The Crigler-Najjar syndrome is due to increased serum bilirubin, which could be toxic to the central nervous system. Crigler-Najjar syndrome type 2 (also called Arias syndrome) is less severe than the type 1 syndrome.

Bilirubin is a degradation product of heme; most of it is derived from the hemoglobin of old or dysfunctional red cells. Bilirubin is a toxic hydrophobic compound that is bound to serum albumin in the circulation. At very high concentrations, it can pass through the blood-brain barrier and cause kernicterus, a severe, often fatal neurological disease. Serum concentrations of bilirubin rise when its production is increased, or its processing or excretion is reduced. In the liver, bilirubin is converted to a form soluble in water (bilirubin-glucuronide) and then excreted in the bile. The conjugation reaction is catalyzed by bilirubin-uridinediphosphoglucuronate-glucuronosyltransferase (UDP-glucuronosyltransferase or UGT1A1) [1]. All three forms of hyperbilirubinemia - Crigler-Najjar syndrome (CNS) types 1 and 2, and Gilbert's syndrome - can be attributed to deficiencies of the UGT1A1 enzyme. The residual enzyme activity defines the severity of the disease: a near-complete absence of UGT1A1 results in CNS1 syndrome, whereas a decreased activity of the enzyme gives rise to CNS2 disease.

Patients suffering from Crigler-Najjar syndrome present with jaundice, but without hemolysis or other evidence of increased production of bilirubin, and without liver disease. Whereas in CNS1 patients jaundice develops almost immediately after birth and continues to progress, CNS2 patients may not present with any symptoms and are often diagnosed later [2]. Kernicterus presenting with hypotonia, deafness, and lethargy, which very often accompanies the CNS1 syndrome, is only exceptionally observed in the CNS2 syndrome. Symptoms are often aggravated by sickness or fasting, but brain damage can usually be avoided in patients with CNS2. High bilirubin levels can be effectively treated in CNS2 patients with phenobarbital or other inducers of UGT1A1 [2]. Some hormones and antibiotics may inhibit the enzyme's activity.

The Crigler-Najjar syndrome is a very rare disease: only a few hundred cases are known in the world (the benign Gilbert's syndrome occurs widely, in around 5% of the population) [3]. Inheritance of the type 2 disease is somewhat complex: early work reported an autosomal dominant pattern [4], but other evidence points to autosomal recessive inheritance. One study describes that a healthy child was born to a CNS2 patient who was treated with phenobarbital during pregnancy [5].

• Asymptomatic

  The babies were asymptomatic, without hepatosplenomegaly or vomiting. An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic causes) was negative. [ijponline.biomedcentral.com]

• Poor Feeding

  Symptoms Symptoms may include: Confusion and changes in thinking Yellow skin (jaundice) and yellow in the whites of the eyes (icterus), which begin a few days after birth and get worse over time Lethargy Poor feeding Vomiting Exams and Tests Tests of [mountsinai.org]

• Vomiting

  Symptoms Symptoms may include: Confusion and changes in thinking Yellow skin (jaundice) and yellow in the whites of the eyes (icterus), which begin a few days after birth and get worse over time Lethargy Poor feeding Vomiting Exams and Tests Tests of [mountsinai.org]

  Postoperative vomiting should be avoided by maintaining basal glucose infusion. Ondansetron appears to be efficacious in preventing severe vomiting, but furosemide, salicylates, ampicillin, sulfonamide, and ceftriaxone should be avoided (17). [frontiersin.org]

  Nausea or vomiting. Periods of weak muscle tone (hypotonia) and/or tight muscles (hypertonia). Issues with cognitive development. What causes Crigler-Najjar syndrome? A mutation of the UGT1A1 gene causes Crigler-Najjar syndrome. [my.clevelandclinic.org]

  Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. [liverfoundation.org]

• Nausea

  He denied any associated nausea, emesis or diarrhea. The night prior to symptom onset, he consumed several alcoholic beverages along with an unknown amount of acetaminophen. [journals.lww.com]

