Crigler-Najjar syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Crigler-Najjar syndrome is a severe condition characterized by high levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). Bilirubin is produced when red blood cells are broken down. This substance is removed from the body only after it undergoes a chemical reaction in the liver, which converts the toxic form of bilirubin (called unconjugated bilirubin) to a nontoxic form called conjugated bilirubin. People with Crigler-Najjar syndrome have a buildup of unconjugated bilirubin in their blood (unconjugated hyperbilirubinemia).

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. Severe unconjugated hyperbilirubinemia can lead to a condition called kernicterus, which is a form of brain damage caused by the accumulation of unconjugated bilirubin in the brain and nerve tissues. Babies with kernicterus are often extremely tired (lethargic) and may have weak muscle tone (hypotonia). These babies may experience episodes of increased muscle tone (hypertonia) and arching of their backs. Kernicterus can lead to other neurological problems, including involuntary writhing movements of the body (choreoathetosis), hearing problems, or intellectual disability.

Crigler-Najjar syndrome is divided into two types. Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Type 2 (CN2) is less severe. People with CN2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the UGT1A1 gene cause Crigler-Najjar syndrome. This gene provides instructions for making the bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme, which is found primarily in liver cells and is necessary for the removal of bilirubin from the body.

The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. During this reaction, the enzyme transfers a compound called glucuronic acid to unconjugated bilirubin, converting it to conjugated bilirubin. Glucuronidation makes bilirubin dissolvable in water so that it can be removed from the body.

Mutations in the UGT1A1 gene that cause Crigler-Najjar syndrome result in reduced or absent function of the bilirubin-UGT enzyme. People with CN1 have no enzyme function, while people with CN2 have less than 20 percent of normal function. The loss of bilirubin-UGT function decreases glucuronidation of unconjugated bilirubin. This toxic substance then builds up in the body, causing unconjugated hyperbilirubinemia and jaundice.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Crigler-Najjar syndrome is inherited in an autosomal recessive pattern, which means both copies of the UGT1A1 gene in each cell have mutations. A less severe condition called Gilbert syndrome can occur when one copy of the UGT1A1 gene has a mutation.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Crigler-Najjar syndrome is estimated to affect fewer than 1 in 1 million newborns worldwide.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Jaundice · Very frequent (99-80%)

Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.

Neonatal hyperbilirubinemia · Very frequent (99-80%)

A type of hyperbilirubinemia with neonatal onset.

Unconjugated hyperbilirubinemia · Very frequent (99-80%)

An increased amount of unconjugated (indirect) bilurubin in the blood.

Hypotonia · Frequent (79-30%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Poor suck · Frequent (79-30%)

An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.

Abnormal auditory evoked potentials · Occasional (29-5%)

An abnormality of the auditory evoked potentials, which are used to trace the signal generated by a sound, from the cochlear nerve, through the lateral lemniscus, to the medial geniculate nucleus, and to the cortex.

Cognitive impairment · Occasional (29-5%)

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

Coma · Occasional (29-5%)

The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.

Drowsiness · Occasional (29-5%)

Abnormal feeling of sleepiness or difficulty staying awake.

Enamel hypoplasia · Occasional (29-5%)

Developmental hypoplasia of the dental enamel.

Hearing impairment · Occasional (29-5%)

A decreased magnitude of the sensory perception of sound.

Hepatosplenomegaly · Occasional (29-5%)

Simultaneous enlargement of the liver and spleen.

High-pitched cry · Occasional (29-5%)

A type of crying in an abnormally high-pitched voice.

Infectious encephalitis · Occasional (29-5%)

A disorder of the brain caused by an infectious agent that presents with fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity.

Other findings in the same source

From: Orphanet

Additional reported features include Kernicterus (Occasional (29-5%)); Lethargy (Occasional (29-5%)); Memory impairment (Occasional (29-5%)); Ophthalmoparesis (Occasional (29-5%)); Opisthotonus (Occasional (29-5%)); Pruritus (Occasional (29-5%)); Seizure (Occasional (29-5%)); Vertigo (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Crigler-Najjar syndrome is Hepatology, with a hepatologist / gastroenterologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What is known about the cause and extent of liver involvement?
• Which medicines, supplements or exposures should be reviewed?
• What follow-up is appropriate for the specific diagnosis and stage?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.