Crigler-Najjar syndrome type 1 (CNS1) is the most severe form of CNS (see this term), a hereditary disorder of hepatic bilirubin conjugation, characterized by severe neonatal unconjugated hyperbilirubinemia due to a complete absence of hepatic bilirubin glucuronosyltransferase (BGT). The prevalence of CNS1 is unknown. CNS has an estimated annual incidence at birth of 1/1,000,000. Infants present with persistent jaundice at or soon after birth. Bilirubin encephalopathy (kernicterus manifesting as hypotonia, deafness, oculomotor palsy and lethargy) due to hyperbilirubinemia is a permanent risk. Neurologic defects (injury to basal ganglia, cerebellar and likely hippocampal structures) can occur, generally associated with intellectual and motor impairment. Numerous mutations in the UGT1A1 gene (2q37) are linked to CNS1 and result in absent bilirubin GT activity with marked impairment of bilirubin conjugation. Transmission is autosomal recessive. Diagnosis is based on findings of total serum bilirubin between 20 and 45 mg/dL and presence of traces of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). When liver biopsy was performed, it showed a total deficiency of hepatic BGT activity. Differential diagnosis includes disorders of excessive bilirubin production (hemolysis, infections). CNS2 can be excluded by the absence of GT activity and lack of response to phenobarbital treatment and by DNA analysis. Antenatal diagnosis is available (chorionic villi sampling). Genetic counseling is recommended when parents have a family history of CNS. Preimplantatory genetic diagnosis may also be discussed in affected couples. Treatment relies on phototherapy for 10-12 hours a day (to maintain levels of unconjugated hyperbilirubinemia below the neurotoxic threshold and the bilirubin/albumin molar ratio <0.7). Orthotopic liver transplantation may be considered and is more effective when performed before onset of neurologic damage. Bilirubin chelators (calcium salts, cholestyramine) may be used. Treatment with heme oxygenase inhibitors (tin-mesoporphyrin) can decrease plasma bilirubin concentrations but are not advised in the long term, because of their side effects (photosensitization). They may be useful for treating acute and severe hyperbilirubinemia. Prompt treatment of neurologic manifestations is required to avoid potentially devastating neurologic sequelae (intensive phototherapy, albumin infusions, and plasma exchanges). Unlike CNS2, patients with CNS1 do not respond to phenobarbital. Gene therapy projects are ongoing. Without treatment, CNS1 is lethal as a result of kernicterus. With treatment and management children have a good prognosis and may follow normal schooling, even though the treatment is very restrictive. Adult patients who have not undergone liver transplantation still require phototherapy but may have ``near normal'' social and familial lives. A few adult women have given birth to normal children, provided their pregnancies have been carefully followed up.
Last update: February 2010