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What is Alagille Syndrome?
Alagille Syndrome (OMIM #118450) is the most commonly encountered rare cholestatic liver disease seen by pediatric hepatologists. It can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms.
Most people with Alagille syndrome have mutations in one copy of the JAG1 gene. A small percentage (less than 1 percent) of patients have mutations of the NOTCH2 gene. These mutations are inherited as autosomal dominant traits, however in about half of cases the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is between 1:30,000 and 1:70,000 with no difference in gender.
The video is on top, in English and Spanish, is a wonderful animated description of Alagille Syndrome. Sponsored by Travere Therapeutics for the ALGS community, it was developed by National Organization for Rare Disorders (NORD).
Below, you will find frequently asked questions about Alagille Syndrome which will continue to be expanded through 2024.
Frequently Asked Questions
How is Alagille syndrome diagnosed?
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What are the symptoms / characteristics of Alagille Syndrome?
Is Alagille syndrome hereditary?
Reference:
Gilbert MA, Bauer RC, Rajagopalan R, et al. Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum mutt. 2019;40(12):2197-220.
Are there treatments for Alagille syndrome?
Treatment for those with a cardiac phenotype depends of the type of cardiac defect being treated, and needs to be managed aggressively in patients who may need a liver transplant.
Is Alagille syndrome life limiting or life threatening?
Alagille syndrome can be both life threatening and life limiting depending on disease involvement and severity of organs and systems affected. The spectrum of severity can be different for each patient so it is very important to be careful not to compare your/your child’s ALGS experience, symptoms, or disease involvement to anyone elses as it simply would not be the same experience for both. Life threatening circumstances are particularly around severe cardiac involvement that may include severe pumlonary stenosis or severe tetralogy of fallot, and other life threatening circumstances that may include intracranial hemorrhaging, liver cell cancers, and risks associated with invasive surgeries like liver transplant and open-heart surgery. Life limiting circumstances may include liver cholestasis with pruritus, fatigue, poor growth, general weakness, renal dysfunction, and metabolic bone disease with bone fractures.
It’s important to note that there are many adults living with ALGS around the world living well into their 70’s and beyond who also have families, careers, and very happy lives. Despite the life-limiting, life-threatening aspects of ALGS for some patients affected, there are also many patients who do not experience these risks.
How is Alagille syndrome diagnosed?
Alagille syndrome and biliary atresia (BA) may require differentiation due to similarities, as ALGS is sometimes misdiagnosed as BA.
References:Ayoub MD, Kamath BM. Alagille syndrome: Current understanding of pathogenesis, and challenges in diagnosis and management. Clin Liver Dis. 2022;26:355-70.
How is Alagille syndrome diagnosed?
Alagille syndrome and biliary atresia (BA) may require differentiation due to similarities, as ALGS is sometimes misdiagnosed as BA.
References:Ayoub MD, Kamath BM. Alagille syndrome: Current understanding of pathogenesis, and challenges in diagnosis and management. Clin Liver Dis. 2022;26:355-70.
What might the specific organ system involvement include?
Below is a list of possible organ system involvement and the differerent manifestations. This DOES NOT mean a patient will have all of these.
Facial features may include a triangular face appearance with a broad and prominent forehead and small, pointed chin. Also, deep-set eyes and a bulbous tipped nose may be identified.
Hepatic features may include a reduction in intrahepatic bile ducts called bile duct paucity, hepatomegaly, cholestatic jaundice, and splenomegaly secondary to progressive hepatic fibrosis and portal hypertension.
Cardiac features may include at least one finding or more of peripheral pulmonary artery stenosis and/or hypoplasia (PPS), right-sided/left-sided/left and right-sided lesions, heart murmur, or complex intracardiac anomalies like tetralogy of Fallot (TOF) and valvular/supravalvular aortic stenosis.
Skeletal features may include butterfly vertebrae, the most common skeletal finding, shortening of the radius, ulna, and phalanges, and other affects to the upper limbs and ribs.
Ocular findings may include posterior embryotoxon, the most common eye finding which does not generally interfere with vision. Other findings may include Axenfeld anomaly, retinitis pigmentosa, and other abnormalities involving the pupillary, optic disk, cornea, iris, and/or retina.
Renal features may include both structural and functional renal abnormalities. These may include malformations cystic and structural, like renal dysplasia, cysts, absent kidnetm, horseshoe kidney, and/or a duplex ureter. Other findings may include renal tubular acidosis, mesangiolipidosis, osteopathy, renal artery stenosis, midaortic syndrome, hypertension, glomerulopathy, tubulopathy, and hyperkalaemia.
Vascular features may include inracranial and systemic abnormalities including internal carotid artery stenosis, middle cerebral and basilar artery aneurysms, moyamoya disease, and bleeding intracranially or in the subdural, epidural, or subarachnoid space.
Other findings may include immune dysregulation, thyroid and/or parathyroid involvement, failure to thrive, and hepatopulmonary syndrome.