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Alagille syndrome: for professionals

Overview

PrevalenceEstimated at 1 in 70,000 live births
InheritanceAutosomal dominant
Genes Involved (OMIM No.)JAG1 (#118450), NOTCH2 (#610205)
SymptomsProgressive vision loss
Pruritus
Jaundice
Malnutrition and growth failure
Developmental delay
Ocular FeaturesPosterior embryotoxon
Optic disk drusen
Macular atrophy
Retinal pigmentary changes
Systemic featuresNeonatal cholestasis
Xanthomas
Pulmonic stenosis
Tetratology of fallot
AV septal defects
Aortic stenosis
Hypertension Structural renal abnormalities
Butterfly vertebrae
Craniosynostosis  
Key InvestigationsOphthalmic
Fundoscopy Fundus autofluorescence (FAF)
Optical coherence tomography (OCT)
Electroretinogram (ERG)
Systemic
Hepatic, cardiovascular and renal blood and imaging studies through appropriate specialist referral.
Molecular DiagnosisWhole genome sequencing with structural eye disease gene panel
ManagementOcular:
Regular ophthalmic monitoring
Corrective measures for refractive errors
Low vision services
Systemic:
Paediatric/clinical genetics review
Multidisciplinary approach with appropriate specialist referrals to hepatology, cardiology, nephrology etc as appropriate if systemic features are present
Therapies under ResearchOngoing studies on natural history and management strategies

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Clinical phenotype

Alagille syndrome (ALGS) is a multisystemic genetic disorder primarily affecting the liver, heart, eyes, face, and skeleton. It is caused by mutations in the JAG1 or NOTCH2 genes, both of which are involved in the Notch signalling pathway.1,2

Presenting features

Ocular:

  • Posterior embryotoxon: Most common ocular finding. Prominent Schwalbe ring, identified on slit lamp examination. Does not affect visual acuity, but useful diagnostically.3
  • Axenfeld anomaly and Rieger anomaly: Defects of the anterior chamber.4
  • Optic disk drusen: Found in 90% of children with ALGS on ultrasonographic examination.5
  • Retinal pigmentary changes: Occur in 32% of individuals.
  • Peripheral chorioretinal changes: Atrophy with accompanying loss of function in the visual field.
  • Macular atrophy and progressive vision loss.6

Systemic

  • Hepatic:
    • Neonatal cholestasis: Present in 85% of cases. Jaundice and conjugated hyperbilirubinemia. Increased bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase, triglycerides, and aminotransferases. Pruritus (74% onset at 12 months), xanthomas (24% onset at 25 months).7
    • Liver disease: Ranges from asymptomatic to end-stage liver disease. 50.4% with neonatal cholestasis undergo liver transplant by age 18 (median age 2.8 years).
    • Hepatocellular carcinoma (HCC): Increased risk even without other ALGS features.
  • Cardiovascular:
    • Pulmonary vascular involvement: Pulmonic stenosis (67%), tetralogy of Fallot (7%-16%).5
    • Other cardiac defects: Ventricular septal defect, atrial septal defect, aortic stenosis, coarctation of the aorta.
    • Neurovascular and renovascular anomalies: Moyamoya disease, anomalies of basilar, carotid, and middle cerebral arteries. Increased risk of neurovascular accidents (15%).
  • Skeletal:
    • Butterfly vertebrae: Most common radiographic finding, usually asymptomatic.8
    • Craniosynostosis: Reported in 0.9% of individuals.
    • Bone mineral deficiency: High risk for fractures.
  • Facial features:
    • Broad forehead, deep-set eyes, pointed chin, concave or straight nasal ridge with a bulbous tip.
    • Variability in recognisability across populations.
  • Renal:
    • Structural abnormalities: Small hyperechoic kidneys, ureteropelvic obstruction, renal cysts.5
    • Functional abnormalities: Renal tubular acidosis, renal dysplasia.
    • Hypertension and renal artery stenosis: Noted in adults.
  • Growth Failure:
    • Observed in 50%-90% of individuals.
    • Attributed to malnutrition/malabsorption and cholestasis.
  • Neurodevelopmental:
    • Mild delays in gross motor skills (16%).
    • Mild intellectual disability (2%).
    • Increased risk for attention and executive function impairment.
  • Other Features:
    • Delayed puberty, high-pitched voice.
    • Splenomegaly.
    • Reduced lifespan due to complications from liver transplants, cardiac disease, severe liver disease, and intracranial bleeding.
    • Overall mortality rate of 8.5%, with most deaths occurring in the first five years of life.

