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Alagille syndrome (ALGS): for professionals


Clinical phenotype

There is significant intra- and interfamilial variability in clinical presentation among patients affected by Alagille syndrome.

Incidence
  • 1:30,000 – 100,000
Ocular Features
  • Posterior embryotoxon is the most common feature (95%)[1]
  • Other reported ocular abnormalities– keratoconus, microcornea, strabismus, iris nodules, optic nerve head drusen, mild lens opacities, retinal pigmentary speckling and hypopigmentation[1-5]
Systemic FeaturesMajor features:
  • Cardiac defects (>90%)– pulmonary/aortic stenosis, tetralogy of Fallot, coarctation of the aorta, atrial/ventral septal defects[4,6]
  • Jaundice (95%) due to bile duct paucity, causing subsequent chronic cholestasis and conjugate hyperbilirubinaemia[4]
  • Vertebral anomalies (66%)– A characteristic “butterfly” vertebrae may be observed but is of no structural significance[4]
  • Dysmorphic facial features (prominent forehead, moderate hypertelorism with deep set eyes, prominent ears, triangular face with a pointed chin and broad nasal bridge)[6,7]
Other features:
  • Secondary metabolic bone disease– risk of long bone fractures and osteoporosis[4,6]
  • Renal abnormalities (renal dysplasia and renal tubular acidosis)[4,6,7]
  • Vascular events
  • Pancreatic insufficiency
  • Immunodeficiency
  • Failure to thrive, growth and developmental delay
  • Delayed puberty
  • Supernumerary flexion creases

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Genetics

Gene/Locus
(OMIM no.)
Phenotype (OMIM no.)Remarks
JAG1 (#601920)Alagille syndrome 1 (#118450)Identified in 94-95% of Alagille syndrome patients[8]
NOTCH2 (#600275)Alagille syndrome 2 (#610205)Identified in 1-2% of Alagille syndrome patients[8]

The ALGS phenotype is indistinguishable between JAG1 and NOTCH2 variants.[7]

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Key investigations

Ocular

  • Visual acuity and refraction
  • Orthoptic assessment if indicated as strabismus can be a feature

Systemic

Patients with Alagille syndrome are complex. Their presentations can vary from asymptomatic to having life-threatening cardiac and hepatic abnormalities with a high mortality rate. A multidisciplinary approach led by a paediatrician is therefore recommended. Systemic investigations include:  

  • Blood tests – Liver function tests (raised gamma glutamyl transferase levels are seen with conjugated hyperbilirubinaemia), serum cholesterol, triglycerides, clotting screen, serum bile acids, fat-soluble vitamin levels
  • Technitium-99m-DISIDA hepatobiliary scintiscan
  • Liver ultrasound +/- guided biopsy
  • Echocardiogram – to exclude heart defects
  • AP spinal radiograph – to look for “butterfly” vertebrae
  • Renal ultrasound and renal function tests  
  • Urine analysis – to assess for renal tubular acidosis
  • Stool analysis – may be useful in the diagnosis of pancreatic insufficiency
  • Growth and development assessments

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Diagnosis

Clinically, Alagille syndrome is diagnosed when a histological finding of bile duct paucity (increased portal tract-to-bile duct ratio) is accompanied by at least 3 of the 5 major clinical features, which includes cardiac defects, cholestasis, skeletal abnormalities, ophthalmic abnormalities and characteristic dysmorphic facial features.[7,9]

In patients with an affected first-degree relative, a clinical diagnosis can be made if one or more major clinical features are present.[6,7]

Genetic testing should be undertaken to confirm the diagnosis, facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.

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Management

Ocular

Ophthalmic abnormalities in Alagille syndrome do not usually warrant intervention or monitoring. Most patients achieve good visual acuities of at least Snellen 6/9-6/12 (LogMAR 0.18-0.3).[10]

However, all patients presenting with a posterior embryotoxon should have a formal ophthalmic examination to exclude Alagille syndrome and other anterior segment dysgenesis conditions where posterior embryotoxon is part of the feature, such as Axenfeld-Rieger anomaly and Axenfeld-Reiger syndrome.

