What are the presenting clinical features of Crigler-Najjar syndrome?

Presenting Clinical Features of Crigler-Najjar Syndrome

Crigler-Najjar syndrome (CNS) presents primarily with marked unconjugated hyperbilirubinemia in the neonatal period, with normal liver function tests, and requires aggressive management to prevent kernicterus and permanent neurological damage. 1

Types and Pathophysiology

Crigler-Najjar syndrome is a rare autosomal recessive disorder caused by mutations in the UGT1A1 gene, resulting in deficiency of the hepatocyte enzyme uridine diphosphate glucuronosyl transferase (UGT). There are two types:

• Type I (CNI): Complete absence of UGT enzyme activity
• Type II (CNII): Partial deficiency of UGT enzyme activity

Key Clinical Presentations

Neonatal Presentation (Most Common)

• Severe jaundice: Appears within the first 3 days of life 2
• Marked unconjugated hyperbilirubinemia: Bilirubin levels typically between 12.5-32 mg/dL 2
• Normal liver function tests: Distinguishes from other causes of neonatal jaundice 1
• Absence of hemolysis: No evidence of blood disorders 2

Neurological Manifestations

• Risk of kernicterus: Particularly when bilirubin levels approach 25 mg/dL 2
• Neurological symptoms: May include:
  • Poor feeding
  • Lethargy
  • Hypotonia
  • Seizures
  • Hearing loss
  • Developmental delay

Type-Specific Features

Type I (Severe Form)

• Persistent severe jaundice: Does not respond to phenobarbital 1
• Very high bilirubin levels: Often >20 mg/dL
• Early risk of kernicterus: Can occur at any age, including infancy 1
• Requires intensive phototherapy: 20-24 hours/day during crises and 8-12 hours daily maintenance 1

Type II (Milder Form)

• Lower bilirubin levels: Typically <20 mg/dL
• Responds to phenobarbital: Shows reduction in bilirubin levels with treatment 3
• Better prognosis: Patients often survive into adulthood without neurological impairment 4

Diagnostic Considerations

Laboratory Findings

• Elevated unconjugated (indirect) bilirubin: Hallmark finding
• Normal direct bilirubin: Distinguishes from obstructive causes
• Normal liver enzymes: ALT, AST, alkaline phosphatase typically normal
• Genetic testing: Mutations in the UGT1A1 gene 2
• Liver biopsy: May show normal histology but inactive UGT enzyme 2

Differential Diagnosis

• Physiologic jaundice (resolves within 2 weeks)
• Breast milk jaundice (resolves by 12 weeks)
• Hemolytic disorders (G6PD deficiency, spherocytosis)
• Gilbert syndrome (milder form of UGT1A1 deficiency)
• Other metabolic liver diseases

Long-Term Complications

• Kernicterus: Permanent neurological damage from bilirubin encephalopathy 5
• Progressive liver disease: Recently identified in some patients with specific genetic variants (c.115C>G) despite mild CNS phenotype 6
• Complications during pregnancy: Unconjugated bilirubin can cross placental barrier causing neurological damage to the fetus 3

Important Clinical Pearls

1. Early diagnosis is critical: Jaundice persisting beyond 2 weeks requires urgent evaluation to rule out CNS and other serious conditions like biliary atresia 7

2. Monitoring is essential: Regular measurement of total serum bilirubin levels until clearly declining 7

3. Type I CNS requires liver transplantation: It is the only definitive treatment, ideally performed before the onset of irreversible brain damage 1, 5

4. Phototherapy requirements are intensive: For Type I, phototherapy needs to be maintained for 8-16 hours daily, which becomes increasingly difficult as children grow 2

5. Recent research indicates: Some patients with mild CNS may develop progressive liver disease despite having lower bilirubin levels, requiring close monitoring 6

By recognizing these clinical features early, clinicians can initiate appropriate management to prevent the devastating neurological consequences of this rare but serious disorder.