What is Alagille Syndrome?
Alagille Syndrome is the most common of the rare cholestatic liver diseases encountered by pediatric hepatologists. This syndrome can affect multiple organs and systems, including the liver, heart, skeletal system, eyes, and kidneys. Its clinical features and severity vary widely—even among members of the same family. In some patients, symptoms may be mild, while in others the condition can be severe.
In most cases, Alagille Syndrome is caused by a mutation in one copy of the JAG1 gene. Less commonly (fewer than 1% of cases), it results from mutations in the NOTCH2 gene. Both forms are inherited in an autosomal dominant pattern. However, in about 50% of affected individuals, the genetic change arises spontaneously (a de novo mutation) and is not inherited from the parents.
The estimated prevalence of Alagille Syndrome is between 1 in 30,000 and 1 in 70,000 individuals, with no difference between sexes.
Typical manifestations, which usually appear within the first three months of life, include impaired bile flow (cholestasis), deficiency of fat-soluble vitamins (A, D, E, K), jaundice (yellowing of the skin and mucous membranes), poor weight gain and growth, severe itching, and pale, watery stools. Other common symptoms include heart murmurs, congenital heart defects, vertebral anomalies, posterior embryotoxon (thickening at the back of the cornea), and distinctive facial features. A more detailed description of systemic involvement is provided in the next question.
Yes, it is an autosomal dominant genetic condition. Fewer than half of patients diagnosed with ALGS have a positive family history. It is often found that first- or second-degree relatives also have the syndrome or receive a retrospective diagnosis. In most cases (50–70%), it is caused by new (de novo) mutations not inherited from the parents. Mutations in the JAG1 gene are most common.
Therapy is aimed at improving bile flow from the liver to the intestine, ensuring normal physical development, and relieving symptoms, especially itching. Specific approaches depend on the involvement of other systems. For patients with heart defects, management depends on the type of defect and may include liver transplantation or cardiac surgery. More information about treatment methods can be found in the relevant section of the website.
The severity of the condition largely depends on the degree of organ involvement. In some patients, ALGS can be life-threatening or life-limiting, especially in cases of serious heart defects (pulmonary artery stenosis, Tetralogy of Fallot), intracranial hemorrhage, liver cancer, or post-transplant complications. Other manifestations include severe itching, fatigue, weakness, poor growth, kidney dysfunction, or bone abnormalities. At the same time, many adults with this diagnosis live full lives, have families, careers, and reach 70 years of age or more.
Because symptoms can vary, diagnosis may take time. A clinical diagnosis is established when at least three of seven organ systems are affected: vascular, ocular, facial, skeletal, cardiac, hepatic, or renal. Alternatively, the presence of a characteristic mutation in JAG1 or NOTCH2, together with one clinical manifestation, is sufficient to confirm the diagnosis. ALGS can be mistaken for biliary atresia, making proper differentiation important.
Possible manifestations (not all present in every patient):
Face: triangular shape with broad forehead and pointed chin, deep-set eyes, bulbous nose
Liver: bile duct hypoplasia, hepatomegaly, cholestasis, splenomegaly, fibrosis, portal hypertension
Heart: pulmonary artery stenosis or hypoplasia, murmurs, complex defects such as Tetralogy of Fallot, aortic stenosis
Skeleton: “butterfly” vertebrae, shortening of forearm bones and fingers, other skeletal anomalies
Eyes: posterior embryotoxon (often does not affect vision), other abnormalities of the cornea, iris, or retina
Kidneys: dysplasia, cysts, absent kidney, ureter anomalies, tubulopathies, hypertension, hyperkalemia
Vessels: intracranial and peripheral vascular anomalies, stenoses, aneurysms, hemorrhages, Moyamoya syndrome
Other issues: immune dysregulation, thyroid and parathyroid dysfunction, developmental delay, hepatopulmonary syndrome
At present, there is no radical cure for Alagille Syndrome.
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