Diseases title

Crigler-Najjar syndrome )

Orpha Number: 205
Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency, Hereditary unconjugated hyperbilirubinemia, UGT deficiency

Crigler-Najjar syndrome (CNS) is a hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to a hepatic deficit of bilirubin glucuronosyltransferase (GT) activity. Two types have been described, CNS types 1 and 2 (see these terms). CNS1 is characterized by a complete deficit of the enzyme and is unaffected by phenobarbital induction therapy, whereas the enzymatic deficit is partial and responds to phenobarbital in CNS2.The disease is extremely rare with an annual incidence at birth of 1/1,000,000. Prevalence is unknown and only a few hundred cases have been reported so far. Both sexes are equally affected.CNS1 appears in the first days of life and persists thereafter; CNS2 also has an early onset. Patients present with isolated jaundice that appears early in life and is more severe in CNS1 than in CNS2. In CNS1, it may evolve to bilirubin encephalopathy (kernicterus) with hypotonia, deafness, oculomotor palsy and lethargy when the treatment is delayed or inadequate. In CNS2, the risk of kernicterus is much lower but does exist.Numerous mutations in the UGT1A1 gene (2q37) are linked to both CNS types and result in absent or reduced bilirubin GT activity, with marked impairment of bilirubin conjugation.The physical examination shows isolated jaundice and biological analyses detect only severe unconjugated hyperbilirubinemia with normal liver function tests. Abdominal imaging studies (plain X-rays, CT scans or ultrasonograms) and liver histology findings (when liver biopsy is performed) are normal. Definitive diagnosis is based on demonstration of the enzymatic deficiency in the liver (hepatic biopsy performed after three months of age). Diagnosis is generally confirmed by genomic DNA analysis (ruling out the need for liver biopsy).Differential diagnosis varies depending of the type of CNS and includes disorders of excessive bilirubin production (hemolysis) and impaired hepatic handling of bilirubin (Gilbert syndrome; see this term).Antenatal diagnosis is available for CNS1 and genetic counseling is recommended when parents have a family history of CNS. For CNS2, owing to the efficacy of phenobarbital, antenatal diagnosis is not usually indicated. During the neonatal period exchange transfusion may be necessary.Both types of CNS are inherited as autosomal recessive conditions.Treatment of CNS1 relies on phototherapy (initially at hospital and then at home) for 10-12 hours per day. Bilirubin chelators and ursodeoxycholic acid may also be prescribed in these patients. The only effective treatment for CNS1 is liver transplantation. Treatment of CNS2 consists of daily phenobarbital.Children with CNS1 may develop neurological complications as a consequence of the neurotoxicity of unconjugated bilirubin whereas prognosis is generally good for patients with CNS2.
source: Orphanet