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A congenital disorder characterized by unconjugated hyperbilirubinemia.

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Bilirubin Uridine-Diphosphate Glucuronyltransferase Deficiency; Hereditary Unconjugated Hyperbilirubinemia.

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Type I: Bilirubin Glucuronyltransferase Deficiency; Congenital Hyperbilirubinemia; Congenital Familial Nonhemolytic Jaundice.

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Type II: Arias Syndrome.

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Not precisely known but estimated to be approximately 1:1,000,000 live births, with approximately 120 cases with Crigler-Najjar syndrome type I described in the literature. No racial or sexual predilection has been reported.

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Crigler-Najjar syndrome type I is an autosomal recessive inherited disorder with a mutation in the uridine diphosphate glucuronyltransferase (UGT)-1 gene located on 2q37. Crigler-Najjar syndrome type II, which is much more frequent than type I, is autosomal recessive inherited with a mutation mapping to the UGT-2 gene also on 2q37. Autosomal dominant forms have also been reported.

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This enzymopathy affects the conjugation of bilirubin with glucuronic acid. Unconjugated bilirubin has the ability to penetrate into the neonatal brain and cause neurologic damage and encephalopathy (kernicterus). Uridine diphosphate glucuronyltransferases (UGT) are enzymes that detoxify numerous compounds by conjugating them with glucuronic acid and rendering them water soluble and harmless at the same time (glucuronidation). Crigler-Najjar syndrome type I is characterized by complete absence of bilirubin UGT, which leads to unconjugated hyperbilirubinemia with total serum bilirubin levels greater than 340 μmol/liter (20 mg/dl). In Crigler-Najjar syndrome type II, a partial deficiency of bilirubin UGT occurs with total serum bilirubin concentrations in the range from 100 to 340 μmol/liter (6-20 mg/dl). Because of residual enzyme activity in type II, phenobarbital treatment can be used to induce the enzyme and lower serum bilirubin concentration significantly.

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In Crigler-Najjar syndrome type I, biliary bilirubin concentration is decreased and bilirubin glucuronide is absent. The diagnosis is confirmed by decreased glucuronyltransferase activity on the liver biopsy specimen. In contrast to Crigler-Najjar syndrome type II, there is no response to treatment with phenobarbital. Neonatal jaundice presenting soon after birth and lasting longer than 13 days in the absence of hemolysis may point to the diagnosis. The stool color often is pale yellow. Untreated, survival past the neonatal period is uncommon. Persistent jaundice during the neonatal period occurs in Crigler-Najjar syndrome type II, however, the levels of total bilirubin are significantly lower and generally neurologic symptoms do not appear. Confirmation of the diagnosis also requires a liver biopsy specimen to measure enzyme activity. Biliary bilirubin is (sub)normal, and stool color is normal.

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Crigler-Najjar syndrome type I. Severe unconjugated hyperbilirubinemia with intense jaundice appears in the first 3 days of life and persists through the neonatal period. Diffusion of unconjugated (lipid-soluble) bilirubin into the brain may be favored by a damaged blood-brain barrier (e.g., hypoxia, hyperosmolality), but also by prematurity and the presence of hypoalbuminemia or highly protein-bound drugs (e.g., sulfonamides). Kernicterus usually presents in the first week of life (although it may occur at any time, especially during the neonatal period, but is not limited to this period) with lethargy, loss of ...

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