Alagille's syndrome: what is it, causes, symptoms, treatment

What is Alagille Syndrome?

Alagille's Syndrome (also called arteriohepatic dysplasia, Alagille-Watson syndrome) Is a rare genetic disorder that can affect various organ systems in the body, including the liver, heart, skeleton, eyes, and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from person to person, even within the same family. Some people may have a mild form of the disorder, while others may have a more serious form of the disease.

Common symptoms that often develop during the first three months of life include blockage of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor growth and weight gain, and severe itching. Additional symptoms include heart murmurs, congenital heart defects, back problems, ring thickening that usually lines the cornea of ​​the eye (posterior embryotoxon) and distinguishing features faces.

Most people with Alagille syndrome have changes (mutations) in one copy of the gene JAG1. A small percentage (2 percent) of patients have gene mutations NOTCH2. These mutations can be inherited in an autosomal dominant manner, but in about half of cases, the mutation occurs as a new change (“de novo”) in a person and is not inherited from the parent. Currently, the estimated incidence of this syndrome is approximately 1 / 30,000 - 1 / 45,000.

Signs and symptoms

The symptoms and severity of Alagille syndrome can vary greatly from person to person, even among members of the same family. Some people may have a mild form of the disorder that may go virtually unnoticed; other people may have a serious form of the disorder that can potentially cause life-threatening complications. It is important to note that affected individuals may not have all of the symptoms described below.

The syndrome can be associated with disorders of the liver, heart, eyes, skeleton, kidneys and other organ systems of the body. The main feature Alagille's syndrome is liver disease, which often appears during the first three months of life. However, people with mild liver damage can only be diagnosed at a later age. Liver disease in the syndrome, if present, can range in severity from jaundice or mild cholestasis to severe progressive liver disease that could potentially lead to liver failure.

About 90 percent of people with Alagille syndrome have a reduced number of bile ducts in their liver (insufficiency of the bile ducts). The bile ducts are small tubular structures that carry bile from the liver to the small intestine. Bile production is one of the functions of the liver. Bile is a liquid that contains water, some minerals that carry an electrical charge (electrolytes), and other materials, including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin), which is a byproduct of the natural breakdown of hemoglobin in red blood cells cells. The flow of bile performs two important tasks in the body: it aids in the digestion and absorption of dietary fats, vitamins, and other nutrients, and helps eliminate excess cholesterol, bilirubin, waste and toxins from the body. Consequently, the problem of bile secretion often leads to the malabsorption of vital nutrients and the accumulation of toxic materials in the body.

Because of the reduced number of bile ducts, people with the disease may develop jaundice and cholestasis, usually within the first four months of life. Cholestasis is a reduced or obstructed flow of bile from the liver. Cholestasis can cause yellowing of the skin or the whites of the eyes (jaundice), itching that can be intense, pale stools, dark urine, fatty bumps (xanthomas) directly under the surface of the skin, and abnormal enlargement of the liver (hepatomegaly) and / or enlarged spleen (splenomegaly). Because the body cannot properly absorb fats and fat-soluble vitamins (vitamins A, D, E, and K), affected children may also experience growth deficits and an inability to develop. Impaired absorption of vital nutrients can also lead to rickets, - a condition characterized by softening, weakening of bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and developmental delays (vitamin E deficiency), and blood clotting problems (vitamin K deficiency).

In about 15 percent of patients, progressive liver disease leads to scarring of the liver (cirrhosis) and liver failure. It is impossible to determine which children are at risk for serious progressive liver disease with Alagille syndrome.

Many people with Alagille syndrome have heart problemswhich can range from benign heart murmurs to severe structural defects. Murmur in the heart Is an additional sound that is heard during a heartbeat. Heart murmurs in children with the disorder are usually caused by narrowing of the blood vessels in the lungs (pulmonary artery stenosis). The most common heart condition is peripheral pulmonary stenosis, in which some of the blood vessels that carry blood to the lungs (pulmonary arteries) are narrowed (stenosis). Some children with Alagille syndrome may have complex heart defects, the most common of which is tetrad of Fallot. Fallot's tetralogy is a rare form of cyanotic heart diseases. Cyanosis Is an abnormal bluish-bluish discoloration of the skin and mucous membranes that occurs due to low levels of circulating oxygen in the blood.

