Última actualización:
August 02, 2016
Años publicados: 1997, 1998, 2002, 2008, 2016
NORD gratefully acknowledges Jayanta Roy-Chowdhury, MD, Professor, Departments of Medicine and Genetics, Director, Genetic Engineering and Gene Therapy Facility. Albert Einstein College of Medicine, for assistance in the preparation of this report.
Summary
Crigler-Najjar syndrome is a rare genetic disorder characterized by an inability to properly convert and clear bilirubin from the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of old or worn out red blood cells (hemolysis). Normally, bilirubin created in this process is converted from an unconjugated form to a form that can be dissolved in water and excreted from the body (called conjugated bilirubin). Affected individuals cannot convert unconjugated bilirubin to the conjugated form because they lack a specific liver enzyme required to break down (metabolize) bilirubin. Since they cannot convert bilirubin, they develop abnormally high levels of unconjugated bilirubin in the blood (hyperbilirubinemia).
The hallmark finding of Crigler-Najjar syndrome is a persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of enzyme activity and severe, even life-threatening symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Both forms are inherited as autosomal recessive traits and are caused by errors or disruptions (mutations) of the UGT1A1 gene.
Introduction
Crigler-Najjar syndrome was first recognized in six infants of three couples who were blood relatives (consanguineous). These cases were reported in the medical literature in 1952 by Drs. Crigler and Najjar. In 1962, Dr. Arias reported a milder version of this disorder, which is now termed Crigler-Najjar syndrome type II.
The symptoms of Crigler-Najjar syndrome type I become apparent shortly after birth. Affected infants develop severe, persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). These symptoms persist after the first three weeks of life.
Infants are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. Kernicterus is a potentially life-threatening neurological condition in which toxic levels of bilirubin accumulate in the brain, causing damage to the central nervous system. Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. Other symptoms that may follow include absence of certain reflexes (Moro reflex); mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In addition, affected infants may suck or nurse weakly, develop a high-pitched cry, and/or exhibit diminished muscle tone (hypotonia), resulting in abnormal “floppiness.”
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, and slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs or the entire body. An episode of kernicterus can ultimately result in life-threatening brain damage.
Although kernicterus usually develops early during infancy, in some cases, individuals with Crigler-Najjar syndrome type I may not develop kernicterus until later during childhood or in early adulthood. Patients in whom the blood bilirubin concentration is maintained at safe levels by exposure to light (see below under treatment) can develop kernicterus at any age if the light treatment is interrupted or the patient is affected by other illnesses.
Crigler-Najjar syndrome type II is a milder disorder than type I. Affected infants develop jaundice, which increases during times when an infant is sick (concurrent illness), has not eaten for an extended period of time (prolonged fasting) or is under general anesthesia. Some people have not been diagnosed until they are adults. Kernicterus is rare in Crigler-Najjar syndrome type II, but can occur especially when an affected individual is sick, not eating or under anesthesia.
Crigler-Najjar syndrome is caused by an alteration (mutation) in the UGT1A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase-1 (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body.
Symptoms are caused by a complete or partial absence of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin circulates in the liquid portion of the blood (plasma) in conjunction with a protein called albumin; this is called unconjugated bilirubin, which does not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, converted to form water-soluble bilirubin glucuronides (conjugated bilirubin), which are then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces. When bilirubin levels increase high enough, it can eventually cross the blood-brain barrier, infiltrating brain tissue and causing the neurological symptoms sometimes associated with Crigler-Najjar syndrome.
Parents of children with Crigler-Najjar syndrome type I may exhibit some defects in bilirubin metabolism; however, they do not display any physical findings of this disorder because they are have only one copy (heterozygous) of the altered UGT1A1 gene).
Crigler-Najjar syndrome is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Crigler-Najjar syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 750,000-1,000,000 people in the general population. Many researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine its true frequency in the general population. It is likely more common than estimated.
