Alagille Syndrome (ALGS)

Alagille syndrome (ALGS) is a rare genetic disorder that affects multiple organs and systems, including the liver, heart, eyes, kidneys, nervous system, and skeleton. In most patients with ALGS, a scarcity of intrahepatic bile ducts caused by defects in the Notch signaling pathway results in the development of symptoms of varying severity.^1,2 

Genetics

In approximately 30% to 50% of cases, ALGS is inherited in an autosomal dominant pattern. Thus, a child has a 50% chance of inheriting the disease if one parent has a mutation in either the JAG1 or the NOTCH2 gene.^3,4 However, in at least half of individuals with ALGS, novel, spontaneous changes develop in a JAG1 or NOTCH2 gene that were not inherited from a parent. Approximately 90% of individuals with ALGS have mutations in the JAG1 gene; NOTCH2 mutations account for a smaller percentage of cases (1%-2%).^1-3   

Age

Investigators investigated age at the onset of ALGS in a systematic review; their work revealed that age at initial diagnosis ranged from less than 16 weeks to 10 years, with the disease diagnosed in most individuals before 1 year of age. Predominant clinical manifestations of ALGS included failure to thrive, growth delay, jaundice, cholestatic dysfunction, cardiovascular problems, facial abnormalities, pruritus, renal dysfunction, xanthomas, and other abnormalities of the liver and spleen.⁵

Associated Risks and Complications

The primary manifestation of ALGS is chronic cholestasis, which occurs in approximately 95% of individuals with the disorder. The accumulation of bile acids within the liver as the consequence of a paucity of bile ducts results in hepatic inflammation and damage, although bile duct paucity is not consistently present in all individuals with ALGS. Progressive liver disease, characterized by cirrhosis and eventually liver failure, occurs in 15% of individuals with ALGS, necessitating liver transplant. At present, clinicians lack reliable prognostic methods to determine which infants are most at risk for progressive liver disease.¹

Cardiovascular abnormalities occur in more than 90% of patients with ALGS, especially peripheral pulmonary stenosis, which affects approximately two-thirds of individuals in whom the disease is diagnosed. Other cardiovascular abnormalities include tetralogy of Fallot (16%), septal defects of the atria or ventricles, aortic stenosis, aortic coarctation, and hypoplastic left heart syndrome. Congenital heart disease may be the only manifestation of ALGS and is the most significant predictor of early mortality, whereas hepatic complications account for later deaths.¹

Because of the failure of anterior vertebral arch fusion, “butterfly” vertebrae occur in up to approximately 80% of patients with ALGS, predisposing them to metabolic bone disease characterized by osteoporosis and fractures. Bone disease may also be related to nutritional deficiencies and multisystem organ dysfunction.¹

Intracranial bleeding may occur in individuals with ALGS following minor head trauma. Vascular abnormalities such as middle aortic syndrome, moyamoya syndrome, and anomalies of the basilar, carotid, and middle cerebral arteries and the renal vasculature have all been documented in the medical literature.¹

Although renal dysfunction is usually a minor complication of ALGS, more severe renal abnormalities and disease may present in individuals with NOTCH2 gene mutations as well as in more mildly affected relatives who are carriers.⁷ 

Ocular abnormalities include posterior embryotoxon and Axenfeld anomaly. In most cases, the visual prognosis is good.^1,8

In a subset (approximately 40%) of patients with ALGS, pancreatic insufficiency associated with bile duct paucity results in steatorrhea and the development of insulin-dependent diabetes mellitus.¹

Significantly delayed growth and sexual development in patients with ALGS are associated with failure to thrive, malabsorption, malnutrition, and hormonal dysfunction.¹ Approximately 50% to 90% of patients with ALGS have growth failure, potentially explained by digestive complications. Individuals with ALGS who are deficient in fat-soluble vitamins may require supplementation with vitamins A, D, E, and K ,as well as calcium and zinc.⁸

Race, Gender, and Location

ALGS affects both sexes equally. No predilections according to racial or ethnic background and geographical location have been noted.⁶

References

1. 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
2. Alagille syndrome. NORD (National Organization for Rare Disorders). Accessed March 15, 2022.
3. Alagille syndrome. UCSF Department of Surgery. Accessed March 15, 2022.
4. Alagille syndrome. Johns Hopkins Medicine. Accessed March 15, 2022. 
5. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148. doi:10.1097/MPG.0000000000001958
6. Alagille syndrome. American Liver Foundation. Updated May 13, 2021. Accessed March 15, 2022. 
7. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet. 2006;79(1):169-173. doi:10.1086/505332
8. Alagille syndrome. Children’s Hospital of Philadelphia. Accessed March 15, 2022. 

Reviewed by Harshi Dhingra, MD, on 3/16/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.