A congenital disorder characterized by unconjugated
Glucuronyltransferase Deficiency; Hereditary Unconjugated
Type I: Bilirubin Glucuronyltransferase Deficiency; Congenital Hyperbilirubinemia;
Congenital Familial Nonhemolytic Jaundice.
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.
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.
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
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
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 ...