OOA (Old Order Amish)

MEN (General Swiss-German Mennonite)

Inheritance: autosomal recessive
Genes: UDP-glucuronosyltransferase (UGT1A1)

Crigler-Najjar syndrome type 1

Kernicterus
Jaundice
Hyperbilirubinemia
Dystonia
Developmental delay
Irritability
Lack of muscle control

Crigler-Najjar Syndrome

Clinical Characteristics

General description (for patients):

Severe jaundice begins in the first days of life and persists unless treated, unlike the usual newborn jaundice.  The whites of the eyes and the skin are deeply yellow.  The circulating bilirubin is toxic to brain cells and can cause severe brain damage if not treated promptly.  Exchange blood transfusions for high levels can be effective in acute infants but phototherapy with special blue fluorescent lights is necessary in the maintenance of non-toxic levels.  However, it needs to be used for 10-12 hours on 35-50% of exposed skin and gradually loses its effectiveness as children mature. Liver transplantation is usually necessary to keep bilirubin at a safe level.

Medical description: 

This disorder manifests itself within a few days of life by marked and persistent jaundice.  The toxic effects of hyperbilirubinemia on the nervous system are well known (dystonia, developmental delay, hypotonia, irritability and lack of muscle control).  High levels of circulating bilirubin can be acutely lowered with exchange transfusions but this may be avoided with effectively applied phototherapy.  Unfortunately phototherapy loses some of its effectiveness over time and many patients eventually need orthotopic liver transplantation.

Genetics:

Type I Crigler-Najjar disease is caused by a mutation in the UDP-glucuronosyltransferase gene (UGT1A1) located on chromosome 2 (2q37).  A specific mutation (222C>A) that results in total loss of transferase activity has been found in numerous patients in Pennsylvania of Amish/Mennonite heritage in which homozygosity causes disease (autosomal recessive pattern).  Cases have also been seen in Midwestern communities of plain people.

Treatment:

Vigorous and early lowering of circulating bilirubin is essential to prevent neural damage.  Prompt phototherapy can avoid the need for exchange transfusions.  Albumin and dextrose infusions during phototherapy should be utilized as well.  This may be necessary in older children as well during relapses precipitated by acute illnesses, or during adolescence.  Jaundiced infants born to families in which the mutation is known to segregate should be treated immediately without awaiting a molecular diagnosis. Ursodiol and a lipid-rich diet can increase clearance of hepatic excretions of the bilirubin photo byproducts and stimulate bile flow.  Phenobarbital therapy is less effective in this disorder than it is in the milder type II Crigler-Najjar syndrome.

Prognosis:

Greatly dependent upon vigorous and persistent treatment for hyperbilirubinemia.  Inadequate therapy results in severe and permanent brain damage.  Vigorous monitoring of circulating bilirubin with prompt reduction measures can avoid most long term deleterious effects on the central nervous system.

Ancillary treatments and support:

Orthotopic liver transplantation may be necessary in 30-40% by age 10-20 years.

Specialists and specialty centers:

Pediatrician, gastroenterologist, neurologist, nutritionist.

References:

Strauss, K.A., Robinson, D.L., Vreman, H.J., Puffenberger, E.G., Hart, G., and Morton, D.H.:  Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease.  Eur. J. Pediatr. 2006 May;165(5):306-19. PubMed ID: 16435131

Shevell, M.I., Bernard, B., Adelson, J.W., Doody, D.P., Laberge, J.-M., and Guttman, F.M.:  Crigler-Najjer syndrome type I: treatment by home phototherapy followed by orthotopic hepatic transplantation.  J. Pediat. 110: 429-431, 1987. PubMed ID: 3546653

Resources:

The Crigler-Najjar Association
American Liver Foundation

Associated Graphics