Crigler-Najjar syndrome
3184775
225361016
2008-07-13T08:01:00Z
Rcej
1612789
/* Crigler-Najjar syndrome, type I */ typo
{{DiseaseDisorder infobox |
Name = Crigler-Najjar Syndrome |
ICD10 = {{ICD10|E|80|5|e|70}} |
ICD9 = {{ICD9|277.4}} |
ICDO = |
Image = Bilirubin.svg |
Caption = [[Bilirubin]] |
OMIM = 218800|
OMIM_mult = {{OMIM2|606785}} |
MedlinePlus = 001127 |
eMedicineSubj = med |
eMedicineTopic = 476 |
DiseasesDB = 3176 |
MeshID = D003414 |
}}
'''Crigler-Najjar Syndrome''' or '''CNS''' is a rare disorder affecting the [[metabolism]] of [[bilirubin]], a chemical formed from the breakdown of [[Heme|blood]]. The disorder results in an [[Congenital disease|inherited]] form of non-[[Hemolysis|hemolytic]] [[jaundice]], often leading to [[Kernicterus|brain damage in infants]].
This syndrome is divided into two types: type I and type II, which is sometimes called [[Arias syndrome]]. These two types, along with [[Gilbert's syndrome]] and [[Dubin-Johnson syndrome]], make up the four known [[Heredity|hereditary]] defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few hundred cases of CNS are known to exist.
==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 also be present). [[Inheritance]] is [[autosomal]] [[recessive]].
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a [[blood plasma|serum]] bilirubin usually above 345 µmol/L (310 - 755) (whereas the [[reference range]] for total bilirubin is 2 - 14 μmol/L).
No [[UGT1A1]] expression can be detected in the [[hepatic]] tissue. Hence, there is no response to treatment with [[phenobarbital]]<ref>{{cite journal |pmid=10603107 |year=1999 |month=Dec |author=Jansen PL |title=Diagnosis and management of Crigler-Najjar syndrome |volume=158 |issue=Suppl 2 |pages=S89-S94 |issn=0340-6199 |journal=European journal of pediatrics}}</ref> (which causes [[Enzyme induction and inhibition|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.
Prior to 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]]
<!-- Unsourced image removed: [[Image:infant jaundice treatment.jpg|thumb|Infant undergoing home phototherapy for jaundice using a [[bili light|bili blanket]]]] -->
* [[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]] prior to the onset of brain damage, and before phototherapy becomes ineffective at later age
==Crigler-Najjar syndrome, 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.
[[Inheritance]] is generally considered [[autosomal]] [[dominant]].
==Differential diagnosis==
[[Neonatal jaundice]] may develop in the presence of [[sepsis]], [[hypoxia (medical)|hypoxia]], [[hypoglycemia]], [[hypothyroidism]], [[hypertrophic pyloric stenosis]], [[galactosemia]], [[fructosemia]], and so on.
[[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 [[hematoma]]s)
* 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 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 2 weeks. Prematurity results in higher levels.
<!-- thus all characterized by increased mono- or unconjugated (indirect) [[bilirubin]]. Some puzzling features of these diseases have been clarified since the discovery of the uridine diphosphate glucuronyl transferase 1 ([[UGT1]]) gene complex. The differential diagnosis of hyperbilirubinemia can be divided into 3 broad groups: (1) disorders of excessive bilirubin production (hemolysis, ineffective erythropoiesis), (2) impaired hepatic handling of bilirubin (hepatitis, cirrhosis, inherited syndromes), and (3) defective bile outflow (intrahepatic or extrahepatic biliary obstruction).-->
==Experimental treatments==
One 10-year-old girl with Crigler-Najjar syndrome type I was successfully treated by [[hepatocyte]] transplantation.<ref>{{cite journal |pmid=15753292 |year=2005 |month=Mar |author=Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, Mcdonagh AF, Beaudet AL, Lee B |title=Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector |volume=102 |issue=11 |pages=3930-3935 |pmc=554836 |doi=10.1073/pnas.0500930102 |journal=Proceedings of the National Academy of Sciences of the United States of America |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15753292 |format=Free full text}}</ref>
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.<ref>{{cite journal |pmid=9580649 |year=1998 |month=May |author=Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC |title=Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation |volume=338 |issue=20 |pages=1422-1426 |issn=0028-4793 |journal=The New England journal of medicine}}</ref>
==Eponym==
The condition is named for JF Crigler Jr and VA Najjar.<ref>{{cite journal |pmid=14884759 |year=1952 |month=Feb |author=Crigler JF Jr., Najjar VA |title=Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity |volume=83 |issue=2 |pages=259-260 |issn=0096-8994 |journal=A.M.A. American journal of diseases of children}}</ref><ref>{{WhoNamedIt|synd|86}}</ref>
==See also==
*[[Dubin-Johnson syndrome]]
*[[Gilbert syndrome]]
*[[Rotor syndrome]]
*[[Lucey-Driscoll syndrome]]
*[[Neonatal jaundice]]
==References==
{{reflist}}
==External links==
* [http://www.criglernajjar.info/ Crigler-Najjar Questions and Answers site]
* [http://www.criglernajjar.com/ Crigler-Najjar association]
* [http://it.geocities.com/criglernajjar/ Info and links related to Crigler-Najjar ]
{{Heme metabolism disorders}}
[[Category:Syndromes]]
[[Category:Metabolic disorders]]
[[Category:Genetic disorders]]
[[Category:Inborn errors of metabolism]]
[[Category:Pediatrics]]
[[Category:Hepatology]]
[[de:Crigler-Najjar-Syndrom]]
[[es:Síndrome de Crigler-Najjar]]
[[nl:Syndroom van Crigler-Najjar]]
[[pl:Zespół Criglera-Najjara]]
[[ru:Синдром Криглера — Найяра]]