Crigler–Najjar syndrome

Crigler–Najjar syndrome

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

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,[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

Type II differs from type I in several aspects:

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:

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.[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 only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.[4]

Eponym

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]

References

  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". AMA American Journal of Diseases of Children 83 (2): 259–60. ISSN 0096-8994. PMID 14884759.
  6. synd/86 at Who Named It?

External links

This article is issued from Wikipedia - version of the Monday, March 07, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.