Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The rare disease that we will be learning about today is:

Alagille Syndrome

Sometimes called hepatic ductular hypoplasia.

What is Alagille Syndrome?

• Alagille syndrome is a genetic disorder that primarily impacts the and heart and liver
• Prevalence is estimated to be around 1 in 30,000 to 1 in 40,000 live births
• The syndrome is named after Daniel Alagille, who was a French physician that first described the disease in 1969
• Severity of the syndrome’s effects can vary drastically, even between members of the same family
  • While signs of Alagille syndrome can appear early in life, the disorder can be extremely difficult to diagnose
• In rare cases, Alagille syndrome can be a life-threatening disease

How Do You Get It?

• Alagille syndrome is usually inherited in an autosomal dominant fashion
  • This means that only a single copy of the mutated gene needs to be inherited in order to cause the disorder
• The disorder can be caused by loss of function mutations in two different genes: NOTCH2 or JAG1
  • Overall, JAG1 mutations are more common
• There are also a limited number of reports of an autosomal recessive form of Alagille syndrome
  • This requires both parents to pass along a copy of the mutated gene
  • However, while 40 percent of mutations are inherited, the remaining are the result of acquired mutations.
    • This acquired cases are linked to environmental factors that mutate a single gene copy
    • Potential factors include exposure to the chemical benzene (common in cigarette smoke) and radiation, such as the sun’s UV rays

What Are The Symptoms?

• Symptoms tend to originate in infancy or early childhood
• In some patients, signs and symptoms are so subtle that they may not be noticed; in others, they can be life-threatening
• Symptoms can include:
• Heart
  • A range of congenital heart conditions may appear in Alagille syndrome such as:
    • Overriding aorta
    • Tetralogy of Fallot
      • Mortality reaches 70 percent by age 10, surgical intervention can greatly improve outcomes
    • Right ventricular hypertrophy
    • Ventricular septal defect
    • Coarctation of the aorta
    • Atrial septal defect
    • Patent ductus arteriosus
• Liver
  • Itching
  • Jaundice
  • Enlarged liver
  • Pale stools
  • Low or absent bile ducts
  • Cholesterol deposits on the skin (xanthoma)
  • Cirrhosis
  • Liver failure
  • Hepatocellular carcinoma (very rare)
• Other
  • Retina pigment changes
  • Axenfeld’s anomaly
  • Rieger anomaly
  • Certain facial features, such as deep set eyes, a prominent, broad forehead, and a small, pointed chin
  • Kidney abnormalities
  • Butterfly vertebrae

How Is It Treated?

• Once a diagnosis is reached, early treatment is possible and recommended in severe cases
• Treatment aims to improve nutritional deficiencies, improve bile excretion, and pain reduction
• Medications include:
  • Rifampin (to reduce itching)
  • Cholestyramine (to reduce itching)
  • Maralixibat (to reduce itching)
  • Ursodiol (to improve bile flow)
  • Vitamin supplementation
    • Alagille syndrome patients suffer from reduced nutritional absorption because of low bile flow and therefore benefit from supplements
• Diet
  • Diet can be an important aspect of treating Alagille syndrome
  • A high calorie diet, with the addition of a gastronomy tube, may be necessary
• Surgery
  • Surgery is needed for more severe cases
  • In cases of advanced liver disease or liver failure, a liver transplant may be necessary
    • These operations can be a challenge for Alagille syndrome patients since they often have heart defects and are less able to handle the physical strain of the surgery
  • Partial biliary diversion is used to treat xanthomas, itching, and jaundice

Where Can I Learn More???

• Learn more about this disease from the Alagille Syndrome Alliance.
• Check out our cornerstone on this disease here.