Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with a wide variety of clinical manifestations. It is also known as arteriohepatic dysplasia, Alagille-Watson syndrome, Watson-Miller syndrome or syndromic bile duct paucity. The clinical manifestations are variable, even within the same family, and commonly include hepatic (cholestasis, characterized by bile duct paucity on liver biopsy), cardiac (primarily involving the pulmonary arteries), renal skeletal (butterfly vertebrae), ophthalmologic (posterior embryotoxon), and facial abnormalities. Alagille syndrome can range from a subclinical presentation to a life-threatening condition, with a mortality rate up to 10%.
Alagille syndrome has a wide spectrum of penetrance. Notch signaling pathways play a central role in Alagille syndrome pathophysiology, usually caused by a deletion or duplication in a single gene. Variants of JAG 1 Notch ligand (chromosome 20p12.2), which encodes protein ligands for the NOTCH2 receptor (chromosome 1p11-p12) account for 94% to 96% of Alagille syndrome cases, while variants in NOTCH2 cause around 1% to 2%. The offspring of a patient with Alagille syndrome has a 50% chance of inheriting a gene mutation, whereas, among those affected with Alagille syndrome, 50% to 70% of individuals have a mutation de novo. No correlation has been found between a specific mutation and expressed phenotype.
Due to the variable clinical presentation of Alagille syndrome, it is difficult to know the exact incidence and prevalence. It is estimated that the prevalence of Alagille syndrome varies from 1:30,000 to 1:100,000.
Diagnosis of Alagille syndrome can be challenging due to the variability of clinical manifestations, ranging from no symptoms to life-threatening conditions, even among individuals from the same family who share the same mutation. Most patients present with jaundice or cardiac-related symptoms.
The seven major clinical features include:
Other associated features are short stature, failure to thrive, immunodeficiency, and recurrent infections. Developmental delay, delayed puberty, supernumerary flexion creases, and pancreatic insufficiency cases also have been reported.
Alagille syndrome is diagnosed when an individual has three out of seven major clinical features. Bile duct paucity on liver histology is no longer considered mandatory for the diagnosis of Alagille syndrome, the presence of cholestasis can be used instead. Individuals with an affected first-degree relative and who do not meet full clinical criteria but with the presence of one or more clinical features should be diagnosed with Alagille syndrome. Infants younger than 6 months of age may not present with a marked paucity of the bile ducts or even may present with ductal proliferation that could lead to a misdiagnosis of biliary atresia.
Liver tests show hepatic dysfunction as manifested by elevated direct bilirubin, serum aminotransferases, serum bile acids, cholesterol, triglycerides and gamma-glutamyl transpeptidase levels, and when elevated are associated with worse outcomes. It may be necessary to perform a hepatic ultrasound, technetium 99m scan, and liver biopsy. Urine analysis may be useful to detect renal tubular acidosis, stool exam may indicate pancreatic insufficiency, cardiac evaluation with an echocardiogram, X-rays to assess for the presence of butterfly vertebrae and other skeletal abnormalities, ophthalmologic exam, developmental evaluation, vascular studies and genetic consultation can also aid in the diagnosis.
Clinical diagnosis can be confirmed with genetic testing by finding a mutation with sequence analysis of JAG1 or NOTCH2 on Fluorescence in situ hybridization (FISH). For pregnancies at risk for Alagille syndrome prenatal diagnosis with molecular genetic testing or preimplantation genetic diagnosis can be made, another useful tool is fetal ultrasound examination especially fetal echocardiogram may detect a significant structural defect of the heart.
Alagille syndrome prognosis and mortality risk vary with the difference of organ involvement and the severity. Severe cardiac or hepatic disease cause early mortality, in contrast to vascular accidents which result in later mortality. Management needs a multidisciplinary approach, depending on the findings of each affected individual. With liver disease, the treatment is mainly supportive, trying to ameliorate severe pruritus and xanthomas with agents that help with the cholestasis (ursodeoxycholic acid, naltrexone, rifampin, colesevelam, and cholestyramine). Surgical partial internal biliary diversion and ileal exclusion also have been used for this purpose, without preventing the progression of liver disease. Even though Kasai procedure (portoenterostomy) is used in a patient with biliary atresia, this procedure does not benefit children with Alagille syndrome and may worsen the outcome. Liver transplantation for end-stage liver disease has an 80% five-year survival rate, with improving liver function and catch-up growth.
To prevent secondary complications, contact sports should be avoided; this is especially true for those patients with splenomegaly, chronic liver disease, and vascular involvement. Regular monitoring by specialists in the fields of cardiology, gastroenterology, ophthalmology, nephrology, and nutrition should be performed.
Conditions that cause cholestasis must be included in the differential diagnosis.
Interlobular bile duct paucity also can be found in patients with alpha-1 antitrypsin deficiency, cystic fibrosis, childhood primary sclerosing cholangitis, mitochondrial disorders, congenital hepatic fibrosis, infection (congenital syphilis, congenital cytomegalovirus, congenital rubella and hepatitis B), childhood autoimmune hepatitis, hypopituitarism, graft versus host disease, Zellweger syndrome, Ivemark syndrome and Smith-Lemli-Opitz syndrome.
Cholestasis can be found in neonates with biliary atresia, sepsis, galactosemia, tyrosinemia, choledochal cyst or other extrahepatic structural abnormalities. It is also found in individuals with progressive familial intrahepatic cholestasis types 1 and 2, arthrogryposis-renal dysfunction-cholestasis syndrome, benign recurrent intrahepatic cholestasis, and Norwegian cholestasis (Aagenaes syndrome).
Pulmonic vascular abnormalities also are seen with Noonan syndrome, Watson syndrome, William syndrome, Down syndrome, and LEOPARD syndrome.
Ventricular septal defects and Tetralogy of Fallot are common in patients with deletion 22q11.2 as well as butterfly vertebrae and failure to thrive.
Posterior embryotoxon also can be seen in 8% to 15% of the general population as well as other syndromes like Bannayan-Riley-Ruvalcaba syndrome and Axenfeld-Rieger syndrome.
Algaille syndrome is a very rare genetic disorder that has a varied presentation. Because the syndrome is associated with a very high mortality, it is best managed by a multidisciplinary team that includes a geneticist, pediatrician, gastroenterologist, ophthalmologist, cardiologist, urologist and a cardiac surgeon. Because of the bile duct atresia, most infants need a biliary drainage procedure or a liver transplant. The need to monitor these infants for complications cannot be overstated.