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.

• Pain

  These damaged cells release chemicals that provoke a natural inflammatory response in the body, which result in redness, swelling, warmth and pain in the injured area. [neomedlight.com]

  Crigler-Najjar Syndrome Symptoms in Children In a baseline case of this condition, the child is jaundiced and the following Crigler-Najjar symptoms may occur: Fatigue Abdominal pain related to biliary stones Symptoms of the acute stage of the illness [chp.edu]

  Crigler-Najjar syndrome type II (CN-II) ASHISH ANJANKAR JNMC, Sawangi, Wardha Corresponding Author:[email protected] Author Profile Abstract This case concerns 8-year-old boy who reported the chief complaints of severe nausea, persistent sore throat and pain [authorea.com]

  Other symptoms include: Stomach pain Diarrhea and vomiting Fever Confusion Slurred speech Difficulty swallowing Seizures Treatments for Crigler-Najjar Syndrome The most common treatment for Crigler-Najjar syndrome is phototherapy. [share.upmc.com]

• Inflammation

  Persistent or recurrent inflammation can predispose athletes to early-onset arthritis or degenerative changes in their joints. [neomedlight.com]

  High levels of adenovirus-specific antibodies and CTL, and hepatic inflammation were found. This is the first demonstration that coexpression of CTLA4Ig permits prolonged expression and repeatable gene transfer by an adenoviral vector. [ncbi.nlm.nih.gov]

  That’s why it’s important to catch liver disease early, in the inflammation and fibrosis stages. If you are treated successfully at these stages, your liver may have a chance to heal itself and recover. Talk to your doctor about liver disease. [liverfoundation.org]

  […] criteria: 1) a medical history of persistent unconjugated hyperbilirubinemia with TB > 102.6 μmol/L, comprising predominantly unconjugated bilirubin; 2) normal alanine transaminase and aspartate aminotransferase levels, to exclude hepatitis-related inflammation [journals.plos.org]

• Death in Infancy

  […] in infancy or childhood. [ncbi.nlm.nih.gov]

• Recurrent Inflammation

  Persistent or recurrent inflammation can predispose athletes to early-onset arthritis or degenerative changes in their joints. [neomedlight.com]

• Swelling

  These damaged cells release chemicals that provoke a natural inflammatory response in the body, which result in redness, swelling, warmth and pain in the injured area. [neomedlight.com]

• Jaundice

  Type II (Arias syndrome) contains some glucuronyltransferase enzyme activity, usually <10% of the normal, and jaundice appears later. Now unconjugated bilirubin (indirect bilirubin) can build up in the body and lead to jaundice. [labpedia.net]

  Bilirubin has an orange-yellow tint, and hyperbilirubinemia causes yellowing of the skin and whites of the eyes (jaundice). In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. [ghr.nlm.nih.gov]

  Presents with severe jaundice in the first few days after birth. Inheritance is autosomal dominant with incomplete penetration and varied expressivity. [whonamedit.com]

  Type I: Bilirubin Glucuronyltransferase Deficiency; Congenital Hyperbilirubinemia; Congenital Familial Nonhemolytic Jaundice. [accessanesthesiology.mhmedical.com]

  Differential diagnosis Other causes of neonatal jaundice, including: Gilbert's syndrome. Haemolysis. Inconsequential neonatal jaundice. Breast-milk jaundice. [patient.info]

• Neonatal Jaundice

  Neonatal jaundice and Gilbert syndrome are common causes of unconjugated hyperbilirubinemia. [pubmed.ncbi.nlm.nih.gov]

  Differential diagnosis Other causes of neonatal jaundice, including: Gilbert's syndrome. Haemolysis. Inconsequential neonatal jaundice. Breast-milk jaundice. [patient.info]

  2016 2017 2018 2019 Billable/Specific Code Crigler-Najjar E80.5 newborn P59.9 ICD-10-CM Diagnosis Code P59.9 Neonatal jaundice, unspecified 2016 2017 2018 2019 Billable/Specific Code Code on Newborn Record Applicable To Neonatal physiological jaundice [icd10data.com]