Systemic

Growth monitoring and specialist dietary input with food and vitamin supplementation are indicated if Alagille syndrome is diagnosed in childhood, and particularly if the child is demonstrating failure to thrive.

Intractable pruritus and xanthomas may present in severe liver disease. Medical treatment includes ursodeoxycholic acid and cholestyramine, naltrexone or rifampicin. Surgical options include partial internal biliary diversion and ileal exclusion to relieve symptoms, but these do not regress or prevent liver disease progression.[6,7] A liver transplantation is necessitated in end-stage liver disease.

Cardiac and renal examinations should be performed, and any identified abnormalities should be managed accordingly with specialist input.

Intracranial vessel abnormalities leading to increased risk of intracranial haemorrhage and strokes have been reported. Therefore, patients should be screened for intracranial vascular anomalies, and if presenting with head injuries or new neurological symptoms, they should be examined with a high degree of suspicion. Contact sports should be avoided in patients with splenomegaly and chronic liver disease, and a spleen guard is recommended in those with splenomegaly to reduce the risk of splenic rupture. Alcohol consumption should be avoided if there is liver involvement.

Family management and counselling

De novo sporadic mutations account for 50-70% of individuals with Alagille syndrome while approximately 40% inherit the associated genetic changes in an autosomal dominant manner, with variable expressivity and penetrance.[11] As clinical presentation and disease severity can be highly variable within families, genetic testing should be offered to parents of simplex cases to facilitate genetic counselling.

 If an affected patient is considering pregnancy, specialist input should be sought as liver and cardiac dysfunction can worsen during pregnancy. Family planning advice should be considered and discussed with all patients.

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Current research

Induced pluripotent stem cells (iPSCs) are showing promise as a prospective treatment option for the sequelae of chronic liver disease. iPSC-derived cholangiocytes have been considered a potential method of delivering genetically corrected cholangiocytes from a patient to their diseased liver, without the risks of rejection nor the need for immunosuppression associated with liver transplants.[8]

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9) is another potential therapeutic option but only limited specifically to Alagille syndrome patients harbouring nonsense or missense mutations in JAG1.[8] Majority of patients (58%) tend to have full gene deletions, insertions, deletions and splice site mutations, and may not be able to benefit from this technology yet.[8]

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Further information and support

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References

  1.  Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. Feb 1999;106(2):330-7. doi:10.1016/s0161-6420(99)90072-6
  2.  Ma AS, Grigg JR, Jamieson RV. Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Human genetics. Sep 2019;138(8-9):899-915. doi:10.1007/s00439-018-1935-7
  3.  Ho DK, Levin AV, Anninger WV, Piccoli DA, Eagle RC, Jr. Anterior Chamber Pathology in Alagille Syndrome. Ocular oncology and pathology. Oct 2016;2(4):270-275. doi:10.1159/000446804
  4.  Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. European journal of human genetics : EJHG. Mar 2012;20(3):251-7. doi:10.1038/ejhg.2011.181
  5.  El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features. European journal of ophthalmology. Mar-Apr 2011;21(2):199-206. doi:10.5301/ejo.2010.5675
  6.  Diaz-Frias J, Kondamudi NP. Alagille Syndrome. StatPearls. StatPearls Publishing StatPearls Publishing LLC.; 2019
  7.  Spinner NB, Leonard LD, Krantz ID. Alagille Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews((R)). University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993
  8.  Gilbert MA, Spinner NB. Alagille syndrome: Genetics and Functional Models. Current pathobiology reports. Sep 2017;5(3):233-241. doi:10.1007/s40139-017-0144-8
  9.  Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. The application of clinical genetics. 2016;9:75-82. doi:10.2147/tacg.S86420
  10.  Kim BJ, Fulton AB. The genetics and ocular findings of Alagille syndrome. Seminars in ophthalmology. Oct-Dec 2007;22(4):205-10. doi:10.1080/08820530701745108
  11.  Diaz-Frias J, Kondamudi NP. Alagille Syndrome. StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.; 2020

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Updated on November 30, 2020
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