Genetics

Alagille syndrome is primarily caused by mutations in the JAG1 gene, located on chromosome 20p12, which encodes a ligand in the Notch signalling pathway. Approximately 94% of diagnosed individuals have identifiable mutations in JAG1. Another subset of patients (less than 1%) carries mutations in the NOTCH2 gene. Both genes play crucial roles in embryonic development, and mutations disrupt normal cellular processes, leading to the syndrome’s diverse manifestations.9,10

1. JAG1 (OMIM: 601920):

  • JAG1 encodes Jagged1, a ligand for Notch receptors. Notch signalling is vital for cell differentiation, development, and tissue homeostasis.
  • Mutations in JAG1 lead to loss of function in the Notch signalling pathway. This disruption affects various organs, causing bile duct paucity in the liver, cardiac defects, and ocular abnormalities in ALGS patients.

2. NOTCH2 (OMIM: 600275):

  • NOTCH2 encodes Notch homolog 2, a receptor for Notch ligands. Activation of Notch signalling regulates cell fate determination, differentiation, and development.
  • Mutations in NOTCH2 result in impaired Notch signalling, leading to similar phenotypic features seen in JAG1 mutations, including liver and cardiac abnormalities. However, mutations in NOTCH2 tend to have a milder effect on facial and vertebral features compared to JAG1 mutations.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

When diagnosing ALGS, a combination of clinical evaluations, genetic testing, and imaging studies is utilised. These investigations are crucial in confirming the diagnosis, assessing the extent of organ involvement, and guiding appropriate management strategies.

Ocular

  1. Ophthalmic Examination
    • Comprehensive assessment of visual acuity, intraocular pressure, and anterior and posterior segment examination.
  2. Fundoscopy1,3
    • Posterior Embryotoxon: Identification of a prominent Schwalbe ring.
    • Axenfeld and Rieger anomalies
    • Optic disk drusen: Identification of calcified deposits on the optic nerve head.
    • Retinal pigmentary changes: Observing mottling or clumping of retinal pigment.
    • Peripheral chorioretinal changes: Detection of atrophy and associated loss of function in the visual field.
    • Macular atrophy
  3. Fundus Autofluorescence (FAF)
    • Hyper-autofluorescence indicating areas of drusen deposition.
    • Hypo-autofluorescence indicating macular atrophy.1
  4. Optical Coherence Tomography (OCT)
    • Visualisation of hyperreflective deposits.
    • Assessment of retinal thickness for macular oedema or atrophy.
  5. Electroretinogram (ERG)
    • May show low-normal scotopic and photopic responses.
    • In severe cases, these responses become sub-normal.
  6. Genetic Testing
    • JAG1 and NOTCH2 gene mutations.9,10

Systemic

  1. Hepatic Investigations
    • Liver function tests: Elevated serum bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase, triglycerides, and aminotransferases. Monitoring conjugated hyperbilirubinaemia.7
    • Liver biopsy: Paucity of intrahepatic bile ducts. Possible ductal proliferation in infants under six months.
    • Imaging: Ultrasound and MRI for assessing liver structure and detecting anomalies.
  2. Cardiovascular Investigations
    • Echocardiography: Detection of structural heart defects (e.g., pulmonic stenosis, tetralogy of Fallot).
    • MRI and CT angiography: Evaluation of vascular abnormalities (e.g., moyamoya disease, renal artery stenosis).
  3. Renal Investigations
    • Ultrasound: Detection of structural anomalies (e.g., small hyperechoic kidneys, renal cysts).
    • Functional testing: Assessment for renal tubular acidosis and hypertension.5
  4. Neurodevelopmental and Skeletal Investigations
    • Screening for motor skill delays and intellectual disability.
    • Bone Density Scan (DXA): Assessment for bone mineral deficiency.
    • Radiographic imaging: Identification of butterfly vertebrae and other skeletal abnormalities.

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Diagnosis

Combining clinical evaluation, imaging studies, and genetic testing ensures an accurate diagnosis of Alagille syndrome. A multidisciplinary approach involving paediatricians, geneticists, hepatologists, cardiologists, ophthalmologists, and other specialists is required for comprehensive evaluation and management of patients with suspected ALGS.

