Crigler-Najjar syndrome type 2 (ORPHA:79235)
A form of Crigler Najjar syndrome (CNS), a rare hereditary disorder of bilirubin metabolism, characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated jaundice with a risk of developing bilirubin encephalopathy later in life due to triggers such as stress or infection.
Epidemiology
The prevalence of Crigler Najjar syndrome type 2 (CNS2) is unknown.
Clinical description
First clinical manifestations usually appear soon after birth. CNS2 patients are less severely jaundiced than CNS type 1 (CNS1) patients, have pigmented bile that contains bilirubin glucuronides, and generally do not present neurologic or intellectual impairment. Bilirubin encephalopathy may develop in later life when patients experience a superimposed infection or stress.
Etiology
Numerous variants in the UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS2. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in reduced, but inducible bilirubin UGT1A1 activity, with marked impairment of bilirubin conjugation.
Diagnostic methods
Diagnosis is based on biochemical findings with total serum bilirubin ranging from 6 to 20 mg/dL and presence of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). It may also help in differentiating between the two types of CNS. Liver biopsy, when it was performed, revealed residual enzymatic activity.
Differential diagnosis
Differential diagnosis includes disorders of excessive bilirubin production (hemolysis). CNS2 can be differentiated from CNS1 by the response to phenobarbital treatment and from mild hepatic deficiency of UGT1A1 (Gilbert syndrome).
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 daily phenobarbital administration that can induce the expression of UGT1A1 resulting in a decrease in the serum bilirubin level by approximately 60-70%. Patients and their families must be educated to be very careful during infectious episodes and/or fasting periods that are likely to increase bilirubin production and thus increase hyperbilirubinemia. Should this occur, patients must be examined by their physician and serum bilirubin concentration must be measured.
Prognosis
Prognosis is good: this form does not cause cognitive or motor impairment during childhood. Adult patients remain jaundiced and must continue phenobarbital treatment throughout their life. However, all patients have to be educated and informed regarding at-risk-for-increase of bilirubin production (infection, stress and prolonged fasting).

                            Last update: 
                            June 2021


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


                                * European Reference Network