Alagille Syndrome (ALGS)

Alagille syndrome (ALGS) is a multisystem disease with autosomal dominant inheritance. It is caused by defects in the Notch signaling pathway due to mutations in the Jagged 1 (JAG1) and Notch 2 (NOTCH2) genes. The disease is characterized by intrahepatic bile duct paucity.¹

The diagnosis is based on the presence of chronic cholestasis and congenital heart defects.² A definitive diagnosis may be reached by genetic testing.

Classic Criteria for a Diagnosis of ALGS

A diagnosis of ALGS is based on 5 classic phenotypic features³:

1. Cholestasis, usually presenting as jaundice and pale stools in the neonatal period;
2. Characteristic facial features, such as a broad forehead, deep-set eyes, prominent ears, a straight nose with a bulbous tip, and a pointed chin;
3. Congenital heart disease, including peripheral pulmonary artery stenosis, pulmonary atresia, atrial septal defects, and ventricular septal defects; 
4. Tetralogy of Fallot and skeletal abnormalities that include “butterfly” vertebrae, hemivertebrae, fusion of adjacent vertebrae, and spina bifida occulta; 
5. Eye abnormalities, such as posterior embryotoxon.²

A diagnosis can usually be reached if a patient presents with 3 of these characteristics in addition to bile duct paucity on a liver biopsy specimen.

Liver Biopsy

Bile duct paucity is usually evident in a liver biopsy specimen from a patient with ALGS. However, bile duct paucity can be a common feature of many other conditions, including Down syndrome, cystic fibrosis, congenital infections, α₁-antitrypsin deficiency, Zellweger syndrome, and Ivemark syndrome.² Moreover, bile duct paucity in ALGS, as in these other conditions, may change over time.

Blood Tests

Cholestasis is now considered sufficient for a diagnosis of ALGS, without a routine liver biopsy. Cholestasis can be diagnosed with blood tests that measure levels of alkaline phosphatase and γ-glutamyl transpeptidase, which are very elevated in ALGS.⁴

Levels of bilirubin should also be checked. In ALGS, the serum bilirubin values are up to 30 times normal levels, and serum bile salts are up to 100 times normal levels.⁵

Patients with ALGS also often have elevated blood levels of cholesterol and triglycerides.⁶

Finally, a blood test can be used to check levels of fat-soluble vitamins, such as vitamins A, D, E, and K, which are lower than normal in patients with ALGS.⁶ 

Heart Examination

Congenital heart disease affecting primarily the pulmonary outflow tract and vasculature is one of the main features of ALGS and can be assessed in a heart examination.² 

Tetralogy of Fallot is the most common complex structural cardiac anomaly. Other anomalies include ventricular septal defect, atrial septal defect, aortic stenosis, coarctation of the aorta, and hypoplastic left heart syndrome.²

Radiography and Other Imaging Tests

Radiography of the spine can assess the vertebrae. The most common vertebral anomalies are butterfly vertebrae, characterized by clefts in the vertebral bodies of the mid and lower thoracic spine. Additional abnormalities that can be revealed by spinal radiography include hemivertebrae and fused adjacent vertebrae.⁷

Other imaging tests can visualize the structure of the biliary tracts and kidneys to aid in the diagnosis of ALGS. These include ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance imaging (MRI), and hepatobiliary scan. Magnetic resonance angiography may be used to detect vascular abnormalities.⁶

Eye Examination

The ocular findings of ALGS include posterior embryotoxon, decreased axial length, unilateral myopia, small corneal diameter, and shallow anterior chamber.⁸ These affect between 78% and 98% of patients with the disease. In approximately a third of cases, pigmentary retinopathy may also be present. 

However, these findings alone are not sufficient for a diagnosis of ALGS. For example, posterior embryotoxon can also be caused by anterior segment dysgenesis and Axenfeld-Rieger syndrome.⁹

Genetic Testing

If the classic criteria for a diagnosis of ALGS are not met but some features of the disease are present, genetic testing to assess the JAG1 gene should be performed.² However, this test may not detect all cases of ALGS. A negative JAG1 finding is expected in about 40% of patients suspected to have ALGS.¹⁰

In case of a negative JAG1 test result, genetic testing to assess the NOTCH2 gene should be considered. If the result of this test is positive, a diagnosis of ALGS can be confirmed. However, if this test result is also negative, alternative diagnoses should be considered.²

Differential Diagnosis

The differential diagnosis of ALGS includes biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia.¹¹

References

1. Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;36(6):343-347. doi:10.1891/0730-0832.36.6.343
2. 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
3. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
4. Cholestasis. MSD Manual. Updated February 2021. Accessed June 14, 2021.
5. Huang H, Wang LF. Radiological changes of spine and liver in a case of Alagille syndrome. Quant Imaging Med Surg. 2018;8(3):368-371. doi:10.21037/qims.2018.04.06
6. Diagnosis for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 14, 2021.
7. Katsuura Y, Kim HJ. Butterfly vertebrae: a systematic review of the literature and analysis. Global Spine J. 2019;9(6):666–679. doi:10.1177/2192568218801016
8. Neiberg M, Lee R. Ocular expression of Alagille syndrome. American Academy of Optometry. 2012. Accessed June 14, 2021.
9. Posterior embryotoxon. MedGen. Accessed June 14, 2021.
10. Krantz ID, Colliton RP, Genin A, et al. Spectrum and frequency of Jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. 1998;62(6):1361-1369. doi:10.1086/301875
11. Alagille syndrome. Orphanet. Updated March 2009. Accessed June 14, 2021.

Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.

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Ozge Ozkaya, MSc, PhD

Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.