Crigler-Najjar syndrome

Crigler-Najjar syndrome is a metabolic liver disorder that impairs the body’s ability to process bilirubin, leading to a buildup of unconjugated (indirect) bilirubin in the bloodstream. It is caused by pathogenic variants in the UGT1A1 gene, which encodes the enzyme responsible for attaching a water-soluble molecule (glucuronic acid) to bilirubin so it can be excreted. Symptoms usually begin in the newborn period, although the condition can affect individuals throughout life. Crigler-Najjar syndrome is considered uncommon, affecting an estimated one to nine individuals per 100,000 people worldwide. Severity and symptoms vary widely between individuals.

Jaundice that appears within the first few days of life is the hallmark feature and often prompts medical evaluation. The yellow discoloration results from unconjugated hyperbilirubinemia, which can reach very high levels in some infants. Early manifestations may also include poor feeding, lethargy, and a high-pitched cry. If bilirubin levels remain uncontrolled, the pigment can cross into the brain and cause kernicterus, a form of bilirubin-induced neurological damage characterized by hypotonia, seizures, opisthotonus, hearing impairment, and, in severe cases, coma. Cognitive impairment and other longer-term neurological difficulties have been reported in a subset of individuals who experience high bilirubin exposure, highlighting the condition’s potential cognitive impact. Over time, some children develop pruritus (intense itching) and hepatosplenomegaly. Less common features include vertigo, ophthalmoparesis, memory difficulties, and enamel hypoplasia. Not all individuals experience all features, and severity varies considerably. People with the milder type 2 form often respond to certain medications that induce residual enzyme activity, whereas those with type 1 have a complete enzyme deficiency and usually exhibit more severe symptoms.

Crigler-Najjar syndrome results from pathogenic variants in the UGT1A1 gene. This gene provides instructions for making bilirubin UDP-glucuronosyltransferase, the liver enzyme that converts unconjugated bilirubin into a conjugated form that can be eliminated from the body. When both copies of UGT1A1 carry harmful changes, the enzyme’s activity is greatly reduced (type 2) or virtually absent (type 1), leading to bilirubin accumulation. Most families described in the medical literature show a pattern in which affected individuals inherit two altered copies of the gene, one from each parent, suggesting autosomal recessive inheritance. However, specific inheritance information should be confirmed for each family through genetic counseling and testing. Even within families, the exact enzyme activity and clinical severity can differ, illustrating variable expressivity.

Currently, management focuses on supportive care and symptom control, and typically involves a multidisciplinary team experienced in metabolic liver disorders. High-intensity phototherapy is the mainstay of care for many infants and children; the light helps convert bilirubin into forms that can be excreted without liver processing. Some individuals with the milder type 2 form benefit from phenobarbital, which induces residual enzyme activity and lowers bilirubin levels. For those with severe, treatment-resistant hyperbilirubinemia, liver transplantation may be considered to provide a permanent source of functional enzyme. Long-term management includes regular surveillance of bilirubin levels, liver function, growth, hearing, and neurodevelopment to detect complications early. Families often work closely with hepatologists, neurologists, dietitians, and other specialists to coordinate care. Genetic counseling is recommended for affected individuals and their relatives to discuss inheritance, testing options, and family planning.

Outcomes depend on the type of enzyme deficiency, the effectiveness of bilirubin-lowering therapies, and timely access to specialized care. Individuals with type 2, who retain some enzyme activity, often achieve good bilirubin control and can lead active lives with appropriate treatment. Those with type 1 are at higher risk for kernicterus and its neurological consequences unless aggressive phototherapy or liver transplantation is instituted early. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic liver specialists and genetic counselors who can tailor management plans and advise on emerging treatment options.

Several clinical trials are currently investigating new treatments, including gene-based approaches aimed at restoring UGT1A1 activity. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.