William F. Balistreri, MD: Hello, and thank you all for joining this HCPLive® Peer Exchange program. We’re going to be talking about updates in the treatment of Alagille syndrome. I’m Bill Balistreri, a pediatric hepatologist and a professor of pediatrics and medicine at the University of Cincinnati and Cincinnati Children’s Hospital. I’m joined by a terrific panel. Let me start by asking Dr Rosenthal to introduce himself.
Philip Rosenthal, MD: Hi, everyone. I’m Phil Rosenthal. I’m a pediatric hepatologist at the University of California, San Francisco [UCSF]. I’m a professor of pediatrics and surgery, the director of pediatric clinical research, the director of pediatric liver and liver transplant research, and I direct pediatric hepatology at UCSF Benioff Children’s Hospitals.
William F. Balistreri, MD: Thank you, Phil. Welcome. Dr Vittorio?
Jennifer M. Vittorio, MD: Hi, I’m Jennifer Vittorio. I’m an associate professor of pediatrics in surgery in the Division of Gastroenterology, Hepatology, and Nutrition at Columbia University Medical Center in New York, [New York]. I’m also an attending pediatrician at the NewYork-Presbyterian Morgan Stanley Children’s Hospital. I direct our transition-of-care program known as PLATinum, the Pediatric Liver to Adult Transition program, and I’m happy to be here.
William F. Balistreri, MD: Thank you for joining us. Dr Gonzalez-Peralta?
Regino P. Gonzalez-Peralta, MD: Thank you, Bill. I’m Reggie Gonzalez-Peralta. I’m the medical director for pediatric hepatology and the pediatric liver transplant program at the AdventHealth for Children hospital and the AdventHealth Transplant Institute. Thank you all for the opportunity to be here.
William F. Balistreri, MD: Thank you for joining us, Reggie. Dr Fischer?
Ryan T. Fischer, MD: Thanks. I’m Ryan Fischer, the section chief of hepatology and transplant medicine at Children’s Mercy in Kansas City, and professor of pediatrics at the University of Missouri–Kansas City in Kansas City, Missouri.
William F. Balistreri, MD: Thank you, Ryan. Let’s get started. Let’s talk about this very fascinating syndrome, Alagille syndrome. It’s fascinating and frustrating. I’d guess that my panelists would agree that over the years this disease has excited us but also frustrated us with its unmet needs. Let’s talk about [this syndrome] and what’s new. Phil, do you want to lead off and tell us what Alagille syndrome is all about?
Philip Rosenthal, MD: I’m happy to do that, Bill. Alagille syndrome is a multisystem disease. There are multiple organs and areas that may be affected in patients with Alagille syndrome. These include the face, liver, kidneys, eyes, heart, skeleton, and vasculature. It’s estimated that [approximately] 1 in 30,000 to 45,000 individuals [have] Alagille Syndrome. There’s an equal prevalence in men and women, and it’s estimated that there are [approximately] 2500 children in the United States with Alagille.
The diagnosis of Alagille syndrome requires fulfillment of clinical diagnostic criteria. This is based on having 3 of 7 major organ systems involved. In the liver, one sees cholestasis, jaundice, or hepatomegaly. The classic histologic finding in the liver of patients with Alagille is… not enough bile ducts in the liver. The heart can be involved in Alagille syndrome. The classic cardiac lesion is peripheral pulmonic stenosis, but tetralogy of Fallot and aortic stenosis can also be seen. There’s a characteristic facies associated with Alagille syndrome. This includes a prominent forehead, pointed chin, deep-set eyes, and a bulbous tip nose. Ophthalmologically, one can see a posterior embryotoxon or optic disc drusen. In the skeletal system, there can be butterfly or hemivertebrae and pathological fractures. Kidneywise, there may be renal dysplasia or renal tubular acidosis. The final organ system, the vascular system, may [have] intracranial bleeding or central nervous system vascular malformations.
William F. Balistreri, MD: Thank you, Phil. Your statement implies that this is a clinical diagnosis, correct?
Philip Rosenthal, MD: Yes. One can make that diagnosis from a clinical standpoint, but nowadays, thanks to genetic testing, we have the ability to make the diagnosis based on gene diagnoses.
William F. Balistreri, MD: In your clinic, would clinical suspicion require further testing or are you confident enough that you can make a clinical diagnosis?
Philip Rosenthal, MD: Before genetic testing, I was pretty confident in using the 3 out of the 7 criteria. But now, to confirm the diagnosis, I’d definitely get genetic testing.
William F. Balistreri, MD: All right. Let’s ask Jennifer how we go about that. Jennifer, first of all, do you agree [with getting the] clinical diagnosis confirmed by genetic testing?
Jennifer M. Vittorio, MD: I absolutely agree with Dr Rosenthal. It’s quite interesting, because we were all so used to relying on our clinical acumen and making sure to look for the multiple organs that have been involved. Nowadays it’s almost like a trigger to send off genetic testing, sometimes earlier, before we even can order the echocardiogram or do the x-ray and whatnot. As Dr Rosenthal mentioned, there’s an incidence of 1 in 30,000 to 50,000 live births. But given some of the frustrations with the incomplete penetrance and variability of presentation, even among family members, the [incidence] is probably even [higher] than that.
Genetic testing is going to be very helpful in terms of screening for family members. We know that mutations in JAG1 are probably responsible for upward of 90% of patients with Alagille. A smaller percentage, somewhere between 5% or 10%, [can be] attributed to NOTCH2. There [are] also a fair number of patients who probably develop a de novo mutation. The estimates are a little more difficult to determine based on what we’re talking about with the variability in presentation.
William F. Balistreri, MD: Thank you. This is autosomal dominant, correct?
Jennifer M. Vittorio, MD: [Yes].
William F. Balistreri, MD: There’s also significant variability, as you mentioned. You also made an important point that it’s “more than that.” We’ve all had the experience of seeing a child in front of us with Alagille syndrome and glancing over at the parents and saying, “Oh my gosh,” which suggests the clinical variability, which we’ll talk about a little later.
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