Alagille Syndrome

Etiology

Alagille syndrome has a wide spectrum of penetrance. Notch signaling pathways play a central role in Alagille syndrome pathophysiology[4], 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.

Epidemiology

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.

History and Physical

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.[5][6][7]

The seven major clinical features include:

1. Cardiac defects: reported in greater than 90% of patients and include peripheral pulmonic stenosis (67%), tetralogy of Fallot (16%), ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta.
2.  Hepatic manifestations: usually presenting with cholestasis caused by the paucity of biliary ducts, conjugated hyperbilirubinemia, pruritus, xanthomas, cirrhosis that can lead to end-stage liver disease in up to 15% of the cases.
3.  Renal abnormalities: characterized by renal dysplasia, glomerular mesangiolipidosis, and renal tubular acidosis.
4.  Skeletal abnormalities: identified include butterfly vertebrae, hemivertebrae, and/or pathological fractures of long bones.
5.  Ophthalmologic manifestations: that can occur include posterior embryotoxon with a prominent Schwalbe line.
6.  Dysmorphic facies: characterized by the prominent, broad forehead, deep-set eyes with moderate hypertelorism, prominent ears, triangular face with a pointed chin, and broad nasal bridge.
7.  Vasculature abnormalities: when present, are often associated with neurovascular abnormalities such as aneurysms, Moyamoya syndrome, abnormalities in cerebral arteries, reno-vascular abnormalities, and middle aortic syndrome.

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.

Evaluation

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 present with ductal proliferation that could lead to a misdiagnosis of biliary atresia.[8]

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, is 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.

Treatment / Management

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 the 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, improving liver function and catch-up growth.[9][10](A1)

• Cardiac, renal, and vascular involvement are managed according to the existing symptoms. No neurovascular screening guidelines exist for Alagille syndrome, and manifestations are treated in a standard manner.
• Ophthalmological and vertebral anomalies usually do not need intervention.
• Malnutrition should be managed proactively with supplements and fat-soluble vitamin supplementation; optimization maximizes growth and development.

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.

Differential Diagnosis

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.