  Nausea or vomiting. Periods of weak muscle tone (hypotonia) and/or tight muscles (hypertonia). Issues with cognitive development. What causes Crigler-Najjar syndrome? A mutation of the UGT1A1 gene causes Crigler-Najjar syndrome. [my.clevelandclinic.org]

• Jaundice

  Children with Crigler-Najjar syndrome have persistent jaundice beyond the newborn period. [my.clevelandclinic.org]

  We present a case of Crigler-Najjar type 2 (Arias syndrome) in an adult Amish male with new unexplained jaundice. [journals.lww.com]

  People who are affected with a mild form still have jaundice, but they have fewer symptoms and less organ damage. Infants with the severe form of the disease (type I) may continue to have jaundice into adulthood, and may need daily treatment. [mountsinai.org]

  The efficacy of jaundice drugs in the patient was poor, but the jaundice could be reduced. Hepatic encephalopathy may also occur as a postsurgical complication. If necessary, plasma exchange should be performed. [frontiersin.org]

  Further studies evaluated the presence of Gilbert syndrome mutation in breastfed jaundiced infants versus breastfed babies without jaundice and found no differences [12]. [ijponline.biomedcentral.com]

• Yellow Discoloration of the Skin

  Yellow discoloration of the skin and sclera was observed. [frontiersin.org]

• Encephalopathy

  Rarely, a person with CN-2 may develop bilirubin encephalopathy (also called kernicterus), especially during illness, prolonged fasting, or while under anesthesia. [rarediseases.info.nih.gov]

  Infants are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. [liverfoundation.org]

  Hepatic encephalopathy may also occur as a postsurgical complication. If necessary, plasma exchange should be performed. [frontiersin.org]

• Clumsiness

  Mild symptoms of kernicterus include: Clumsiness. Muscle spasms. Problems with sensory perception. Trouble with fine motor skills (grasping objects, fastening buttons). Twisting or squirming movements of their body (choreoathetosis). [my.clevelandclinic.org]

  Kernicterus can result in milder symptoms such as clumsiness, difficulty with fine motor skills and underdevelopment of the enamel of teeth, or it can result in severe complications such as hearing loss, problems with sensory perception, convulsions, [liverfoundation.org]

The only physical sign of hyperbilirubinemia is jaundice. Crigler-Najjar syndrome may be suspected in neonates if jaundice lasts longer than usual. Differentiating Crigler-Najjar syndrome from other disease involves exclusion of increased production of bilirubin (for example of hemolysis) and conditions leading to impaired uptake or excretion by the liver. Since the Crigler-Najjar syndromes are due to deficiencies in the conjugating enzyme, elevated levels of unconjugated bilirubin (indirect bilirubin), as opposed to conjugated bilirubin (direct bilirubin), will be detected in both type 1 and type 2 disease.

Type 2 and type 1 versions of Crigler-Najjar syndrome can be distinguished from one another on the basis of several criteria. Serum bilirubin concentrations are usually much higher in type 1 disease (20-50 mg/dL) than in type 2 (7-20 mg/dL). CNS2 patients respond to enzyme induction by phenobarbital, whereas patients with CNS1 - with essentially complete lack of the conjugating enzyme – do not [4]. For the same reason, CNS2 patients, but not CNS1 patients, have bilirubin glucuronides (albeit at reduced concentrations) in their bile.

Definitive diagnosis and distinction between type 1 and type 2 conditions can be reached by examining UGT1A1 activities in liver biopsies, or by identifying the types of deficiency in the UGT1A1 gene. Patients with CNS2 often display homozygous or double heterozygous missense mutations [6]; or, occasionally, are heterozygous for a nonsense and missense mutation [7]. The presence of a promoter mutation characteristic of Gilbert's syndrome occurring together with a missense mutation can also result in CNS2 [8]. Certain mutations have been shown to be associated with relatively high levels of bilirubin in some populations of CNS2 patients [9].