A diagnosis may be suspected within the first few days of life in infants with persistent jaundice. A diagnosis may be confirmed by a thorough clinical evaluation, characteristic findings, detailed patient history, and specialized testing. For example, in infants with this disorder, blood tests reveal abnormally high levels of unconjugated bilirubin in the absence of increased levels of red blood cell degeneration (hemolysis), as in Rh disease (isoimmunization). In addition, bile analysis reveals no detectable bilirubin glucuronides and urine analysis may demonstrate a lack of bilirubin.
Molecular genetic testing can confirm a diagnosis of Crigler-Najjar syndrome. Molecular genetic testing can detect mutations in the UGT1A1 gene that are known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
It is important to distinguish Crigler-Najjar syndrome type I and type II. The administration of phenobarbital, a barbiturate, reduces blood bilirubin levels individuals affected with Crigler-Najjar syndrome type II and Gilbert syndrome, but is ineffective for those with Crigler-Najjar syndrome type I. Therefore, failure to respond to this medication is an important indication for differential diagnostic purposes.
Treatment is directed toward lowering the level of unconjugated bilirubin in the blood. Early treatment is imperative in Crigler-Najjar syndrome type I to prevent the development of kernicterus during the first few months of life. 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. During this procedure, the bare skin is exposed to intense light, while the eyes are shielded. This helps to change the bilirubin molecules in the skin, so that it can be excreted in bile without conjugation. As affected individuals age, the body mass increases and the skin thickens, making phototherapy less effective for preventing kernicterus. For years, fluorescent light has been used, but has drawbacks including exposing patients to ultraviolet radiation. Some doctors recommend using light-emitting diodes (LEDs) technology, which uses blue light. This technology can be adjusted to the specific treatment level needed in an individual and does not expose people to ultraviolet radiation. However, it is not widely available. Exposure of skin to sun light is very effective in reducing blood bilirubin levels.
Infections, episodes of fevers, and other types of illnesses should be treated immediately to reduce the risk of an affected individual developing kernicterus.
Plasmapherersis has been used to rapidly lower bilirubin levels in the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances and plasma components) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual.
Liver transplantation is the only definitive treatment for individuals with Crigler-Najjar syndrome type I. Liver transplantation has drawbacks such as cost, limited availability of a donor, need for prolonged use of immunosuppressive drugs and the potential of rejection. Some physicians recommend a liver transplant if infants or children with severely elevated levels of unconjugated bilirubin do not respond to other therapy (refractory hyperbilirubinemia) or if there is a progression of neurological symptoms. Other physicians believe that liver transplantation should be performed before adolescence as preventive therapy, before brain damage can result from early onset kernicterus.
Crigler-Najjar syndrome type II responds to treatment with phenobarbital. In some instances, during an episode of severe hyperbilirubinemia, individuals with Crigler-Najjar syndrome type II may need phototherapy. Some affected individuals may not require any treatment, but should be monitored routinely.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Other treatment is symptomatic and supportive.
Research on inborn errors of metabolism such as Crigler-Najjar syndrome is ongoing. Scientists are studying the causes of these disorders and attempting to design enzyme replacement therapies (ERT) that may return missing and/or deficient enzymes to the body. ERT has been successful in treating other metabolic disorders and research is underway to develop an ERT for Crigler-Najjar syndrome.
Gene therapy is also being studied as another approach to therapy for individuals with Crigler-Najjar syndrome. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme and prevent the development and progression of the disease in question. Gene transfer could be permanent, leading to life-long cure of the disease. However, at this time, some technical difficulties need to be resolved before this type of gene therapy can be advocated. Other types of gene transfer that can reduce the bilirubin levels for several years, but not lifelong, is being considered for the treatment of Crigler-Najjar syndrome type 1.
Researchers are studying whether the transplantation of liver cells (hepatocytes) are beneficial as a treatment of Crigler-Najjar syndrome. Because the liver is structurally sound in individuals with Crigler-Najjar syndrome, researchers are exploring the possibility that transplanting hepatocytes may provide partial correction of the UGT1A1 enzyme deficiency. More studies are needed to determine the long-term effectiveness of this treatment. Like liver transplantation, transplantation of hepatocytes requires prolonged treatment with immunosuppressive drugs.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., jaundice, central nervous system damage, etc.].)