  Differential diagnosis [ edit ] Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, etc. [en.wikipedia.org]

  Physiological neonatal jaundice may peak at 85 - 170 µmol/L, and decline to normal adult concentrations within 2 weeks. Prematurity results in higher levels. [bionity.com]

• Liver Dysfunction

  The disease process that causes liver dysfunction or injury increases both conjugated and unconjugated bilirubin. However, there is an increased proportion of conjugated bilirubin in plasma. [pubmed.ncbi.nlm.nih.gov]

  Decreased Clearance Liver diseases: Since the liver is involved in conjugation of bilirubin for efficient excretion, liver dysfunction in any disease process can lead to jaundice. [ncbi.nlm.nih.gov]

  He showed no signs of hemolysis, infection or liver dysfunction. The patient was treated with phototherapy (66 h) for 7 days and phenobarbital (5 mg/kg/day) for 3 days. [spandidos-publications.com]

• Scleral Icterus

  On preoperative examination, the patient was awake and alert and had no stigmata of hyperbilirubinemia, except for mild scleral icterus. [journals.lww.com]

• Arthritis

  Skip to content Top Health Categories Coronavirus Disease COVID-19 Mpox Allergies Alzheimer's & Dementia Arthritis & Rheumatology Breast Cancer Cold, Flu & Cough Diet & Nutrition Eating Disorders Eye Health Gastrointestinal Health Heart Disease High Blood [news-medical.net]

  Persistent or recurrent inflammation can predispose athletes to early-onset arthritis or degenerative changes in their joints. [neomedlight.com]

  Article Ins and Outs of a Rare Genetic Condition: Nonketotic Hyperglycinemia Article An Overview of Addison's Disease Article What You Should Know About the Dexamethasone Suppression Test Article This Unusual Childhood Hip Problem Often Leads to Early Arthritis [rarediseases.about.com]

• Ulcer

  It is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. Oral mucositis is a serious and acute side-effect for patients undergoing cancer therapy (chemotherapy and/or radiotherapy). [neomedlight.com]

  Gastric endoscopy showed a cauliflower-like ulcero-proliferative growth in the lower part of the esophagus, which was considered to be esophageal squamous cell carcinoma according to the symptoms of the ulcerating surface covered with white moss, and [frontiersin.org]

  Holter electrocardiograph ホルター心電計 Holt-Oram ホルト・オーラム Holt-Oram syndrome ホルト・オーラム症候群 Holtzman ホルツマン Holtzman inkblot test ホルツマン・インクしみテスト Holzknecht ホルツクネヒト Holzknecht space ホルツクネヒト腔 Horner ホルネル Horner-Spalding sign ホルネル・スパルディング徴候 Hunner ハンナー Hunner's ulcer [jams.med.or.jp]

• Dermatitis

  Section : Epithelitis Epithelitis is a radio-induced dermatitis related to cancer radiotherapy treatments. Some patients undergoing radiation treatment develop this kind of induced skin disease depending on the radiation levels. [neomedlight.com]

  Dubin-Johnson デュビン・ジョンソン Dubin-Johnson syndrome デュビン・ジョンソン症候群 Dubos デュボス Dubos medium デュボス培地 Duchenne デュシェンヌ Duchenne muscular dystrophy デュシェンヌ型筋ジストロフィー GuillaumeBenjamin Amand Duchenne （1806 - 1875） French neurologist Duhring デューリング Duhring's herpetiform dermatitis [jams.med.or.jp]

• Yellow Discoloration of the Skin

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

• Skin Disease

  Some patients undergoing radiation treatment develop this kind of induced skin disease depending on the radiation levels. [neomedlight.com]

