Crigler-Najjar syndrome (ORPHA:205)
A rare hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to a either a complete (type 1) or partial and inducible (type 2) hepatic deficit of UDP-glucuronosyltransferase 1A1 activity. The disorder manifests with neonatal jaundice with a risk of developing bilirubin encephalopathy.
Epidemiology
Whilst data on prevalence is very limited, Crigler Najjar syndrome (CNS) is estimated to affect less than 1/100,000 people in Europe. Both sexes are equally affected.
Clinical description
First clinical manifestations usually appear soon after birth, presenting with isolated jaundice that is more severe in CNS type 1 (CNS1) than in CNS type 2 (CNS2). In CNS1, it may evolve to bilirubin encephalopathy (kernicterus) with hypertonia, deafness, oculomotor palsy and lethargy when the treatment is delayed or inadequate. In CNS2, the risk of kernicterus is much lower but does exist.
Etiology
Numerous variants in the gene UGT1A1 (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS. 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 (CNS1) or reduced (CNS2) UGT1A1 activity, with marked impairment of bilirubin conjugation.
Diagnostic methods
The physical examination shows isolated jaundice and biological analyses detect only severe unconjugated hyperbilirubinemia with normal liver function tests. Abdominal imaging studies (CT scans or ultrasonograms) are normal. Currently, definitive diagnosis relies on genomic DNA analysis (ruling out the need for liver biopsy). In the past, definitive diagnosis was based on demonstration of the enzymatic deficiency in the liver (hepatic biopsy performed after three months of age); however, liver biopsy is no longer performed.
Differential diagnosis
Differential diagnosis varies depending of the type of CNS and includes disorders of excessive bilirubin production (hemolysis) and mild hepatic deficiency of hepatic 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 of CNS1 relies on phototherapy (initially at hospital and then at home) for 10-12 hours per day. Bilirubin chelators and ursodeoxycholic acid may also be prescribed in these patients. To date, the only effective treatment for CNS1 is liver transplantation. Treatment of CNS2 consists of daily phenobarbital.
Prognosis
Children with CNS1 may develop neurological complications as a consequence of the neurotoxicity of unconjugated bilirubin whereas prognosis is generally good for patients with CNS2.

                            Last update: 
                            June 2021


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


                                * European Reference Network