Alagille syndrome (ALGS) is a rare multisystem genetic disorder caused by defects in the Notch signaling pathway and characterized by the buildup of bile in the liver and hepatic damage because of a paucity of intrahepatic bile ducts.1 Although it mainly affects the liver, Alagille syndrome can also affect the heart, spine, eyes, face, kidneys, and vasculature.
It is estimated that the condition affects around 1 in 70,000 newborns2; however, this figure is based on the diagnosis of liver disease in infants and may be an underestimate, as not all patients with ALGS develop liver disease in infancy.
History of ALGS
Alagille syndrome was first described in 1969 by the French pediatric hepatologist Daniel Alagille, who recognized the organs affected by the disorder.3 He called the disorder “syndromic bile duct paucity,” which was later referred to as “Alagille syndrome” or “Alagille-Watson syndrome.” It is sometimes also referred to as “arteriohepatic dysplasia.”
Alagille Syndrome Causes
Alagille syndrome is caused by mutations in the JAG1 or NOTCH2 gene; more than 90% of all cases are caused by mutations in JAG1, and only a few patients have mutations in the NOTCH2 gene.2 Approximately 7% of patients with ALGS have deletions on chromosome 20 that include the JAG1 gene.
The JAG1 gene encodes the Jagged-1 protein, which plays a key role in Notch signaling during embryonic development.4 Jagged-1 acts as a ligand to the Notch receptor and is thought to be involved in cell fate decisions during hematopoiesis. Jagged-1 may also be involved in early and late-stage cardiovascular development and angiogenesis.5
Mutations in either JAG1 or NOTCH2 disrupt Notch signaling and lead to developmental problems especially affecting the bile ducts, heart, spinal column, and face.6
Alagille Syndrome Inheritance
Alagille syndrome is inherited in an autosomal dominant manner, so a child has a 50% chance of inheriting the disease from an affected parent.2
Around half of all cases of ALGS are the result of spontaneous mutations that occur during gametogenesis or embryonic development. The condition affects male and female individuals equally.
Alagille Syndrome Symptoms
ALGS affects many tissues and organs in the body. The first symptoms of the disease include pruritus; jaundice; xanthomas; darkening of the color of urine and lightening of the color of stools; loose, greasy, and odorous stools; hepatomegaly; and splenomegaly. These symptoms usually appear in the first year of life.
Other symptoms include poor growth and energy, heart murmur and congenital heart defects, posterior embryotoxon, butterfly vertebrae, narrowing and weakness in the walls of blood vessels, kidney dysplasia, renal tubular acidosis, and vesicoureteral reflux.
Patients with ALGS also have typical facial features, which include a large forehead, deep-set eyes, and a pointy chin and nose.
Symptoms may vary greatly from one patient to the other and sometimes even among the members of the same family, with some experiencing severe complications and others not even aware of their condition.7
Read more about Alagille syndrome symptoms.
Alagille Syndrome Diagnosis
Diagnosis starts with a physical examination and the family and medical history of the patient.
Tests that may be performed to reach a diagnosis of ALGS include liver biopsy, cardiovascular tests, eye exams, spine x-ray, abdominal ultrasound, renal function tests, and genetic tests.8
A final diagnosis can be reached if the liver biopsy shows bile duct paucity and ≥3 of the following signs and symptoms are present: facial features of ALGS, butterfly vertebrae, heart murmur or unusual cardiovascular structure, liver problems, or posterior embryotoxon. There are several differential diagnoses. They include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia.9
Read more about Alagille syndrome diagnosis.
Alagille Syndrome Treatment
To treat hepatic problems caused by ALGS, ursodiol may be prescribed to improve bile flow from the liver to the small intestine. Ursodiol may also help relieve pruritus and reduce the yellow bumps on the skin, which are characteristic of the disease.
Cholestyramine, rifampin, naltrexone, and antihistamines may also be prescribed to treat pruritus.
If symptoms cannot be controlled with medical treatment, surgical operations, such as partial external biliary diversion or a liver transplant, may be recommended; however, patients with severe heart defects are not good candidates for liver transplantation.10
Changes in diet and nutrition, such as a high-calorie diet that contains carbohydrates and medium-chain triglycerides that are easier to digest, are also recommended. For patients who are not able to eat enough on their own, a nasogastric or gastrostomy tube may be recommended. Vitamin supplements may also be recommended on a case-by-case basis.11
Read more about ALGS treatment
- Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;1;36(6):343-347. doi:10.1891/0730-08126.96.36.1993
- Alagille_syndrome. MedlinePlus. Updated April 7, 2021. Accessed May 4, 2021.
- Alagille_syndrome. The Childhood Liver Disease Research Network. Accessed June 22, 2021.
- JAG1 gene. MedlinePlus. Updated August 18, 2020. Accessed May 4, 2021.
- UniProtKB – P78504 (JAG1_HUMAN). Uniprot. Last updated April 7, 2021. Accessed May 4, 2021.
- Grochowski CM, Loomes KM, Spinner NB. Jagged1 (JAG1): structure, expression, and disease associations. Gene. 2016;576(1 Pt 3):381-384. doi:10.1016/j.gene.2015.10.065
- Symptoms & causes for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed January 2019. Accessed May 4, 2021.
- Alagille_syndrome. Johns Hopkins Medicine. Accessed May 4, 2021.
- Alagille_syndrome. Orphanet. Updated March 2009. Accessed May 4, 2021.
- Treatment for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed January 2019. Accessed May 4, 2021.
- Eating, diet, & nutrition for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed January 2019. Accessed May 4, 2021.
Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.