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Crigler-Najjar syndrome type 2
A hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic bilirubin glucuronosyltransferase (GT). Crigler-Najjar syndrome type 2 (CNS2) is a milder form of Crigler-Najjar syndrome (CNS) than Crigler-Najjar syndrome type 1 (CNS1).
ORPHA:79235Classification level: Subtype of disorder
- Arias syndrome
- Bilirubin uridinediphosphate glucuronosyltransferase deficiency type 2
- Bilirubin-UGT deficiency type 2
- Hereditary unconjugated hyperbilirubinemia type 2
- UGT deficiency type 2
- Prevalence: Unknown
- Inheritance: Autosomal recessive
- Age of onset: Childhood
- ICD-10: E80.5
- OMIM: 606785
- UMLS: C0268311 C2931132
- MeSH: C536213
- GARD: 8683
- MedDRA: 10011387
The prevalence of CNS2 is unknown. CNS has an estimated annual incidence at birth of 1/1,000,000.
First clinical manifestations usually appear soon after birth. CNS2 patients are less severely jaundiced than 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.
Numerous mutations in the UGT1A1 gene on 2q37 are linked to CNS2 and result in reduced bilirubin GT activity, with marked impairment of bilirubin conjugation.
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 includes disorders of excessive bilirubin production (hemolysis) and impaired hepatic handling of bilirubin (hepatitis and Gilbert syndrome; see this term). CNS2 can be differentiated from CNS1 by measurement of transferase activity and the response to phenobarbital treatment.
Antenatal diagnosis is not usually indicated for CNS2.
The mode of inheritance is autosomal recessive.
Management and treatment
Treatment relies on daily phenobarbital administration that can induce the expression of bilirubin GT 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 toincrease bilirubin production and thus increase hyperbilirubinemia. Should this occur, patients must be examined by their physician and serum bilirubin concentration must be measured.
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.