Multidisciplinary Management of Alagille Syndrome

Abstract

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.

Case Report: Novel JAG1 gene mutations in two infants with alagille syndrome characterized by cholestasis

“…In the presence of a family history of ALGS, the presence of the JAG1 mutation is diagnostic of ALGS even if all of the above criteria are not present. If the mutation or family history is positive, at least one major criterion is required to make the diagnosis ( 7 ). The patient's face is an important factor that raises clinical suspicion: deep-set eyes, hypertelorism, triangular shaped face and bulbous nose tip.…”

“…Jagged1 is required for angiogenesis and is found to be strongly expressed in all major systemic arteries. Thus, its deficiency leads to the various vascular abnormalities observed in ALGS ( 7 ). Except for JAG1 and NOTCH2, no other genes other than Notch signaling genes were found to cause ALGS ( 14 ).…”

“…LT in ALGS is primarily used for end-stage liver disease leading to synthetic failure and/or portal hypertension. The median age of LT is 28 months, and the most common indication is intractable pruritus ( 7 ). > 40% of patients with ALGS receive a LT before the age of 5 years, and the estimated liver transplant-free survival rate is approximately 24% by age 18.5 years, suggesting the need for new treatment norms ( 15 ).…”

“…Notch2 signaling is important for the differentiation of hepatoblasts into biliary epithelial cells and for the survival of these cells. Thus, the typical hepatic manifestation of ALGS is the paucity of interlobular bile duct (PIBD), which is due to defects in the morphology of the bile ducts ( 7 ).…”

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

“…Although we have a deeper understanding of the clinical characteristics of ALGS, there is no effective method to treat this condition. Current therapeutic strategies for ALGS are mainly symptomatic support treatments that focus on solving the symptoms of each patient (14)(15)(16)(17). The prognosis and risk of death depend on the severity of the liver, kidney, heart, and the other organs involved.…”