Crigler–Najjar syndrome

Updated on Jan 28, 2024

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Specialty endocrinology ICD-9-CM 277.4 DiseasesDB 3176		ICD-10 E80.5 OMIM 218800 606785 MedlinePlus 001127

Crigler–Najjar syndrome or CNS is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner.

This syndrome is divided into types I and II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome, Dubin–Johnson syndrome, and Rotor syndrome, make up the five known hereditary defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few hundred cases of CNS are known.

Type I

This is a very rare disease (estimated at 0.6–1.0 per million live births), and consanguinity increases the risk of this condition (other rare diseases may be present). Inheritance is autosomal recessive.

Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum bilirubin usually above 345 µmol/L [20 mg/dL] (range 310–755 µmol/L [18–44 mg/dL]) (whereas the reference range for total bilirubin is 2–14 μmol/L [0.1-0.8 md/dL]).

No UDP glucuronosyltransferase 1-A1 expression can be detected in the liver tissue. Hence, there is no response to treatment with phenobarbital, which causes CYP450 enzyme induction. Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.

Before the availability of phototherapy, these children died of kernicterus (bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes

exchange transfusions in the immediate neonatal period

12 hours/day phototherapy

heme oxygenase inhibitors to reduce transient worsening of hyperbilirubinemia (although the effect decreases over time)

oral calcium phosphate and carbonate to form complexes with bilirubin in the gut

liver transplantation before the onset of brain damage and before phototherapy becomes ineffective at later age

Type II

Type II differs from type I in several aspects:

Bilirubin levels are generally below 345 µmol/L [20 mg/dL] (range 100–430 µmol/L [6–24 mg/dL]; thus, overlap occurs), and some cases are only detected later in life.

Because of lower serum bilirubin, kernicterus is rare in type II.

Bile is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates.

UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pair mutations.

Therefore, treatment with phenobarbital is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II.

The inheritance pattern of Crigler–Najjar syndrome type II has been difficult to determine, but is generally considered to be autosomal recessive.

Differential diagnosis

Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, etc.

Hyperbilirubinemia of the unconjugated type may be caused by:

increased production

hemolysis (e.g., hemolytic disease of the newborn, hereditary spherocytosis, sickle cell disease)

ineffective erythropoiesis

massive tissue necrosis or large hematomas

decreased clearance

drug-induced

physiological neonatal jaundice and prematurity

liver diseases such as advanced hepatitis or cirrhosis

breast milk jaundice and Lucey–Driscoll syndrome

Crigler–Najjar syndrome and Gilbert syndrome

In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is normal, too. No evidence for hemolysis is seen. Drug-induced cases typically regress after discontinuation of the substance. Physiological neonatal jaundice may peak at 85–170 µmol/l and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.

Research

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.

Eponym

The condition is named for John Fielding Crigler (b. 1919), an American pediatrician and Victor Assad Najjar (b. 1914), a Lebanese-American pediatrician.

References

Crigler–Najjar syndrome Wikipedia

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