Alagille Syndrome

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Alagille Syndrome is an autosomal-dominant inherited disease caused by mutations in the JAG1 and NOTCH2 genes.[1] First described by its characteristic intrahepatic bile duct hypoplasia, Alagille Syndrome is now known to impact multiple organ systems[2]. The estimated prevalence of Alagille syndrome ranges from 1:30,000 to 1:100,000[3]. Those that are most commonly affected are the hepatobiliary, oral maxillofacial, ophthalmic, cardiovascular, renal and musculoskeletal[2]. Variable disease presentation is thought to be due to variable penetrance, with many family members of those diagnosed having characteristics but not meeting clinical diagnostic criteria.[2][4][5]


Mutations are much more common in JAG1, with very few cases being caused by mutation of the NOTCH2 gene.[6] These genes function in development to aide in cell differentiation in utero.[7] Thus, it is believed that mutations affecting these genes may disrupt normal differentiation and development of the many organ systems affected.

Systemic presentation

There are seven major clinical features of Alagille syndrome:

  1. Cardiac defects
  2. Hepatic abnormalities
  3. Renal dysfunction
  4. Skeletal abnormalities
  5. Ophthalmic findings
  6. Facial features
  7. Vascular anomalies

Cardiac involvement is reported in more than 90% of patients[8], with presentations ranging from benign murmur to structural defects requiring surgical intervention.[5] Reported cardiac anomalies include: peripheral pulmonic stenosis, tetralogy of Fallot, ventricular septal defect, atrial septal defect, and coarctation of the aorta[8]. Right-sided heart defects are more common than left in these patients.[9] More severe defects in cardiac structure correlate with greater morbidity and mortality.[5]

The liver is the primarily affected organ, and hepatobiliary symptoms are what tend to guide the primary physician to investigate further. Parents may notice their child developing jaundice, pruritis, and cutaneous xanthomas. Patients may also develop coagulopathy as a consequence of poor hepatic function and decreased bile-assisted digestion of fat-soluble vitamins. Upon investigation, the inspecting physician may find an indirect bilirubinemia, hepatomegaly, and imaging suggestive of biliary atresia.[10] As the disease progresses, patients may require liver transplant due to cholestasis, or due to the development of portal hypertension and fibrosis.[5][3] A total bilirubin greater than 3.8mg/dL between ages of 12-24 months, as well as the presence of xanthomas and liver fibrosis before the age of 5 years correlate with a worse prognosis.[11] Up to 15% of patients will develop end-stage liver disease[8].

Renal involvement may include renal tubular acidosis, vesicoureteral reflux, glomerular mesangiolipidosis and renal dysplasia.[12][8]

Patients may present with fractures and clinical signs of osteopenia. The most frequent musculoskeletal abnormality in Alagille Syndrome is a butterfly abnormality of the vertebral column.[13]

Facial features are notable for a saddle-like nose, deep-set eyes with hypertelorism, prominent ears, triangular face with a pointed chin and a high forehead with frontal bossing or flattening.[4][8]

Patients are more likely to have cerebral vessel anomalies like aneurysms and Moyamoya syndrome[8], but many vessels extracranially can be affected by Alagille Syndrome. Although pulmonary vessels are commonly involved in disease, the renal vascular system and middle aorta may also be affected.

Ophthalmic presentation

The most common ocular manifestation in patients with Alagille Syndrome is posterior embryotoxon. Anterior segment involvement may also include iris abnormalities, but intraocular pressures and pupillary function tend to be normal. Posterior segment abnormalities may include pathologic changes to the optic disc including hypoplasia, elevation, and irregular tilting of the disc. Chorioretinal findings may include diffuse hypopigmentation of the choroid and retina, and irregular pigmentation of the retinal pigment epithelium. Even with these various ocular findings associated with Alagille Syndrome, visual function in these patients tends to be unaffected.[14]

Differential Diagnosis

Main considerations in the differential diagnosis of Alagille involve diseases that lead to cholestasis. However one could consider a differential for each organ system affected.

  1. Bile duct paucity: alpha-1 antitrypsin deficiency, cystic fibrosis, childhood primary sclerosing cholangitis, mitochondrial disorders, congenital hepatic fibrosis, infectious etiologies (congenital syphilis, congenital cytomegalovirus, congenital rubella, hepatitis B), childhood autoimmune hepatitis, hypopituitarism, graft versus host disease, Zellweger syndrome, Ivemark syndrome, Smith-Lemli-Opitz syndrome
  2. Cholestasis: biliary atresia, sepsis, galactosemia, tyrosinemia, choledochal cyst, progressive familial intrahepatic cholestasis types 1 and 2, arthrogryposis-renal dysfunction-cholestasis syndrome, benign recurrent intrahepatic cholestasis, Norwegian cholestasis (also called Aagenaes syndrome)
  3. Pulmonary vessel anomalies: Noonan syndrome, Watson syndrome, William syndrome, Down syndrome, LEOPARD syndrome
  4. Cardiac and skeletal malformations: deletion 22q11.2
  5. Posterior embryotoxin: Bannayan-Riley-Ruvalcaba syndrome, Axenfeld-Rieger syndrome. Also seen in 8-15% of the general population.


Diagnosis without a confirmed genetic test can be deduced by the characteristic inclusion of at least three of the seven major clinical features. With available technology in genetics, patients with clinically suspected Alagille Syndrome are able to undergo genetic testing for mutations in the JAG1 and/or NOTCH2 genes for confirmation. Up to 95% of patients with Alagille Syndrome have an identifiable mutation that will confirm the diagnosis.[15] In cases of pregnancy with a family history, prenatal and preimplantation testing may be available. If both genetic panels come back negative for mutations, findings should be clinically correlated with other possible diagnoses. Previously, diagnosis was confirmed with liver biopsy, with the sparsity of bile ducts being the correlating factor examined for confirmation.


Treatment of Alagille Syndrome is mainly geared toward managing the dysfunction of the affected organ systems. Patients often present with symptoms related to their lack of a mature hepatobiliary system, including pruritis, jaundice, right upper quadrant pain, and malabsorption. To manage this hepatobiliary dysfunction, patients are advised to ingest calorie-dense food and supplement fat-soluble vitamins to ensure proper overall absorption of nutrients.[16] Medical treatment focuses primarily on increased bile secretion into the intestines. Ursodeoxycholic acid (UDCA), rifampin, cholestyramine, opioid antagonists, antihistamines and selective serotonin re-uptake inhibitors may all be trialed. UDCA is the first-line medication prescribed for pruritis in these patients.[17] Patients that fail medical therapy may opt for partial external biliary diversion as surgical intervention.[18]

Cardiac, renal and vascular issues may be managed medically or surgically depending on their disease severity. Ophthalmic and skeletal disease rarely requires intervention. However, due to the variability in disease manifestation, coordination of a multisubspecialty team of providers is often necessary for diagnosis and surveillance of disease.


Prognosis varies depending on disease severity. Up to 75% of patients require liver transplantation by age 18.[19] Cerebrovascular events are a significant cause of morbidity and mortality.[20]

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  6. Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, et al. Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum. Mutat. 2019, 40, 2197–2220.
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  16. Ayoub MD, Kamath BM. Alagille Syndrome: Diagnostic Challenges and Advances in Management. Diagnostics. 2020; 10(11):907.
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  18. Wang KS, Tiao G, Bass LM, Hertel PM, et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology 2017, 65, 1645–1654.
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