TEXTBOOKS
Downs E, Gourley GR. Neonatal Jaundice and Disorders of Bilirubin Metabolism. In: Nathan and Oski’s Hematology of Infancy and Childhood, 7th ed. Orkin SH, Nathan DG, Ginsburg D, Look AL, Fisher DE, Lux SE, editors. 2015 Elsevier Saunders, Philadelphia, PA. pp.101-127.e12.
Askari FK. Crigler-Najjar Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:337.
Behrman RE, Kliegman RM, Jenson HB. Eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:1320-1321.
Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3078-3087.
JOURNAL ARTICLES
Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016;79(3):378-386. https://www.ncbi.nlm.nih.gov/pubmed/26595536
Van Dijk R, Beuers U, Bosma PJ. Gene replacement therapy for genetic hepatocellular jaundice. Clin Rev Allergy Immunol. 2015;48:243-253. https://www.ncbi.nlm.nih.gov/pubmed/25315738
Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol. 2013;196398-6407. https://www.ncbi.nlm.nih.gov/pubmed/24151358
Miranda PS, Bosma PJ. Towards liver-directed gene therapy for Crigler-Najjar syndrome. Curr Gene Ther. 2009;9:72-82. https://www.ncbi.nlm.nih.gov/pubmed/19355865
Strauss KA, Robinson DL, Vreman HJ, et al. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease. Eur J Pediatr. 2006;165:306-319. https://www.ncbi.nlm.nih.gov/pubmed/16435131
Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis. 2006;29:431-5. https://www.ncbi.nlm.nih.gov/pubmed/16763914
Ambrosino G, Varotto S, Strom SC, et al. Cell Transplant. 2005;14:151-157. https://www.ncbi.nlm.nih.gov/pubmed/15881424
Sappal BS, Ghosh SS, Shneider B, et al. A novel intronic mutation results in the use of a cryptic splice acceptor site within the coding region of UGT1A1, causing Crigler-Najjar syndrome type I. Mol Genet Metab. 2002;75:134-42. https://www.ncbi.nlm.nih.gov/pubmed/11855932
Roy-Chowdhury N, Kadakol A, Sappal BS, et al. Gene therapy for inherited hyperbilirubinemias. J Perinatol. 2001; 21 Suppl 1:S114-18; discussion S125-27. https://www.ncbi.nlm.nih.gov/pubmed/11803431
Schauer R, Lang T, Zimmermann A, et al. Successful liver transplantation of two brothers with crigler-najjar syndrome type 1 using a single cadaveric organ. Transplantation. 2002;73:67-69. https://www.ncbi.nlm.nih.gov/pubmed/11792980
Kadakol A, Ghosh SS, Sappal BS, et al. Genetic lesions of bilirubin uridine-diphospho- glucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes correlation of genotype to phenotype. Human Mutation. 2000;16:297-306. https://www.ncbi.nlm.nih.gov/pubmed/11013440
Jansen PL. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr. 1999;158 Suppl 2:S89-94. https://www.ncbi.nlm.nih.gov/pubmed/10603107
Sampietro M, Iolascon A. Molecular pathology of Crigler-Najjar type I and type II and Gilbert’s syndromes. Haematologica. 1999;84:150-57. https://www.ncbi.nlm.nih.gov/pubmed/10091414
Arias IM, Gartner LM, Cohen M, et al. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronosyltransferase deficiency. Am J Med. 1969;47:395-409.
Crigler FJ, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics. 1952;10:169-170. https://www.ncbi.nlm.nih.gov/pubmed/12983120
INTERNET
Labrune P. Crigler-Najjar syndrome type 1. Orphanet Encyclopedia, February 2010. Available at: https://www.orpha.net/ Accessed July 2016.
Labrune P. Crigler-Najjar syndrome type 2. Orphanet Encyclopedia, February 2010. Available at: https://www.orpha.net/ Accessed July 2016.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:218800; Last Update:07/09/2016. Available at: https://omim.org/entry/218800 Accessed July 2016.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:606785; Last Update:07/09/2016. Available at: https://omim.org/entry/606785 Accessed July 2016.
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