Crigler-Najjar syndrome

Crigler-Najjar syndrome (CNS) is a rare inherited disorder of bilirubin conjugation characterised by persistent severe unconjugated hyperbilirubinaemia in the absence of haemolysis or hepatocellular dysfunction. Two clinical forms are distinguished.

Type 1 (CN1) is the severe form, defined by complete absence of UGT1A1 enzyme activity; affected neonates present from the first days of life with profound jaundice and, without intervention, are at high risk of kernicterus and irreversible bilirubin encephalopathy.

Type 2 (CN2) is the milder form, with partial residual enzyme activity, typically lower bilirubin levels, and a substantially reduced risk of kernicterus. Clinical manifestations reflect hyperbilirubinaemia and, in severe cases, its neurological complications, including kernicterus. Type 2 typically responds to phenobarbital with a measurable reduction in serum bilirubin, whereas type 1 does not.

Crigler–Najjar syndrome is an extremely rare disorder with an estimated incidence of approximately 1 per million live births.

Crigler–Najjar syndrome is caused by biallelic germline pathogenic variants in UGT1A1 (2q37.1), which encodes the hepatic enzyme UDP-glucuronosyltransferase 1A1. Complete loss of enzymatic activity results in the severe type I phenotype, whereas markedly reduced but residual activity leads to the milder type II phenotype. Impaired UGT1A1 function prevents glucuronidation of unconjugated bilirubin in hepatocytes, resulting in accumulation of unconjugated bilirubin in the circulation and causing severe unconjugated hyperbilirubinaemia.

Crigler-Najjar syndrome is inherited in an autosomal recessive manner.

The diagnosis of Crigler–Najjar syndrome is based on the demonstration of persistent, severe unconjugated (indirect) hyperbilirubinaemia in the absence of haemolysis or hepatocellular dysfunction. Type II is distinguished from type I by a partial reduction in serum bilirubin levels in response to phenobarbital. As no single biochemical or imaging marker reliably distinguishes Crigler–Najjar syndrome from other inherited causes of unconjugated hyperbilirubinaemia, the diagnosis is confirmed by molecular genetic testing identifying biallelic pathogenic variants in UGT1A1.

Main differential diagnoses include:

• : mild, intermittent unconjugated hyperbilirubinaemia without kernicterus risk; allelic disorder caused by reduced (rather than absent or markedly reduced) UGT1A1 activity, most commonly the A(TA)7TAA promoter variant; UGT1A1
• Hemolytic disorders: associated with increased bilirubin production due to red blood cell breakdown and characterised by laboratory evidence of haemolysis.
• Physiological or neonatal jaundice: a transient and self-limited condition occurring in newborns, in contrast to the persistent and often severe hyperbilirubinaemia seen in Crigler–Najjar syndrome.

• Establishing the diagnosis: molecular genetic testing confirms the diagnosis by identifying pathogenic variants in UGT1A1 and enables differentiation between Crigler–Najjar syndrome and other inherited unconjugated hyperbilirubinaemias.
• Clinical management: identification of the underlying genotype helps distinguish between Crigler–Najjar syndrome types I and II and can inform prognosis and management.
• Family member testing: identification of the familial pathogenic variant(s) enables testing of at-risk relatives and supports genetic counselling.

• Sambati V, Laudisio S, Motta M, Esposito S. Therapeutic options for Crigler-Najjar syndrome: a scoping review. Int J Mol Sci. 2024;25(20):11006. doi:10.3390/ijms252011006. PMID: . PMCID: PMC11508002.
• Strauss KA, Ahlfors CE, Soltys K, Mazareigos GV, Young M, Bowser LE, et al. Crigler-Najjar syndrome type 1: pathophysiology, natural history, and therapeutic frontier. Hepatology. 2020;71(6):1923-1939. doi:10.1002/hep.30959. PMID: . PMCID: PMC7909716.