Fallot's tetralogy consists of a combination of various heart defects:ventricular septal defectpreventing the outflow of blood from the right ventricle to the lungs due to abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), a displaced aorta causing blood to flow into the aorta from both the right and left ventricles and an abnormal enlargement of the right ventricle.

Additional heart defectsthat can occur with Alagilles syndrome include ventricular septal defects, atrial septal defects, patent ductus arteriosus, and coarctation of the aorta. Some studies have shown that, in rare cases, there is an association with Wolff-Parkinson-White syndrome, a condition characterized by electrical disturbances in the heart.

Some people with the disorder may have eye abnormalities, especially posterior embryotoxone, a condition marked by a thickening of the annulus that usually lines the cornea of ​​the eye. The cornea is a thin, transparent membrane that covers the eyeball. In most cases, posterior embryotoxone is a benign abnormality that primarily helps make a clinical diagnosis and vision usually does not change, although there may be a slight decrease in clarity vision. Less commonly, there may be other eye abnormalitiessuch as Axenfeld's anomaly, a condition in which the filaments of the iris are abnormally attached to the cornea, or progressive retinal degeneration (retinopathy pigmentosa). The retina is the thin layers of nerve cells that line the inner surface of the back of the eyes, sense light and convert it into nerve signals, which are then transmitted to the brain through the visual nerve.

People with Alagille syndrome usually have distinctive facial featuresincluding deep-set and wide-set (hypertelorism) eyes, pointed chin, broad forehead, and low-set eyes. In older people and adults, the chin may appear larger and more prominent (prognathia).

Some people with the disorder may have skeletal abnormalitiesincluding a butterfly vertebra, a condition in which certain bones in the spine are irregular in shape. This condition is often noted on radiographs, but usually the pathology does not cause any symptoms or problems.

Also, people with the disorder may experience additional symptoms, including:

• renal abnormalities;
• pancreatic insufficiency;
• vascular abnormalities;
• mild developmental delays and cognitive impairment.

Renal abnormalities may be more common in people with Alagille syndrome, caused by a mutation in a gene NOTCH2 and include abnormally small kidneys, the presence kidney cysts and decreased or impaired renal function. Pancreas Is a small organ located behind the stomach that secretes enzymes that enter the intestines and aid in digestion. The pancreas also secretes other hormones such as insulinwhich helps break down sugar. Pancreatic insufficiency This is when the pancreas cannot produce or transport enough enzymes to the intestines to aid in the breakdown and absorption of food and nutrients.

People with Alagille syndrome can also develop abnormalities of certain blood vessels (vascular abnormalities), including those in the brain, liver, lungs, heart, and kidneys. Vascular abnormalities in the brain can lead to bleeding inside the brain (intracranial bleeding) and stroke. Some people with the disorder develop a condition known as Moyamoya syndrome. Moyamoya syndrome is a progressive disorder characterized by narrowing (stenosis) and / or closure (occlusion) within the skull of the carotid artery, the main artery that carries blood to the brain. Intracranial bleeding and other vascular abnormalities are potentially life-threatening complications and account for a significant percentage of mortality and morbidity in Alagille syndrome.

Causes

Alagille syndrome is caused by mutations in one of two genes - JAG1 or NOTCH2. Gene mutations JAG1 were identified in more than 88 percent of cases. Gene mutations NOTCH2 make up less than 1 percent of cases. These mutations are inherited in an autosomal dominant manner. In some cases, mutations occur randomly due to a spontaneous genetic change (i.e. a new mutation).

