Crigler-Najjar syndrome (Type I)

What is Crigler-Najjar syndrome (Type I)?

It is a rare genetic syndrome that leads to the build up of high levels of unconjugated bilirubin. This form of bilirubin is a toxic substance and causes most serious symptoms of this syndrome.

There are two types of the syndrome: Type 1 is the severe form of the diseases, Type 2 is less severe and the symptoms are much milder.

Syndrome Synonyms:
Crigler-najjar Syndrome; Hyperbilirubinemia, Crigler-najjar Type I; Hblrcn1

What gene changes cause Crigler-Najjar syndrome (Type I)?

Mutations in the UGT1A1 gene are responsible for the syndrome. It is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Crigler-Najjar syndrome (Type I)?

The buildup of toxic unconjugated bilirubin in the blood can trigger kernicterus. This is a severe symptom in individuals with the Type 1 form of the syndrome. Kernicterus is a form of brain damage when the unconjugated bilirubin damages the nerves of the brain leading also to lethargy and hypotonia, as well as involuntary body movements, hearing issues and intellectual disability.

This buildup also causes jaundice, which is the yellowing of the skin and whites of the eyes.

Possible clinical traits/features:
Encephalopathy, Elevated hepatic transaminase, Hearing impairment, Memory impairment, Abnormality of the liver, Autosomal recessive inheritance, Seizure, Ophthalmoparesis, Jaundice, Kernicterus, Unconjugated hyperbilirubinemia

How does someone get tested for Crigler-Najjar syndrome (Type I)?

The initial diagnosis of Crigler-Najjar can begin with facial genetic analysis screening, as offered by FDNA Telehealth, which can identify the key markers of the syndrome and outline the need for further testing. If further testing is recommended what will follow is a consultation with a genetic counselor and then a geneticist. These consultations will usually involve a comprehensive review of the patient’s medical history, a generational family history documenting health issues and genetic conditions, and a detailed physical examination. Based on this clinical consultation, the options and recommendations for genetic testing will be shared with the individual’s parents/guardians and consent will be sought for further testing. This process may take place over the course of several clinic visits. Genetic testing will involve a blood sample. Results from the testing will then be sent back to the geneticist who will explain the resulting report in detail with the parents/guardians of the individual being tested.

Medical information on Crigler-Najjar syndrome (Type I)

Crigler and Najjar (1952) described seven patients from three families with congenital nonhemolytic jaundice with kernicterus. Age of onset was between first and 39th weeks. Clinical characteristics included jaundice, fever, anorexia, swallowing difficulties, vomiting, spasticity, extrapyramidal signs, and athetoid movements. Total bilirubin was between 27.4 and >50 mg/dl; and indirect >23.8 mg/dl. Five patients died, within the first year of life. Liver pathology showed bile thrombi in the canaliculi, and slight periportal fibrosis.

Ritter et al. (1992) characterized the first mutation in a patient with Crigler-Najjar type 1, a homozygous frameshift mutation in the exon 2. Clinical characteristics included jaundice at 12 days of age, persistent unconjugated hyperbilirubinemia (peak 598 μmol/L).

Li et al (2014) described two patients with hyperbilirubinemia due to biallelic mutations in the UGT1A1 gene. Clinical characteristics included developmental delay and icterus due to hyperbilirubinemia (total >411 μmol/L and unconjugated >403 μmol/L). The second patient died because of kernicterus.

Wanlapakorn et al. (2015) described a female from consanguineous family with hyperbilirubinemia due to homozygous nonsense mutations in the UGT1A1 gene. Clinical characteristics included unconjugated hyperbilirubinemia, retrocollis, upward gaze palsy, encephalopathy, developmental delay, and hypertonia of the extremities. SBrain MRI showed symmetrical isointensity in bilateral globi pallidi, whereas in the axial FLAIR image, symmetrical hyperintensity in bilateral globi pallidi.

Maruo et al. (2016) described a family with hyperbilirubinemia due to compound heterozygous mutations. The proband and a cousin had severe unconjugated hyperbilirubinemia (>30 mg/dL) requiring liver transplantation, and kernicterus. The proband died at transplantation. An uncle and the great grandfather are healthy and supposedly had also Crigler-Najjar, but type II.

Bai et al. (2016) described a male patient with hyperbilirubinemia and ichthyosis, due to a heterozygous missense mutation in one allele of the UGT1A1 and deletion of the entire other allele (and a 1.61Mb deletion in the Chr Xp22.31 region, encompassing the the STS gene). Clinical characteristics included icterus, hyperbilirubinemia (total 520.6 μmol/l and unconjugated 499.6 μmol/l), developmental delay, rhombus-shaped brown pigmentation on the trunk and limbs, tracheomalacia, renal dysplasia and renal artery stenosis.

* This information is courtesy of the L M D.
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