Crigler-Najjar Syndrome Type 1

Crigler-Najjar syndrome type 1

The infant with this condition looks healthy at birth with jaundice being the only health concern. Jaundice appears with the first few days of the child’s life and it quickly progresses with the second week. This brings about the need for exchange transfusion even after phototherapy.

The diagnosis will be supported further if the family history shows exchange transfusion, relatives with evidence of liver disease, consanguinity and relatives who had severe jaundice without hemolysis [9].

Consanguinity is a risk factor for the Crigler-Najjar syndrome type 1 because of its autosomal recessive transmission.

Crigler-Najjar syndrome type 2

There have been reports of bilirubin encephalopathy for this condition but usually, no clinical symptom is reported with this disease type.

Crigler-Najjar syndrome type 1

The results of liver tests in patients with the CNS type 1 are normal apart from the presence of high serum unconjugated bilirubin levels. The serum bilirubin levels will fluctuate between 20-50mg/dL. Bilirubin is absent from urine and conjugated bilirubin is absent from serum [10].

Due to the small amounts of unconjugated bilirubin, the bile that is collected through duodenal aspiration is light yellow. There is almost an absence of bilirubin conjugates from the bile.

Crigler-Najjar syndrome type 2

CNS type 2 brings about lower concentrations in bilirubin than what is seen with type 1. The levels range between 7-20 mg/dL. If coexisting hemolysis or intercurrent illness is present, higher bilirubin levels may be seen.

One way to definitively distinguish between this and type 1 is to conduct a chromatographic analysis of the pigments that is excreted in bile. Under the type 2, bile shows a significant amount of conjugated bilirubin. However, the proportion of bilirubin monoglucuronide in bile increases.

Type 1 and type 2 Crigler-Najjar syndrome can equally be distinguished using transferase activity measurements and monitoring of response to phenobarbital treatment. Phenobarbital treatment does not have any effect under type 1. However it causes a 25% reduction in plasma bilirubin levels in individuals with type 2 CNS.

Treatment of CNS1 relies on pharmacologic therapy, exchange transfusions, phototherapy, plasmapheresis and liver transplantation. Treatment of CNS2 consists of daily phenobarbital.

Crigler-Najjar syndrome type 1

The main cause of death in CNS type 1 is kernicterus. Due to bilirubin encephalopathy, this condition can equally lead to permanent neurologic sequalae. Even with treatment, most or all of the patients with CNS syndrome end up developing deficits neurologically.

If not treated strongly, many patients with CNS type 1 die before they reach 15 months of age. Vigorous treatment entails segmental transplantation and orthotopic liver transplant. Advances in the treatment of hyperbilirubinemia have helped more individuals survive to adulthood.

Crigler-Najjar syndrome type 2

A few cases of bilirubin-induced damage have been reported for CNS type 2 though it runs a more clinical benign course than the type 1. Neurologic sequelae can be avoided with adequate treatment however.

Increase in the production of bilirubin can be caused by any of the following:

• Hematoma
• Dyserythropoiesis
• Hemolysis

Impaired hepatic bilirubin uptake can result from any of the following:

• Use of drugs (such as Rifamycin, Rifampin, Probenecid)
• Congestive heart failure
• Portosystemic shunts

Impaired bilirubin conjugation can result from the following:

• Maternal serum jaundice
• Neonatal physiologic jaundice
• Crigler-Najjar syndrome
• Other liver diseases (Wilson disease, cirrhosis, chronic hepatitis)

Occurrence in the United States

In the United States, less than 50 cases of the Crigler Najjar syndrome have been recorded and around the world, only a few hundred cases have been described. A familial occurrence has been reported for 13.9% of cases which shows that in certain cases, a unique genetic factor presents itself [5].

Occurrence internationally

The estimated incidence for this condition is 1 case per 1,000,000 births and this makes the condition a rare one. Only a few hundred cases of this condition have been reported across the world. Communities where there is a high number of consanguineous marriages have the most records for this condition.

There is no sex-based difference in the occurrence of the Crigler-Najjar syndrome [6]. There is however, age difference at which symptoms of unconjugated hyperbilirubinemia appears for the two types of CNS. For the type I, symptoms become visible during the first few days of life while symptoms may not show in patients who have the type II till a few years into life, at which point they may have developed jaundice.

Crigler-Najjar syndrome can be caused by one or more mutations in any of the exons of the gene which codes for UGT1A1 [8]. Over 50 mutations that bring about Crigler-Najjar syndrome have been identified. Majority of these are nonsense and missense mutations [7].