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Differential Diagnoses

Differential diagnoses include progressive familial intrahepatic cholestasis (PFIC) and other syndromic cholestatic liver diseases.

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Management

Alagille Syndrome (ALGS) is a multisystem disorder that demands a multidisciplinary approach. Managing patients with ALGS requires a comprehensive strategy addressing hepatic, cardiac, ocular, and other associated issues.

Ocular

  1. Regular ophthalmology monitoring: monitor disease progression and identify complications promptly. Management is symptomatic, addressing issues like refractive errors, strabismus, and posterior embryotoxon.11

Systemic

  1. Hepatic: Gastroenterology/hepatology referral
    • Regular monitoring of liver function through blood tests (e.g., serum bile acids, liver enzymes) and imaging studies.12
    • Management of cholestasis with medications such as ursodeoxycholic acid and pruritus control with antihistamines or rifampin.Nutritional support to address malabsorption and vitamin deficiencies.
    • Consideration for liver transplant evaluation in cases of progressive liver disease.
  2. Cardiovascular: Cardiology referral
    • Regular echocardiograms to monitor for congenital heart defects and vascular abnormalities.Management of structural heart defects with surgical or interventional procedures as indicated.
    • Monitoring and management of hypertension.
  3. Renal: Nephrology referral
    • Regular monitoring of renal function with blood tests and urinalysis.Management of renal tubular acidosis with bicarbonate supplementation.
    • Monitoring and treatment of hypertension.
  4. Multidisciplinary support:14
    • Nutritional Support: Ensuring adequate nutrition and maintaining a balanced diet to support overall health and growth, especially in paediatric patients.
    • Physical and Occupational Therapy: Sessions to improve motor skills, muscle strength, and overall functional abilities.
    • Speech Therapy: Sessions if speech and communication difficulties are present.
    • Paediatric Neurologist: Referral for evaluation and management of any neurodevelopmental issues or seizures.
    • Endocrinology Referral: Evaluation and management of delayed puberty and other hormonal imbalances.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive comprehensive management of their condition (genetic testing and genetic counselling) and to have the opportunity to participate in clinical research.

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Current research

Ongoing research explores the molecular basis of Alagille syndrome, targeted therapies, and improved genetic diagnostic techniques. Clinical trials investigate novel treatments to alleviate specific manifestations, promising enhanced outcomes for affected individuals. Early diagnosis, comprehensive management, and active involvement in research initiatives are crucial for improving the quality of life for individuals with Alagille syndrome.

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Further information and support

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References

  1. Spinner NB, Loomes KM, Krantz ID, et al. Alagille Syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. 2000 May 19 [updated 2024 Jan 4]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1273/
  2. 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;62:1361–1369.
  3. Hingorani M, Nischal KK, Davies A, Bentley C, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999;106:330–337.
  4. Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22:625–41.
  5. Kohut TJ, Gilbert MA, Loomes KM. Alagille syndrome: a focused review on clinical features, genetics, and treatment. Semin Liver Dis. 2021;41:525-37.
  6. Paez-Escamilla M, Scanga HL, Liasis A, Nischal KK. Macular atrophy in JAG1-related Alagille syndrome: a case series. Ophthalmic Genet. 2022 Apr;43(2):230-234.
  7. Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol. 2021;6:22.
  8. Zanotti S, Canalis E. Notch and the skeleton. Mol Cell Biol. 2010;30:886–96.
  9. Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, et al. Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40:2197–2220.
  10. Rajagopalan R, Gilbert MA, McEldrew DA, Nassur JA, Loomes KM, Piccoli DA, Krantz ID, Conlin LK, Spinner NB. Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results. Genet Med. 2021;23:323-30.
  11. Ayoub MD, Kamath BM. Alagille Syndrome: Diagnostic Challenges and Advances in Management. Diagnostics. 2020;10(11):907.
  12. Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with alagille syndrome: The King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57:149–154.
  13. Spinner NB, Loomes KM, Krantz ID, et al. Alagille Syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. 2000 May 19 [updated 2024 Jan 4].
  14. Menon J, Shanmugam N, Vij M, Rammohan A, Rela M. Multidisciplinary Management of Alagille Syndrome. J Multidiscip Healthc. 2022 Feb 23;15:353-364.

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Updated on June 3, 2024
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