What Is Alagille Syndrome?
Like many infants, Signe Teitelbaum had jaundice when she was born.
But she was also very small — just 3 pounds, 11 ounces — despite being only one day premature. And she had high levels of direct bilirubin, a possible sign of liver problems. Luckily, a neonatologist on duty had experience recognizing and treating an inherited condition called Alagille syndrome (ALGS).
“He started ordering all these tests that were really baffling to everybody else — looking at her spine, doing eye exams,” says Signe’s father, Benjamin R. Teitelbaum, PhD, an associate professor at the University of Colorado Boulder.
Alagille syndrome can happen because of a genetic mutation (a change in your DNA) inherited from one parent. Sometimes though, the gene mutation isn’t inherited.
Teitelbaum and his wife were shocked by Signe’s diagnosis. They’d never heard of Alagille syndrome, and Signe was their first child. Eventually, Signe’s mother was also diagnosed with ALGS.
“You’re overwhelmed with all those feelings of holding a baby for the first time and being parents for the first time, and yet there’s also a lot of concern,” Teitelbaum says. “It was very hard at that time to get a sense of, ‘What does it mean?’ And that’s still hard for parents.”
Children with ALGS often have distinct facial features. They can have chronic itching called pruritus. Along with liver problems, Alagille can affect their heart, kidneys, skeletal system, and eyes. They may have delayed growth and learning challenges, too. But learning disabilities aren’t as common.
ALGS can be difficult to diagnose. Your child may need to have physical exams and tests, including a blood test to look for a gene mutation.
Researchers around the world, such as the Global Alagille Alliance (GALA) study group, are trying to understand more about how ALGS affects children and young adults. But for families and caregivers of children with this condition, there are still many unknowns.
“For me, the biggest challenge is the fact that it can be so unpredictable,” Teitelbaum says. “The range of outcomes is so wide, and our story really exemplifies this.”
How Alagille Syndrome Affects the Body
Alagille syndrome can affect children differently, with symptoms ranging from mild to life-threatening. ALGS is often caused by a change in the JAG1 gene, but rare cases are caused by a change in the NOTCH2 gene.
These changes can affect many organs and systems of the body, says Katelyn Saarela, DO, a pediatric hepatologist and transplant hepatologist at Seattle Children’s Hospital. Your child’s liver, heart, kidneys, eyes, skeletal system, and blood vessels — especially in the brain and neck — can all be affected.
Liver symptoms
The liver is the most commonly affected organ in kids with Alagille syndrome. One study found that 95% of children with ALGS had liver disease. ALGS makes it harder for bile to flow out of your child’s liver.
“Due to specific genetic mutations, the bile ducts — the liver’s plumbing system of tiny tubes that carry bile to the intestines — may be fewer in number or poorly formed,” Saarela says.
When too much bile builds up in the liver, it’s called cholestasis. The same study also found that 85% of children with ALGS had cholestasis as infants. Cholestasis can cause:
- Jaundice (yellow skin)
- Chronic itching
- Malnutrition
- Vitamin deficiencies
Some children with cholestasis have visible cholesterol deposits called xanthomas. Signe had xanthomas on her hands when she was around 4 years old. Her doctor prescribed a very small dose of atorvastatin (Atorvaliq, Lipitor) that was very successful, Teitelbaum says. Later, Signe started taking maralixibat (Livmarli) to control her itching.
Heart symptoms
About 9 in 10 children with ALGS have a heart defect when they’re born. Sometimes, it’s a simple heart murmur with no serious effects. The most common heart defect in ALGS is peripheral pulmonary stenosis, when one or more of the arteries that carry blood from the heart to the lungs has narrowed. This can force the heart to work harder, and may worsen over time. Some children with heart defects need treatment or surgery.
How ALGS affects other systems
Alagille syndrome can also affect other body systems and organs. About 39% of children with ALGS have kidney problems. The kidneys may not develop correctly, a condition called kidney dysplasia. Or the kidneys may not be able to remove acids from the blood like they’re supposed to, a condition called renal tubular acidosis.
The JAG1 gene also affects how the blood vessels develop. Children with ALGS can have problems with their vascular system, such as narrowed blood vessels in the kidneys and heart.
Other characteristics of Alagille syndrome
Your child may have other physical characteristics of ALGS. Many children have a ring on the outer edge of their eye called posterior embryotoxon. This rarely affects vision, Saarela says.
They may also have deep-set eyes, a wider forehead, and a pointed chin.
Many children have “butterfly” vertebrae, which happens when vertebrae don’t fuse properly. This usually shows up on X-rays, which can help doctors make a diagnosis. But butterfly vertebrae usually don’t cause symptoms.
How Alagille Syndrome Affects Growth and Development
Children with ALGS may grow more slowly and go through puberty later than their peers. A combination of factors can cause growth and development issues. Their liver and pancreas may not work properly. The JAG1 gene may also be involved.
