Crigler–Najjar syndrome Classification and external resources
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 blood. 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 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.
Crigler-Najjar syndrome, 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 (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 (which causes 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
- 12h/d 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
Crigler-Najjar syndrome, type II
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.
Hyperbilirubinemia of the unconjugated type may be caused by
- increased production
- decreased clearance
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.
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.
- ^ 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.
- ^ 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.
- ^ 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. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=9580649&promo=ONFLNS19.
- ^ 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. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15753292.
- ^ 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.
- ^ synd/86 at Who Named It?
- Crigler-Najjar Questions and Answers site
- Crigler-Najjar association
- Info and links related to Crigler-Najjar
- Crigler Najjar syndrome, type 1 at NIH's Office of Rare Diseases
- Crigler Najjar syndrome, type 2 at NIH's Office of Rare Diseases
Heme metabolism disorders (E80, 277.1, 277.4) Porphyria,
hepatic and erythropoietic
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