Introduction
Background
Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder of bilirubin metabolism. Two distinct forms have been described, as follows: type 1 and type 2. Type 1 CNS, first described in 1952 by Crigler and Najjar, is associated with neonatal unconjugated hyperbilirubinemia (high levels) and kernicterus. Type 2 CNS (also called Arias syndrome), first described in 1962 by Arias, presents with a lower serum bilirubin level and responds to phenobarbital treatment.
The differential diagnosis of hyperbilirubinemia can be divided into 3 broad groups: (1) disorders of excessive bilirubin production (eg, hemolysis, ineffective erythropoiesis), (2) impaired hepatic handling of bilirubin (eg, hepatitis, cirrhosis, inherited syndromes), and (3) defective bile outflow (eg, intrahepatic or extrahepatic biliary obstruction).
A markedly elevated unconjugated (indirect) hyperbilirubinemia is observed in inherited disorders such as Gilbert syndrome and CNS. Among the inherited unconjugated hyperbilirubinemias, Gilbert syndrome is believed to affect approximately 3-7% of the adult population. CNS is a much rarer disorder, with only a few hundred cases described in the literature.
Pathophysiology
Effective elimination of bilirubin requires its conversion to polar derivatives. In humans, conjugation of bilirubin with the sugar molecule glucuronic acid accomplishes this conversion in a process called glucuronidation.
CNS is elicited by a lack or deficiency of the enzyme uridine diphosphate glycosyltransferase (UGT). Type 1 CNS is associated with an almost complete absence of the enzyme, which results in very high levels of unconjugated hyperbilirubinemia (up to 50 mg/dL) at birth. Lower levels of serum bilirubin (up to 20 mg/dL) and markedly depressed activity of hepatic UGT are characteristic of type 2 CNS (Arias syndrome). Importantly, treatment with phenobarbital can induce the expression of UGT in patients with type 2 CNS, with a decrease in the serum bilirubin level of approximately 25%.
CNS is caused by alterations in the coding sequence of UGT. This results in complete absence of UGT or the presence of abnormal UGT with reduced or no enzyme activity. In contrast, in Gilbert syndrome, the defect is in the promoter region of UGT, and reduced amounts of the normal protein are produced.
Frequency
United States
CNS is an extremely rare disorder that follows an autosomal recessive pattern of inheritance. Incidence is less than 1 case per 1,000,000 births. Only a few hundred cases have been described in the world literature, and the real prevalence is unknown.
Mortality/Morbidity
If left untreated, type 1 CNS is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 CNS, usually when patients experience a superimposed infection or stress.
Race
CNS is thought to affect all races equally.
Sex
CNS occurs in both sexes equally.
Age
If left untreated, type 1 CNS is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 CNS, usually when patients experience a superimposed infection or stress.
Clinical
History
Because of its autosomal recessive transmission, consanguinity is a risk factor for CNS, especially type 1 CNS.
Physical
Persistent jaundice is present at or soon after birth in type 1 CNS. Jaundice may not manifest until later in infancy or childhood in type 2 CNS. Kernicterus is the most worrisome consequence of hyperbilirubinemia and occurs in virtually all patients with untreated type 1 CNS, especially in the first few days of life. Bilirubin encephalopathy is rare in patients with type 2 CNS, but it can be induced by factors such as infection, anesthesia, or drug use. Clinical manifestations of kernicterus are hypotonia, deafness, oculomotor palsy, lethargy, and, ultimately, death.
Causes
Both type 1 CNS and type 2 CNS are transmitted by autosomal recessive inheritance. Alterations in the coding sequence of the UGT1 gene result in absent or reduced UGT activity, with marked impairment of bilirubin conjugation. The UGT1 gene is located on 2q37. Several isoforms of UGT1 enzyme exist based on the variability in the amino-terminal region of the final protein. These differences are the result of alternative splicing among 10 different types of exon 1 at the 5' end of the UGT1 gene and constant exons 2-5 at the 3' end. Thus, the different UGT1 isoforms are distinguished according to the type of exon 1 they contain.
More on Crigler-Najjar Syndrome |
 Overview: Crigler-Najjar Syndrome |
| Differential Diagnoses & Workup: Crigler-Najjar Syndrome |
| Treatment & Medication: Crigler-Najjar Syndrome |
| Follow-up: Crigler-Najjar Syndrome |
| References |
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References
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Further Reading
Keywords
CNS, Crigler-Najjar disease, Gilbert syndrome, Arias syndrome, congenital nonhemolytic jaundice, neonatal jaundice, inherited unconjugated hyperbilirubinemias, uridine diphosphate glycosyltransferase, UGT, kernicterus, bilirubin encephalopathy, plasma exchange transfusion
