Alagille syndrome is an inherited condition that can have an effect on a plethora of systems in the body, including the cardiovascular system, eyes, face, the skeletal structure, arteries, and kidneys.

Someone suffering from Alagille syndrome has fewer than average miniature bile ducts within their liver. The bile ducts are responsible for transporting bile manufactured in the liver to the gallbladder which serves as a storage center and then sending it along to the initial part of the small intestine (duodenum) for digestion. The decreased amount of small bile ducts results in a reduced amount of bile being released from the liver. This condition is called cholestasis. An accumulation of bile in the liver may result in detrimental effects to the organ.

How common is Alagille syndrome?

Approximately 0.0033% of newborns present Alagille syndrome.

Who is more likely to have Alagille syndrome?

Alagille syndrome can be transmitted through parental genetics, resulting from a mutation in the gene. Kids who have one parent affected by Alagille syndrome have a fifty percent probability of getting the gene associated with the disorder and developing it as well.

Approximately half to seventy percent of individuals suffering from Alagille syndrome do not have a parent affected by the condition. In these instances, the condition is brought about by an abruptly arising gene variation that does not come from either of the progenitors.

The effects of Alagille syndrome that can be seen in the liver commonly become noticeable shortly after a baby is born or during the early months of life. Due to this, Alagille syndrome is usually found in infants younger than 1 year old.

What are the complications of Alagille syndrome?

People with Alagille syndrome can be prone to problems with the liver and other areas of the body. Alagille syndrome varies greatly from person to person. In different people, the disease may affect different organs. There can be varying levels of severity in the impact of the disease on different individuals’ organs. Quite a few individuals who have Alagille syndrome experience only slight indications and can enjoy a typical life expectancy and quality of life. While some people experience mild symptoms from the virus, there are others who can suffer from major and potentially fatal health issues such as liver damage, major heart complications, and hemorrhages or strokes due to blood vessel abnormalities.

Liver complications

The impaired circulation of bile in Alagille syndrome may cause a buildup of such and could possibly harm the liver.

In some instances of Alagille syndrome, there is an extreme accumulation of bile in the liver of the young patient. Approximately 50% of these young people will experience an improvement in the elimination of bile from their liver by the age of 5. In the second half, the accumulation of bile inside the liver gets worse and generates more difficulties.

Liver complications of Alagille syndrome may include

cirrhosis, in which scar tissue replaces healthy liver tissue and prevents the liver from working normally. As cirrhosis gets worse, the liver begins to fail.
portal hypertension, which occurs when scar tissue partly blocks the flow of blood through the liver, increasing pressure in the portal vein.
liver failure, a condition in which the liver is badly damaged and stops working. Liver failure may require a liver transplant.
liver cancer NIH external link. Alagille syndrome increases the risk for liver cancer.

Other complications

Alagille syndrome can have an impact on other areas of the body, such as

serious heart defects NIH external link, such as tetralogy of Fallot NIH external link, which require treatment with surgery
narrowing and weakness in the blood vessels in the brain that may lead to bleeding and stroke NIH external link
problems with growth, delayed puberty NIH external link, or failure to thrive NIH external link
bone problems, such as osteoporosis NIH external link or frequent broken bones

Symptoms & Causes

What are the signs and symptoms of Alagille syndrome?

The majority of indications and manifestations of Alagille syndrome are due to a diminished flow of bile from the liver. Alagille syndrome can have an influence on numerous parts of the body, comprising of the heart, eyes, face, skeleton, blood vessels, and kidneys.

The indications and manifestations of Alagille syndrome can differ, even among individuals of the same family. Individuals with Alagille syndrome may show minor manifestations of the condition or could be unaware of their diagnosis. Some folks may experience more significant symptoms, medical issues, and difficulties.

Liver signs and symptoms

In Alagille Syndrome, the inadequate drainage of bile from the liver could lead to indications and manifestations.

severe itchiness of the skin, called pruritus
yellowish color of the whites of the eyes and skin, called jaundice
darkening of the color of urine and lightening of the color of stools
fatty deposits that appear as yellow bumps on the skin, called xanthomas
loose, greasy, bad-smelling stools, a sign that less bile is reaching the small intestine to help digest fats
an enlarged liver or spleen, which a doctor may notice during a physical exam or imaging tests

Early indications of Alagille syndrome normally surface within the initial twelve months of life. Generally, someone diagnosed with this syndrome would present with symptoms of reduced bile flow and liver illness, though in a minority of cases, no deficiencies in bile flow or liver complications might be evident.

Causes of Alagille syndrome

Alagille syndrome is mainly the result of mutations in the Jagged1 gene located on chromosome 20. Approximately three to five percent of situations involve a total absence of the gene from one version of chromosome 20. In most Alagille syndrome instances, there is a difference or alteration in the DNA that makes up the Jagged1 gene. In hardly any occurrences, less than 1%, shifts in Notch 2 gene cause Alagille Syndrome.

Approximately one-third of kids with Alagille syndrome receive a mutation in Jagged1 from one of their parents. In the other two thirds of instances, the alteration in Jagged1 is different for every child. There is a 50 percent likelihood that an individual who has the Jagged1 gene mutation will transmit it to their offspring if they have Alagille syndrome, which is an autosomal dominant disorder.