Liver problems can affect a child’s ability to absorb fat, so they may not have enough of certain vitamins, like A, D, E, and K. Vitamin deficiencies can affect your child’s growth and make it easier for them to get sick. About 50%-90% of children with ALGS who have liver disease also have delayed growth.
The pancreas plays an important role in digestion and helps the body absorb nutrients. If it's not working the way it should, children may not be able to absorb fat, affecting their growth and development.
Vitamin supplements can help. Some kids need a liver transplant, which can also improve vitamin absorption.
“Following liver transplantation, patients often experience some catch-up growth,” Saarela says.
Severe itching can also affect your child’s sleep, making it more difficult for them to pay attention in school. But there are effective medications to help control itching.
“The most transformative recent advance has been the approval of ileal bile acid transporter (IBAT) inhibitors,” Saarela says.
These IBAT inhibitors interrupt the reabsorption of bile acids in the intestines, which leads to less itching, she says.
About 16% of people with ALGS have minor delays in motor skills. Because ALGS is often caught early (and, thanks to nutritional supplements), very few people with ALGS have intellectual disabilities.
As for Signe, while she’s smaller than most kids her age, she’s a typical 11-year-old otherwise.
"She’s very smart, she’s very talented, and she’s an incredible artist," Teitelbaum says. “[She’s] funny, creative … For the most part, she’s living a normal life.”
Does Alagille Syndrome Cause Complications?
For many children with ALGS, liver disease resolves by the time they turn 8 years old. But liver disease can cause complications. In severe cases, cholestasis can lead to liver scarring (also known as cirrhosis). About 15% of people with ALGS will need a liver transplant.
Last spring, a lesion on Signe’s liver started growing very quickly. A biopsy showed adenomas — benign tumors that can become cancerous. Without a new liver, Teitelbaum realized, the lesions would always just be sitting there, “like ticking time bombs,” he says.
Signe’s family started the protocol for her to receive a liver transplant. During that time, more small nodules were found on Signe’s lungs — another terrifying moment for the family — but the nodules weren’t cancerous.
“Waiting for those results … those are certainly the most difficult moments of my life, by a considerable margin,” Teitelbaum says.
This year, Teitelbaum donated a portion of his liver to Signe. Both of them are recovering well.
“We don’t know why these lesions came — they just kind of came out of nowhere. But it feels like we’ve come out on the other side of all that,” Teitelbaum says. “These first six months, at least, for her transplant have gone absolutely as well as they possibly could have.”
People with ALGS can also have potentially serious vascular system complications, such as bleeding within the skull. This usually happens spontaneously but can be caused by a minor trauma, so it’s important to tell your doctor if your child falls or hits their head.
Other vascular complications can include aneurysms, which are bulges in blood vessel walls that can break open and cause bleeding inside the body. Narrowing of blood vessels can also happen in the kidneys and the heart.
Is Every Case the Same?
Alagille syndrome can affect each person differently, even when they’re related. For some people, ALGS is nearly unnoticeable, while others can have serious complications. Signe and her mother are a good example of how members of one family can have such different experiences with ALGS.
“There is significant phenotypic variability in Alagille syndrome, which can range from life-threatening liver and cardiac disease to subclinical features only detectable by targeted testing,” Saarela says. “This variability occurs even among family members carrying the identical mutation.”
There’s no cure for Alagille syndrome. But kids with this condition can lead long lives. Saarela’s young patients often thrive, she says. And in the past decade, research and advocacy have helped lead to new treatments and therapies, including IBAT inhibitors approval in 2021.
“Just in those years, it’s changed so much, and that’s thanks to the efforts of families,” Teitelbaum says. “I feel like there’s momentum with research and understanding of this disease. There’s lots of reasons to be hopeful.”
Show Sources
Photo Credit: E+/Getty Images
SOURCES:
Benjamin R. Teitelbaum, PhD, associate professor, University of Colorado Boulder, Boulder, Colorado.
Katelyn Saarela, DO, pediatric hepatologist, transplant hepatologist, Seattle Children’s Hospital, Seattle, Washington.
American Journal of Medical Genetics: “Renal Anomalies in Alagille Syndrome: A Disease-Defining Feature.”
Hepatology: “Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.”
Statpearls: “Alagille Syndrome.”
National Institute of Diabetes and Digestive and Kidney Diseases: “Diagnosis for Alagille Syndrome,” “Renal Tubular Acidosis.”
UpToDate: “Alagille syndrome.”
FDA: “Livmarli.”
National Organization for Rare Disorders: “Alagille Syndrome - Video.”
American Liver Foundation: “Alagille Syndrome.”
Children’s Hospital of Philadelphia: “Alagille Syndrome.”
Boston Children’s Hospital: “Peripheral Pulmonary Stenosis.”
The Global Alagille Alliance Study: “The GALA Study.”
Mayo Clinic: “Aneurysms.”
Cleveland Clinic: “Jaundice in Newborns,” “Kidney Dysplasia.”
