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Crigler-Najjar Syndrome (CNS)
Tuesday, 28 October 2003
Sunday, 28 November 2004

What

Crigler-Najjar syndrome (CNS) is a rare, inherited disorder of bilirubin (a breakdown product of red blood cells) metabolism and has 2 distinct forms: type 1 and type 2. Both types cause jaundice (yellowing of the skin caused by high bilirubin). Type 1 is much more severe than type 2, and can cause brain damage because of the extremely high bilirubin level. Children with type 2 usually survive without any brain damage.

Who

Type 1 is inherited in an autosomal recessive manner, whereas type 2 is inherited in an autosomal dominant manner (see primer for explanation of inheritance patterns). This is an extremely rare disorder, with only several hundred cases reported world-wide in the medical literature. The true incidence is unknown. However, there does not seem to be any differences in race or sex.

Signs and Symptoms

The signs of the disease begin in infancy, when normal newborn jaundice fails to improve. In type 1, the jaundice worsens and unless treated, will reach a point where it causes deafness, problems with the control of eye and muscle movements, and seizures. These neurologic problems are called kernicterus. Type 2 is not as severe since the bilirubin levels are not as high. Neurologic problems such as those seen in type 1 are rare.

Possible Causes

Elimination of bilirubin from the body requires that it be metabolized (broken down) in the liver. The enzyme necessary for this process is called uridine diphosphate glycosyltransferase (UGT). In Crigler-Najjar Syndrome, UGT is made by a gene that is defective. In type 1, UGT is almost completely absent. In Type 2, UGT is present in an abnormal form and has reduced activity, but can still do part of the job. This is why type 2 is less severe.

Diagnosis

The diagnosis of CNS is made based on the infant’s early age of when symptoms are noticed and the unexplained extremely high levels of bilirubin in the blood. Bilirubin levels in bile (fluid produced by the liver) will be very low in type 1, but normal in type 2. UGT activity can be measured in a piece of liver tissue obtained through biopsy. Diagnosis using genetic testing is also possible, but is most useful when there is a family history of CNS. Type 2 is distinguished from type 1 by the improvement after treatment with a prescription medication called phenobarbital. Infants with type 1 will not improve with this medicine.

Treatment

In order to prevent early-onset kernicterus, it is important to keep the bilirubin concentrations low for at least the first month of life. This is accomplished using exchange transfusions (withdrawing blood from the child and infusing donated blood) and phototherapy (exposing the skin to special lights that helps the skin breakdown bilirubin instead of the liver). Phototherapy is usually continued throughout childhood, although the response is reduced as the child ages. Eventually, no amount of treatment will control the jaundice, so liver transplantation is recommended for all children with type 1 CNS. The transplant effectively cures the disease, but medication is needed for life to prevent rejection of the transplanted liver. These medications can have significant side effects. In children with type 2, treatment with phenobarbital is effective in keeping bilirubin levels low enough not to cause brain damage. Sometimes children with type 2 may not require any ongoing treatment.

Prognosis

Without treatment, type 1 CNS leads to kernicterus and death by 2 years of age. With treatment, the onset of kernicterus can be delayed, but not stopped; children can usually remain healthy until they receive a liver transplant. Children with type 2 can also develop kernicterus, usually as a result of sudden increase in bilirubin during periods of illness, but this is much less common than in type 1. Treating infections early and taking phenobarbital will help prevent this complication. Most children with type 2 survive to adulthood without chronic difficulties. Prospective parents with a family history of Crigler-Najjar syndrome should seek genetic counseling.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

The Crigler-Najjar Association
Offers a newsletter, a parent matching service, an informative website, e-mail list group, and message board. Links families with each other for support.

American Liver foundation
A national non-profit organization dedicated to the prevention, treatment, and cure of liver disease through research, education, and advocacy. This site provides a brief overview of CNS and liver transplantation.

Google Search for Crigler-Najjar Syndrome (CNS)

References and Sources

E-medicine, www.emedicine.com Balistreri W. (2000). Metabolic Diseases of the Liver, Nelson Textbook of Pediatrics, Berman (ed) 16th ed. WB Saunders, p 1208-09.