• Erythema

  Batten disease バッテン病 Frederick Eustace Batten（1865-1918） English neurologist and pediatrician Battle バトル Battle's sign バトル徴候 William HenryBattle （1856-1936） English surgeon Bauhin バウヒン Bauhin's valve バウヒン弁 Bayes ベイズ Bayes theorem ベイズの定理 Bazin バザン Bazin's erythema [jams.med.or.jp]

• Suggestibility

  Furthermore, unconjugated bilirubin-IXα was unquestionably present in the bile of these children and amounted to 30-57% of their total bilirubin pigments ( The present findings suggest that Crigler-Najjar disease represents a more pronounced expression [jci.org]

  Expression study in vitro strongly suggests that the disease in this case is caused by a dominant negative mutation by forming a heterologous subunit structure. [ncbi.nlm.nih.gov]

• Encephalopathy

  It is associated with bilirubin encephalopathy and death unless managed by aggressive phototherapy and exchange transfusions in the immediate newborn period. The risk for kernicterus persists into adult life. [patient.info]

  Patient 1, the 2-month-old infant, with unconjugated bilirubin concentration of 30 mg/dL, had a high-pitched cry, suggestive of bilirubin encephalopathy; results of neurologic examination were normal. [ncbi.nlm.nih.gov]

  Very rarely, kernicterus with bilirubin encephalopathy occurs in these patients (again, not confined to the neonatal period). [accessanesthesiology.mhmedical.com]

• Irritability

  Problems reported with phototherapy were decreased effectiveness with age, poor compliance, restriction of activity and play, inability to travel or take vacations, irritation from eye shades, difficulty keeping eye protection on, difficulties in temperature [ncbi.nlm.nih.gov]

  The toxic effects of hyperbilirubinemia on the nervous system are well known (dystonia, developmental delay, hypotonia, irritability and lack of muscle control). [wohproject.org]

  Fecal transplant is used to treat gut infections and is now being studied as a treatment for obesity, urinary tract infections, irritable bowel syndrome and more. [nytimes.com]

  […] decreases after age 3-4 years, because the ratio of skin surface area to body mass is reduced. [70] Problems associated with phototherapy include restriction of activity and play, poor compliance, inability of the patient to travel or take vacations, irritation [emedicine.medscape.com]

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.

• Unconjugated Bilirubin Increased

  The serum unconjugated bilirubin increased in the proband from 156.4 micromol/L to 243.5 micromol/L after he started a low calorie intake, and it decreased to 51.8 micromol/L within a month of taking oral phenobarbital daily. [ncbi.nlm.nih.gov]

  Type 2: Raised bilirubin level is low in the range of 7 to 20 mg/100 ml. Unconjugated bilirubin increases with fasting and the removal of fats from the diet. It may respond to phenobarbitone therapy, and the level may decrease <5 mg/dL. [labpedia.net]

  […] amounts of unconjugated bilirubin Increased proportion of bilirubin monoglucoronide Prognosis Kernicterus Usually benign Mode of inheritance Autosomal recessive Most likely autosomal recessive Several alteration in the UGT1A1 gene have been described [criglernajjar.altervista.org]

• Liver Biopsy

  Early liver transplantation is the only effective treatment. Lab findings: Fecal urobilinogen is very low. Liver function tests are normal. The BSP test is normal. The liver biopsy is normal. There is no evidence of hemolysis. [labpedia.net]

  Confirmation of the diagnosis also requires a liver biopsy specimen to measure enzyme activity. Biliary bilirubin is (sub)normal, and stool color is normal. Crigler-Najjar syndrome type I. [accessanesthesiology.mhmedical.com]

  A diagnosis of Crigler Najjar type 1 syndrome was made by exclusion and confirmed by liver biopsy. The infant has been successfully treated at home with phototherapy. Liver transplantation remains a therapeutic option. [ncbi.nlm.nih.gov]

  Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). It may also help in differentiating between the two types of CNS. Liver biopsy, when it was performed, revealed residual enzymatic activity. [orpha.net]

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.