What is Alagille Syndrome?
Alagille syndrome, also known as Alagille-Watson syndrome or some other names, is a genetic disorder that affects several body systems. This disease can vary widely in its symptoms, even among members of the same family. Common signs include problems with the liver (such as reduced bile flow), heart (mainly involving the lung blood vessels), kidneys, bones (resulting in ‘butterfly-shaped’ spinal bones), eyes, and facial features.
Alagille syndrome can range in severity. In some cases, a person may have the syndrome without showing any evident signs. However, in more severe cases, it can be life-threatening, and the mortality rate can be up to 10%.
What Causes Alagille Syndrome?
Alagille syndrome is a complex condition with varying levels of severity. The primary cause is due to a disruption in the Notch signaling pathways, which are crucial for the normal functions of our bodies. This disruption usually occurs because of changes in a single gene, either getting removed or repeated.
The significant majority of Alagille syndrome cases, about 94 to 96%, are due to changes in the JAG 1 Notch ligand gene (found on chromosome 20p12.2). This gene produces protein signals that interact with the NOTCH2 receptor (located on chromosome 1p11-p12). Only a tiny percentage, around 1 to 2%, are due to changes in the NOTCH2 gene itself.
If a parent has Alagille syndrome, their child has a 50% chance of inheriting the gene mutation that causes it. However, a significant number of people with Alagille syndrome, between 50 to 70%, develop it due to a new (de novo) mutation that wasn’t inherited. It’s also important to note that no clear relationship has been established between the specific gene mutation and how the syndrome presents itself.
Risk Factors and Frequency for Alagille Syndrome
Alagille syndrome can show different symptoms in different individuals, making it hard to determine its exact occurrence. However, it’s estimated that between 1 in 30,000 to 1 in 100,000 people are affected by Alagille syndrome.
Signs and Symptoms of Alagille Syndrome
Diagnosing Alagille syndrome can be tricky because symptoms can vary greatly from person to person. Some people may not have any symptoms, while others might have serious, life-threatening complications. This can be true even among family members with the same genetic mutation. People with this syndrome often first show symptoms of having yellow skin (jaundice) or heart-related issues.
The condition includes seven main symptoms:
- Heart defects: These are present in over 90% of patients and can include issues like peripheral pulmonic stenosis (found in 67% of patients), tetralogy of Fallot (a group of four heart defects), ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta (or narrowing of the aorta).
- Liver problems: These often present with cholestasis (where the flow of bile from the liver is reduced or blocked), conjugated hyperbilirubinemia, pruritus (itchy skin), xanthomas (fatty deposits under the skin), and cirrhosis. These problems can lead to severe liver disease in about 15% of people with the condition.
- Kidney abnormalities: These are characterized by renal dysplasia, glomerular mesangiolipidosis, and renal tubular acidosis.
- Skeletal abnormalities: Identified include butterfly vertebrae and hemivertebrae, and/or pathological fractures of long bones.
- Eye problems: Can include posterior embryotoxon with a prominent Schwalbe line.
- Different facial features: These include a notable, broad forehead, deep-set eyes that are relatively far apart, prominent ears, a triangular face with a pointed chin, and a broad nasal bridge.
- Vascular abnormalities: These are often associated with neurovascular abnormalities such as aneurysms, Moyamoya syndrome, abnormalities in cerebral arteries, reno-vascular abnormalities, and middle aortic syndrome.
Other possible symptoms are stunted growth, developmental delays, failure to gain weight and grow at the expected rate (failure to thrive), recurrent infections, and a weakened immune system. Delayed puberty, extra flexion creases in the skin, and cases of pancreatic insufficiency have also been reported.
Testing for Alagille Syndrome
Alagille syndrome is diagnosed if a person displays at least three of seven major symptoms. It’s not necessary for a decrease in bile ducts to be seen in liver tissue samples to diagnose this syndrome; instead, a person can present with cholestasis, a condition where bile cannot flow from the liver to the duodenum. It’s crucial to recognize that someone who has a family member with the syndrome and who shows any of its symptoms should be diagnosed with Alagille syndrome. For babies under six months, the lack of bile ducts might not be very noticeable, or they may show a growth of bile ducts, which could lead to a wrong diagnosis of biliary atresia, a serious liver disorder.
