Crigler-Najjar syndrome type 1 (ORPHA:79234)
A form of Crigler Najjar syndrome (CNS), a hereditary disorder of hepatic bilirubin conjugation, characterized by severe neonatal unconjugated hyperbilirubinemia due to a complete absence of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated, severe and permanent jaundice with a permanent risk of bilirubin encephalopathy.
Epidemiology
The prevalence of Crigler-Najjar syndrome type 1 (CNS1) is unknown.
Clinical description
Infants present with persistent jaundice at or soon after birth. Bilirubin encephalopathy (kernicterus manifesting as hypertonia, 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.
Etiology
Numerous variants in the gene UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS1. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in absent UGT1A1 activity with marked impairment of bilirubin conjugation.
Diagnostic methods
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 UGT1A1 activity.
Differential diagnosis
Differential diagnosis includes disorders of excessive bilirubin production (hemolysis, infections). CNS type 2 (CNS2) can be excluded by the lack of response to phenobarbital treatment and by DNA analysis.
Antenatal diagnosis
Prenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment relies on phototherapy for 10-12 hours a day (to maintain levels of unconjugated hyperbilirubinemia below the neurotoxic threshold and the bilirubilbumin 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 but are not available for daily clinical practice. Gene therapy trials are ongoing. 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.
Prognosis
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: 
                            June 2021


                            - Expert reviewer(s): 
                            Pr Philippe LABRUNE | MetabERN*


                                * European Reference Network