Pathology · Year 2 · from Pathology

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:

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

1. 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

1. 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

1. Chronic Complications:

• Functional asplenia (autosplenectomy) → infection risk
• Howell-Jolly bodies indicate splenic dysfunction
• Aplastic crisis (parvovirus B19)
• Stroke, avascular necrosis, priapism

Clinical Image

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

1. Supportive care:

• Monitor for acute chest syndrome
• Incentive spirometry
• Blood transfusion if severe anemia

1. Disease-modifying therapy:

• Hydroxyurea (increases HbF, reduces sickling)
• Folic acid supplementation
• Pneumococcal and meningococcal vaccination
• Consider chronic transfusion therapy if stroke risk

1. 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

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