thick secretions leads to autodigestion and progressive destruction of exocrine tissue, resulting in pancreatic insufficiency with malabsorption of fats and fat-soluble vitamins.*

**Image Source:** Wikimedia Commons - "Cystic Fibrosis Pancreas"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Cystic_fibrosis_-_high_mag.jpg

### Diagnosis
**Cystic Fibrosis** (homozygous deltaF508) with pancreatic insufficiency

### Treatment
1. **Pulmonary:**
   - Airway clearance therapy (chest physiotherapy)
   - Inhaled mucolytics (dornase alfa)
   - Inhaled hypertonic saline
   - Prophylactic antibiotics as needed

2. **Nutritional:**
   - Pancreatic enzyme replacement (lipase, protease, amylase)
   - High-calorie, high-fat diet
   - Fat-soluble vitamin supplementation (A, D, E, K)
   - Salt supplementation

3. **Disease-modifying therapy:**
   - CFTR modulators (for appropriate mutations):
     - Ivacaftor (potentiator)
     - Lumacaftor/tezacaftor (correctors)
     - Elexacaftor/tezacaftor/ivacaftor (triple therapy for deltaF508)

4. **Monitoring:**
   - Quarterly pulmonary function tests (when older)
   - Annual glucose tolerance test
   - Sputum cultures
   - Nutritional status

### Teaching Points
1. **Cystic fibrosis** is the most common lethal autosomal recessive disease in Caucasians
2. The **sweat chloride test** remains the gold standard for diagnosis (>60 mEq/L diagnostic)
3. **DeltaF508** is the most common CFTR mutation (causes protein misfolding)
4. **Pancreatic insufficiency** causes fat malabsorption with steatorrhea
5. **CFTR modulators** represent precision medicine targeting specific mutations
6. Newborn screening uses **immunoreactive trypsinogen** as an initial marker
7. **Median survival** has improved dramatically to >50 years with modern treatment