Liver tests are typically run to check for liver problems, with high levels of direct bilirubin, serum aminotransferases, serum bile acids, cholesterol, triglycerides, and gamma-glutamyl transpeptidase hinting at compromised liver function. If these substance levels are high, it could indicate a more severe case. Additional examinations include a liver ultrasound, a technetium 99m scan, and a liver biopsy. Doctors may conduct a urine test to look for kidney problems, a stool sample test to check for pancreatic issues, a heart evaluation with an echocardiogram, X-rays to look for butterfly vertebrae and other skeletal issues, an eye exam, a developmental evaluation, and a study of blood vessels. A genetic consultation can also help with diagnosis.
Genetic testing is another way to affirm a diagnosis of Alagille syndrome by looking for abnormalities in the JAG1 or NOTCH2 genes using a process called Fluorescence in situ hybridization (FISH). Expectant parents at risk of having a child with Alagille syndrome can opt for prenatal genetic testing or even preimplantation genetic diagnosis. Fetal ultrasound examinations are also helpful, especially fetal echocardiograms, which can highlight severe heart defects.
Treatment Options for Alagille Syndrome
People with Alagille syndrome can expect varied outcomes based on how the disease affects their specific organs and its severity. More serious cases involving heart or liver disease may lead to an early death, whereas vascular complications can result in death later in life. Treatment requires a team of health professionals who create a plan based on each patient’s unique needs.
For those with liver disease, the treatment generally focuses on easing severe itching and fat build-ups with medications that help with bile flow issues (such as ursodeoxycholic acid, naltrexone, rifampin, colesevelam, and cholestyramine). There are also surgical procedures available to help, although they can’t stop the liver disease from getting worse. A specific surgery called the Kasai procedure, which is normally used for a condition called biliary atresia, doesn’t help children with Alagille syndrome and could even make the situation worse. For those whose liver disease has advanced significantly, a liver transplant can be done. About 80% of people survive at least five years after having this surgery, and it often helps improve their liver function and overall growth.
If the syndrome affects the heart, kidneys, or blood vessels, treatment is based on the symptoms the patient has. There aren’t any specific guidelines for treating nerve vessel issues related to this syndrome, so these are managed in the usual way. Eye and vertebral abnormalities that come with the syndrome usually don’t require treatment. For patients struggling with malnutrition, dietary supplements and vitamins that are fat-soluble can be used to boost growth and development.
To avoid further complications, people with this syndrome should stay away from contact sports, especially if they have an enlarged spleen, chronic liver disease, or blood vessel involvement. It’s also recommended that they regularly see specialists in cardiology, gastroenterology, ophthalmology, nephrology, and nutrition for monitoring.
What else can Alagille Syndrome be?
Several conditions could lead to cholestasis, a condition where the flow of bile from the liver is slowed or stopped, and they need to be considered when making a diagnosis.
Certain disorders could lead to a decrease in the small bile ducts in the liver. These include alpha-1 antitrypsin deficiency, cystic fibrosis, primary sclerosing cholangitis in children, mitochondrial disorders, congenital liver fibrosis, and specific infections like congenital syphilis, cytomegalovirus, rubella, and hepatitis B. Childhood autoimmune hepatitis, hypopituitarism, graft versus host disease, Zellweger syndrome, Ivemark syndrome, and Smith-Lemli-Opitz syndrome may also result in this.
In babies, cholestasis could be caused by biliary atresia, sepsis, galactosemia, tyrosinemia, choledochal cyst, or any other structural abnormalities outside the liver. Conditions such as progressive familial intrahepatic cholestasis types 1 and 2, arthrogryposis-renal dysfunction-cholestasis syndrome, benign recurrent intrahepatic cholestasis, and Norwegian cholestasis (Aagenaes syndrome) also feature cholestasis.
Conditions like Noonan syndrome, Watson syndrome, William syndrome, Down syndrome, and LEOPARD syndrome are often accompanied by abnormal changes in lung blood vessels.
The presence of a hole in the heart wall (ventricular septal defects) and a combination of heart defects known as Tetralogy of Fallot are common in patients with the chromosome 22q11.2 deletion syndrome. Other conditions associated with this syndrome include abnormally formed vertebrae and failure to thrive in children.
Lastly, posterior embryotoxon, a specific eye abnormality can occur in 8 to 15% of the general population, and syndromes like Bannayan-Riley-Ruvalcaba syndrome and Axenfeld-Rieger syndrome.