Crigler-Najjar type 1 or type II results depending on the seriousness of the mutation on the enzymatic activity of the gene. The type 1 surfaces when all enzymatic activities are stopped and the type 2 surfaces when the UGT level is less than 10% of the normal level.

Distinguishing between both types of Crigler-Najjar is not always easy as many experts view both types as basically different expressions of a single condition.

There are no guidelines for prevention of Crigler-Najjar syndrome.

Crigler-Najjar syndrome often referred to as CNS is a condition which brings about a breakdown in the metabolism of bilirubin [1]. Bilirubin is the chemical end product formed after the disintegration of the red blood cells. People who have this condition develop non-hemolytic jaundice. Crigler-Najjar syndrome can be inherited. The non-hemolytic jaundice leads to abnormal levels of unconjugated bilirubin. In infants, this leads to brain damage.

The CNS syndrome is of two types, type I and type II. The type II is referred to as the Arias syndrome in some texts. These two types of CNS are part of the group of hereditary defects in metabolism of bilirubin. Other constituents of this group include the Rotor syndrome, Dubin-Johnson syndrome and the Gilbert’s syndrome.

The condition was first recognized in 1952 by Crigler and Najjar [2]. In the initial report, 6 children for 3 related families showed severe unconjugated hyperbilirubinemia which was clearly recognizable at birth.

By 15 months of age, five of these children died of kernicterus. This is a disorder which affects parts of the central nervous system and the basal ganglia. The last child died 15 years later after suffering from serious brain injury a few months earlier.
When an individual has the Crigler-Najjar syndrome, there is the deficiency or complete absence of the bilirubin-UGT.
The two types of Crigler-Najjar syndrome is classified as follows [3]:

• Type I is linked with kernicterus and high levels of neonatal unconjugated hyperbilirubinemia
• Type II comes with a lower serum bilirubin level and phenobarbital treatment often proves effective against it.

The mode of inheritance for type II CNS is not clear but the type I is an autosomal recessive disorder. There have also been reports for autosomal recessive transmission and autosomal dominant transmission with variable penetrance for the type II.

The diagnosis and treatment of the Crigler-Najjar syndrome has seen good progress over the past decades. Formerly, phototherapy was regarded as the only form of treatment but in 1986 the curative option of that liver transplantation was discovered. The locus of the missing gene which leads to this disorder was identified in 1992 [4].

Patients and families must understand the chronic nature of the condition and equally understand the need for continuous treatment all through the life of the individual. There is also need to report any change in mental or neurologic status as fast as possible.

Genetic counseling is recommended for prospective parents with a family history of Crigler-Najjar syndrome.

1. Sneitz N, Bakker CT, de Knegt RJ, et al. Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat 2010; 31:52.
2. Bosma PJ, Seppen J, Goldhoorn B, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994; 269:17960.
3. Roy Chowdhury J, Van Es HH, Roy Chowdhury N, Gunn rat. An animal model of deficiency of bilirubin conjugation. In: Hepatic Transport and Bile Secretion, Physiology and Pathophysiology, Tavoloni N, Berk PD (Eds), Raven, New York 1992. p.713.
4. Arias IM, Gartner LM, Cohen M, et al. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am J Med 1969; 47:395.
5. 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.
6. Crigler JF Jr., Najjar VA (February 1952). "Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity". A.M.A. American Journal of Diseases of Children 83 (2): 259–60. ISSN 0096-8994
7. Hafkamp AM, Nelisse-Haak R, Sinaasappel M, Oude Elferink RP, Verkade HJ. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial. Pediatr Res. Dec 2007;62(6):725-30.
8. Sisson TR, Drummond GS, Samonte D, Calabio R, Kappas A. Sn-protoporphyrin blocks the increase in serum bilirubin levels that develops postnatally in homozygous Gunn rats. J Exp Med. Mar 1 1988;167(3):1247-52.
9. Smith JR, Donze A, Schuller L. An evidence-based review of hyperbilirubinemia in the late preterm infant, with implications for practice: management, follow-up, and breastfeeding support. Neonatal Netw. Nov-Dec 2007;26(6):395-405.
10. Lucey JF, Suresh GK, Kappas A. Crigler-Najjar syndrome, 1952-2000: learning from parents and patients about a very rare disease and using the internet to recruit patients for studies. Pediatrics. May 2000;105(5):1152-3.