Crigler–Najjar syndrome

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Crigler–Najjar syndrome
Classification and external resources
Bilirubin.svg
ICD-10 E80.5
ICD-9 277.4
OMIM 218800 606785
DiseasesDB 3176
MedlinePlus 001127
eMedicine med/476
MeSH D003414

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

This syndrome is divided into type I and type 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[edit]

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 (310–755) (whereas the reference range for total bilirubin is 2–14 μmol/L).

No UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) expression can be detected in the hepatic tissue. Hence, there is no response to treatment with phenobarbital[1] (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

Type II[edit]

Type II differs from type I in several aspects:

  • Bilirubin levels are generally below 345 µmol/L (100–430; thus, there is overlap), 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.[2]

Differential diagnosis[edit]

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

Hyperbilirubinemia of the unconjugated type may be caused by

In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is, too. There is no evidence for hemolysis. Drug-induced case 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[edit]

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by hepatocyte transplantation.[3]

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since there is only one enzyme working improperly, gene therapy for Crigler Najjar is a theoretical option which is being investigated.[4]

Gunn Rat: Dr. C. H. Gunn discovered a mutant rat in 1934 at the Connaught Laboratory in Toronto, Canada. These rats were jaundiced and the defect was transmitted as an autosomal recessive characteristic. Dr Gunn, a Geneticist, bred them at Connaught and later moved to Summerside, Prince Edward Island, Canada to head up the Canadian Experimental Fox Ranch. Gunn rats are still commercially available today from Harlan, Indianapolis, Indiana. Gunn rats are also available from Japan SLC Inc.. This animal model has been extremely valuable for the development of experimental treatments for this disease.

Eponym[edit]

The condition is named for John Fielding Crigler (b. 1919), an American Pediatrician and Victor Assad Najjar (b. 1914), a Lebanese-American Pediatrician.[5][6]

See also[edit]

References[edit]

  1. ^ Jansen PL (December 1999). "Diagnosis and management of Crigler–Najjar syndrome". European journal of pediatrics 158 (Suppl 2): S89–S94. doi:10.1007/PL00014330. PMID 10603107. 
  2. ^ Chowdhury, J. R.; Wolkoff, A. W.; Chowdhury, N. R.; Arias, I. M.: "Hereditary jaundice and disorders of bilirubin metabolism." In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. 2. New York: McGraw-Hill (8th ed.) 2001. Pp. 3063–3101.
  3. ^ Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (May 1998). "Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation". The New England Journal of Medicine 338 (20): 1422–6. doi:10.1056/NEJM199805143382004. PMID 9580649. 
  4. ^ Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, Mcdonagh AF, Beaudet AL, Lee B (March 2005). "Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector". Proceedings of the National Academy of Sciences of the United States of America 102 (11): 3930–5. doi:10.1073/pnas.0500930102. PMC 554836. PMID 15753292. 
  5. ^ Crigler JF Jr., Najjar VA (February 1952). "Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity". A.M.A. American Journal of Diseases of Children 83 (2): 259–60. ISSN 0096-8994. PMID 14884759. 
  6. ^ synd/86 at Who Named It?

External links[edit]