Pathology · Year 2 · from Pathology

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:

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

1. 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)

1. 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)

1. DeltaF508 Mutation:

• Deletion of phenylalanine at position 508
• Causes misfolding and degradation of CFTR protein
• Most common severe mutation

Clinical Image

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

1. Nutritional:

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

1. Disease-modifying therapy:

• CFTR modulators (for appropriate mutations):
• Ivacaftor (potentiator)
• Lumacaftor/tezacaftor (correctors)
• Elexacaftor/tezacaftor/ivacaftor (triple therapy for deltaF508)

1. 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

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