Alagille syndrome is a rare genetic disease caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes.1 This impairs the Notch signaling pathway and affects many organs and systems in the body. The symptoms of the condition vary greatly from one patient to another and even between affected members of the same family.2
Patients with the disease may need to see a multidisciplinary team of Alagille syndrome specialists to manage their condition and symptoms. These ALGS specialists include pediatricians, nutritionists, gastroenterologists, cardiologists, ophthalmologists, nephrologists, transplant hepatologists, and clinical geneticists.
Alagille syndrome (ALGS) symptoms usually appear shortly after birth, and the disease is often diagnosed before the patient reaches 1 year of age.3
A diagnosis is reached in the presence of 3 of the following criteria: cholestasis, usually presenting as jaundice and pale stools; facial features such as a broad forehead, deep-set eyes, prominent ears, a straight nose, and a pointed chin; congenital heart disease, including peripheral pulmonary artery stenosis, pulmonary atresia, atrial septal defects, ventricular septal defects, and tetralogy of Fallot; skeletal abnormalities, including “butterfly” vertebrae, hemivertebrae, adjacent vertebrae fusion, and spina bifida occulta; and ocular conditions such as posterior embryotoxon.4
A pediatrician usually coordinates the care of patients with ALGS and monitors their growth and development. Pediatricians may also prescribe medications to ease the symptoms of the disease, including ursodeoxycholic acid (ursodiol) to increase bile flow from the liver and lower cholesterol levels in the blood. Antihistamines and other medications can also help to reduce pruritus associated with decreased bile flow.5
Intrahepatic bile duct paucity in ALGS leads to reduced bile flow to the small intestine. This causes problems with fat digestion and the absorption of fat-soluble vitamins A, D, E, and K, which leads to malnutrition.6
A nutritionist can develop a suitable diet high in calories and carbohydrates and containing medium-chain triglycerides to ensure patients are getting enough nutrients. They can also suggest a special formula for infants high in medium-chain triglycerides. They can suggest vitamin supplements based on patients’ blood test results.
If a patient cannot eat by mouth, a nutritionist can advise patients on alternative options such as tube feeding. These include a nasogastric tube inserted through the nose or a gastrostomy tube inserted through a surgical incision in the abdomen.
A gastroenterologist conducts hepatic evaluation in patients presenting with cholestasis. These include laboratory tests such as hepatic function panel, gamma-glutamyl transferase, serum bile acids, serum cholesterol with lipid panel, fat-soluble vitamin levels, and prothrombin time.
Other hepatic evaluations include liver ultrasound, hepatobiliary scintigraphy, and intraoperative cholangiogram.7
Some patients with ALGS present with congenital cardiac abnormalities, including peripheral pulmonary stenosis (narrowing of the pulmonary artery), heart murmur, and tetralogy of Fallot (cardiac anomaly typically present on the right side of the heart).8
A cardiologist may perform a physical exam, electrocardiogram, and echocardiogram. The cardiac evaluation is determined by the clinical situation. A lung ventilation/perfusion scan may also be helpful in the case of asymmetric pulmonary vascular supply.8
Ophthalmologists may perform a slit-lamp examination for diagnostic purposes. In ALGS, a typical finding is posterior embryotoxon, which usually does not require treatment or follow-up.7
Other ophthalmological findings include iris hypoplasia, anomalous optic discs, abnormalities of the retinal vessels, and pigmentary retinopathy.
Routine ophthalmological monitoring is recommended to follow disease progression and the development of glaucoma.
The kidneys are also often affected in ALGS, and renal problems range from structural renal anomalies such as solitary kidney, ectopic kidney, small kidney, unilateral and bilateral multicystic kidneys, dysplastic kidneys, and horseshoe kidney to renal diseases such as tubulointerstitial nephropathy and mesangiolysis.8
A nephrologist should evaluate patients’ kidneys through a combination of blood tests, urine tests, and ultrasound.
In some patients with ALGS, liver disease can progress to end-stage liver disease. These patients may require a liver transplant. A transplant hepatologist will evaluate the cardiac and renal involvement of the disease during the transplant assessment.9
Transplant hepatologists also manage the patient after the transplant and monitor immunosuppression and transplant-associated infectious diseases.
A clinical geneticist can perform genetic testing to analyze the patient’s JAG1 and NOTCH2 genes to aid in diagnosis and to determine the type of disease they have.10 They should also review the results of the workup of the patient’s parents or relatives so genetic counseling can be offered to the family. Clinical geneticists can also offer prenatal or preimplantation genetic testing.
- Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 18, 2021.
- Alagille syndrome. National Organization for Rare Disorders. Accessed June 18, 2021.
- Definition & facts for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 18, 2021.
- Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3): 251-257. doi:10.1038/ejhg.2011.181
- Alagille syndrome | diagnosis & treatments. Boston Children’s Hospital. Accessed June 18, 2021.
- Eating, diet, & nutrition for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 18, 2021.
- Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;50(6):580-586. doi:10.1097/MPG.0b013e3181d98ea8
- Alagille syndrome. Children’s Hospital of Philadelphia. Accessed June 18, 2021.
- Transplant hepatology. American College of Physicians. Accessed June 18, 2021.
- Alagille syndrome. Exeter Clinical Laboratory International. Accessed June 18, 2021.
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.