Dominant genetic disorders occur when only one copy of a mutated gene is needed for the disorder to occur. A gene with a mutation can be inherited from either parent or be the result of a new mutation (gene change) in the affected person. The risk of passing a gene with a mutation from one parent to the offspring with each pregnancy is 50 percent. The risk is the same for men and women.

Affected populations

Alagille's syndrome affects men and women in equal numbers. The estimated incidence of the syndrome is approximately 1 in 30,000–45,000 people in the general population. In some cases, the disease may be misdiagnosed or misdiagnosed, making it difficult to determine the true frequency of the syndrome in the general population.

Diagnostics

The diagnosis of Alagilles syndrome is based on the identification of characteristic symptoms, a detailed history of the patient, a thorough clinical assessment, and various specialized tests. Because the symptoms of Alagilles syndrome vary greatly, diagnosis can be difficult. Surgical removal and microscopic examination of liver tissue (liver biopsy) may reveal a deficiency in the bile ducts. Although bile duct deficiency is considered a key characteristic of the disease, this symptom is not always present in children with the disorder.

A doctor may suspect a syndrome if a person has three of the following five clinical signs in addition to biliary insufficiency ducts: symptoms of liver disease or cholestasis, heart defect, skeletal abnormality, eye abnormality (ophthalmology) and / or distinguishing features faces.

In addition to a liver biopsy, doctors may do other tests to help diagnose the disorder. Such tests may include blood tests to determine liver function and to detect deficiencies in fat-soluble vitamins, eye exams, X-ray of the spine to detect characteristic changes, ultrasound of the organs of the hepatobiliary system (for example, liver, pancreas glands, gallbladder and spleen) to detect abnormalities or rule out other conditions, and examining the structure and function of the heart to detect potential cardiac abnormalities.

The diagnosis of Alagilles syndrome can be confirmed in many cases by molecular genetic testing, which shows the presence of a gene mutation JAG1 or NOTCH2. However, in some people with the disorder, genetic testing may not detect the mutation. JAG1 or NOTCH2.

Standard treatments

Treatment for Alagille's syndrome focuses on the specific symptoms that each person experiences. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, gastroenterologists, cardiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child's care. People with Alagilles syndrome should have a basic echocardiogram (ultrasound of the heart) to be screened for subject of cardiac involvement, abdominal ultrasound for examination for liver and kidney abnormalities, and examination eye. In addition, if data on specific symptoms have not been previously obtained, head blood vessel screening is recommended. for children who are old enough to sit for examination without the need for anesthesia or sedation drugs.

Additional treatment with vitamins and nutrients is necessary for persons with malabsorption. Such treatment may include restoring vitamins A, D, E, and K. Young children can be given a medium chain triglyceride formula, as this form of fat is better absorbed by people with Alagille syndrome who have cholestasis. Some sick children may need food through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy a tube).

Specific treatment may be indicated for people with cholestatic liver disease. The drug ursodeoxycholic acid is used to improve the flow of bile, which can lead to a decrease in some symptoms, such as itching or cholesterol deposits (xanthomas). However, disease-related pruritus is often resistant to therapy. Additional medications that have been used to treat itching include antihistamines, rifampin, cholestyramine, and naltrexone. It is also recommended to keep your skin hydrated with moisturizers. Cholestyramine may also be indicated for individuals with high cholesterol or xanthomas.

Some affected infants and children with Alagille syndrome who do not respond to drug and dietary therapies can be treated with surgery. A surgical procedure is used to disrupt or reject the recirculation of bile acids between the liver and the gastrointestinal tract. This therapy has shown that in some children it can improve certain symptoms, such as reduced itching or xanthoma formation.

In severe cases of the disorder (i.e., in cases where cirrhosis or liver failure has progressed) or in which other treatments have failed), a transplant (transplant) may be required liver.

Additional complications that may be associated with Alagilles syndrome, including abnormalities of the heart, blood vessels, and kidneys, are treated in the usual way. In some cases, their therapy may include surgery.