A mutation in Jagged1 can have a wide range of results. Individuals who are born with a mutation could have a serious form of Alagille syndrome, which affects both the heart and liver. However, other people with this mutation may only have slight symptoms, like posterior embryotoxon or distinct facial features.

Diagnosis of Alagille syndrome

When Alagille syndrome was initially described, a diagnosis required that a person have bile duct paucity in addition to at least three of five major criteria:

Cholestasis
Characteristic facial features
Vertebral abnormalities
Eye abnormalities
Heart defects

The discovery of the gene Jagged1 being the cause of Alagille syndrome has led to the alteration of the diagnostic criteria. Within the last few years, it has been accepted that an individual can be diagnosed with Alagille syndrome even if they do not meet all the clinical requirements, if they have an alteration in the Jagged1 gene. As an illustration, a member of the same family who has not been to the same extent as someone else, who might not meet the medical standards for Alagille Syndrome but who has the same alteration in their Jagged1 gene, is assumed to have AGS.

At the research laboratory of CHOP, it is possible to pinpoint a mutation in almost all (90%) patients with symptomatic AGS. Fewer than 1 percent of patients with Alagille syndrome have an alteration in an additional gene labeled Notch2. At this point in time, mutation testing of this gene is predominantly undertaken for experimentation and study.

Evaluation for Alagille syndrome

Alagille syndrome can be tough to spot due to the far-reaching effects it can have as well as its variable intensity. If a healthcare provider believes that your kid might have AGS, they may execute multiple tests and perform certain operations to distinguish between other illnesses and to verify the diagnosis.

Liver function/gastroenterology (GI)

Many individuals diagnosed with Alagille syndrome suffer from some form of liver disease, ranging from mild to severe and can even switch back and forth over time. In most cases, babies will get jaundice at the beginning of life, so it’s common for them to be checked out by a gastroenterologist at this time.

A first checkup for liver problems will include a physical exam in which the doctor specializing in digestive health will be particularly interested in seeing if the liver and/or spleen are larger than expected. The health of the liver can be determined through blood tests known as liver function tests. This set of examinations encompasses ALT, AST, GGT, albumin, bilirubin, conjugated bilirubin, and PT/PTT.

If appropriate, further tests may be necessary. A radiographic scan of the stomach might be used, which won’t only assist in eliminating other reasoning behind jaundice, but can also determine the amount of enhancement of both the liver and spleen. In some cases, a liver biopsy is useful in identifying Alagille Syndrome, however, it is not required for diagnosing it. This test is typically done while the person is alert but relaxed and entails a small sample of liver tissue being extracted through the skin with a needle.

Pancreatic function tests: 72-hour stool collection

Doctors can evaluate an individual’s pancreatic function by having the person keep a 72-hour stool collection and dietary record to observe how much fat from the meals is being absorbed. This collection will take place in the home, and you will be provided with the materials and guidance necessary. All stools are placed in pre-determined containers with their respective weights and then stored in the freezer for 3 days. All of the food consumed by your youngster during these three days should be accurately weighed and documented. The lab then calculates the quantity of fat that is taken in (fat absorption ratio). It is not possible to differentiate between fat malabsorption caused by illnesses of the liver and fat malabsorption brought on by diseases of the pancreas with this test.

Cardiology

A cardiologist, who is an expert in heart care, may be consulted to make certain there are no minor heart difficulties present for your child.

The cardiologist will give a thorough check-up and is likely to do an ECG and echocardiogram. An ECG measures the heart rhythm. An echocardiogram, which is an ultrasound of the heart, can precisely reveal the structure and performance of the heart. The cardiologist will decide based on what the tests and research show if additional tests should be administered or if follow-up appointments need to be set up.

Ophthalmologic (Eye)

Many children who suffer from Alagille syndrome have an unusual defect of the eyes. A common eye condition is called Posterior embryotoxon, which is characterized by an additional concentric ring on the front of the eye. This necessitates a specialized exam for finding it, and does not cause any disturbances in one’s vision. The retina (a thin layer of photoreceptors that coats the interior wall of the eye) has undergone pigmentary alterations in certain children who have AGS. A doctor specialized in eyes can inspect your child’s eyes to check for posterior embryotoxon and any other anomalies.

X-rays

X-rays of the back may be utilized to identify “butterfly” vertebrae, the most prevalent skeletal flaw connected with Alagille syndrome. X-rays show that in individuals with a certain type of abnormality, the vertebrae appear to be shaped like a flying butterfly. In most cases, butterfly vertebrae do not result in any kind of signs and symptoms, however, they do aid in the process of determining the diagnosis.

Genetics evaluation and testing

If the doctor believes your child may have Alagille syndrome, it is important for them to see a medical expert in genetics and speak to a genetic counselor. Most geneticists specialize in dysmorphology, which is the science of the structure of the face and body. A geneticist can examine your child’s face to see if it displays the facial features associated with Alagille syndrome.

The geneticist and the genetic counselor will jointly assess the outcomes of other diagnostic tests (e.g. examination of the eyes, spine X-rays, etc.) in combination with your family historical past. They will give you information regarding the genetic composition and how it is passed down through generations in Alagille syndrome. Using the data accumulated from your family tree and the results of a genetic test, doctors can address any queries concerning the likelihood of Alagille syndrome occurring in any of your future children.

Alagille Syndrome – Signs and Symptoms

How common is Alagille syndrome?

Who is more likely to have Alagille syndrome?