• Liver Biopsy

  Enzyme assay Liver biopsy Treatment Light treatment (phototherapy) is needed throughout a person's life. In infants, this is done using bilirubin lights (bili or 'blue' lights). [mountsinai.org]

Changes in the bilirubin during treatment. CNS-II is a relatively benign disease. [frontiersin.org]

With proper treatment, patients with CNS type II can live a relatively normal life. [liverfoundation.org]

Because Crigler-Najjar syndrome type II is milder and responds to phenobarbital, treatment is different. The mainstay of treatment for Crigler-Najjar syndrome type I is aggressive phototherapy. [rarediseases.org]

Enzyme assay Liver biopsy Treatment Light treatment (phototherapy) is needed throughout a person's life. In infants, this is done using bilirubin lights (bili or 'blue' lights). [mountsinai.org]

Outlook / Prognosis What can I expect if I have Crigler-Najjar syndrome? Children diagnosed with Crigler-Najjar syndrome type 2 will have a good prognosis if their condition receives treatment early to prevent life-threatening symptoms. [my.clevelandclinic.org]

Outlook (Prognosis) Milder forms of the disease (type II) do not cause liver damage or changes in thinking during childhood. People who are affected with a mild form still have jaundice, but they have fewer symptoms and less organ damage. [mountsinai.org]

What is the prognosis for someone living with CNS? With proper treatment, patients with CNS type II can live a relatively normal life. [liverfoundation.org]

When evaluating a prolonged and severe neonatal jaundice, especially in Asiatic patients, clinicians must consider the possibility of the presence of P364L mutation in order to make an appropriate diagnosis and prognosis. [ijponline.biomedcentral.com]

An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. [ijponline.biomedcentral.com]

Crigler-Najjar Syndrome Type 1: pathophysiology, natural history, and therapeutic frontier. Hepatology. 2020;71(6):1923–39. [ijponline.biomedcentral.com]

Prevention How can I prevent Crigler-Najjar syndrome? You can’t prevent Crigler-Najjar syndrome because it’s a genetic condition. [my.clevelandclinic.org]

As affected individuals age, the body mass increases and the skin thickens, making phototherapy less effective for preventing kernicterus. [rarediseases.org]

The most promising treatments are then moved into clinical trials, with the goal of identifying new ways to safely and effectively prevent, screen for, diagnose, or treat a disease. [liverfoundation.org]

Prevention Genetic counseling is recommended for people with a family history of Crigler-Najjar syndrome who want to have children. Blood tests can identify people who carry the genetic variation. [mountsinai.org]

Ondansetron appears to be efficacious in preventing severe vomiting, but furosemide, salicylates, ampicillin, sulfonamide, and ceftriaxone should be avoided (17). [frontiersin.org]

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2. Sampietro M, Iolascon A. Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes. Haematologica. 1999;84(2):150-157.
3. Clementi M, Di Gianantonio E, Fabris L, et al. Inheritance of hyperbilirubinemia: evidence for a major autosomal recessive gene. Dig Liver Dis. 2007;39(4):351-355.
4. Arias IM, Gartner LM, Cohen M, Ben-Ezzer J, Levi AJ. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency: clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am J Med.1969; 47:395-409.
5. Passuello V, Puhl AG, Wirth S, et al. Pregnancy outcome in maternal Crigler-Najjar syndrome type II: a case report and systematic review of the literature. Fetal Diagn Ther. 2009;26(3):121-126
6. Seppen J, Steenken E, Lindhout D, Bosma PJ, Elferink RP. A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP-glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler-Najjar type II. FEBS Lett. 1996; 390:294-298.
7. Seppen J, Bosma PJ, Goldhoorn BG, et al. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest. 1994; 94:2385-2391.
8. Servedio V, d'Apolito M, Maiorano N, et al. Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation. Hum Mutat. 2005;25(3):325.
9. Li L, Deng G, Tang Y, Mao Q. Spectrum of UGT1A1 Variations in Chinese Patients with Crigler-Najjar Syndrome Type II. PLoS One. 2015;10(5):e0126263.