Alagille Syndrome

From Paeds.co.uk the online paediatrician's encyclopaedia

Jump to: navigation, search

Contents

Alagille Syndrome is an autosomal inherited disorder with liver disease as a key feature. Associated abnormalities include characteristic facies and abnormalities of the heart, eyes, skeleton and kidneys. Mild to moderate learning impairment may be present.

  • Expression is variable.
  • Liver disease stems from a paucity of intrahepatic bile ducts.


See also these assocated articles:


Incidence

  • Incidence = 1:100 000 live births
  • Age: presentation is usually <6 months of age (jaundice, murmur or other symptoms)
    • Other family members may be diagnosed following an 'index case'.
  • Sex: no predilection


Aetiology and Genetics

  • Autosomal dominant with variable expression
  • Chromosome 20p12-jagged-1 locus (JAG1)
    • encodes a ligand important within the notch gene-signalling cascade involved in foetal development.
  • ~15% of mutations are spontaneous
  • Only ~5% have complete deletion of JAG1


Clinical features

Hepatic

  • Prolonged Neonatal Jaundice - most infants present with cholestatic jaundice
    • may prompt investigation and diagnosis
  • Hepatosplenomegaly common
  • Elevated serum bile acids and cholesterol - produces pruritis and Xanthomas
  • Fat-soluble vitamin deficiencies
    • Coagulopathy
    • Rickets
  • Liver biopsy: paucity of intrahepatic bile ducts


Poor growth


Typical Facies - not obvious during infancy but develop with age.

  • Broad forehead
  • Elongated nose with a rounded tip
  • Pointed chin


Ophthalmology

  • Posterior Embryotoxon - hypertrophied Schwalbe's ring, displaced anteriorly. Seen as a concentric white line anterior to the limbus.
  • Axenfeld Anomaly - iris attachement to the Descemet membrane.
  • Others: pupillary or optic disc abnormalities, retinitis pigmentosa.


Cardiac Lesions - significant lesions increase risk of mortality

  • Commonly stenoses within the peripheral pulmonary vasculature.
  • Others:
    • ASD
    • VSD
    • Tetralogy of Fallot
    • PDA
    • Pulmonary Atresia


Skeletal

  • Vertebral, rib and hand anomalies (shortened radius, ulna, phalanges)
    • Butterfly Vertebrae found in 50% of patients in one series (Emerick et al.)


Neurological

  • Mild developmental delay in some children


Renal

  • Renal artery stenosis
  • Lipoid nephrosis
  • Glomerulosclerosis - look for hypertension


Vascular ~6%

  • Basilar artery aneurysms
  • Internal carotid artery anomalies
  • Middle cerebral artery aneurysms
  • Aortic aneurysms / coarctation
  • Renal artery stenosis


Other

  • Portal hypertension with varices: risk of GI bleeding


Morbidity and Mortality

Morbidity is largely due to cholestatic liver disease secondary to bile duct paucity, cardiac disease or renal disease.


Investigations

Chronic Liver disease assessment

  • Liver function tests
  • Coagulation screen
  • Vitamin Levels (Fat soluble)
    • Vitamin E deficiency is suggested by reduced deep tendon reflexes, ataxia or mild haemolytic anaemia.
  • Lipid profile
    • Hypercholesterolaemia and hypertriglyceridaemia are commonly present
  • Liver biopsy - paucity of intrahepatic bile ducts.


Imaging

  • Liver imaging
    • Ultrasound
    • HIDA / ERCP / intra-operative cholangiography
  • Spine imaging - for vertebral anomalies


Ophthalmological assessment


Other Tests

  • ECG / Echocardiogram - particularly looking for right sided cardiac lesions


Chromosomal analysis and DNA sequencing of JAG1 gene (20p12) - confirms diagnosis.

Management

  • Correction of vitamin deficiencies
  • Correction of coagulopathy
  • Reduce hyperlipidaemia
  • Palliate pruritis
  • Screen for secondary anomalies
  • Administer vaccinations
    • include pneumococcal, particularly if ascites present (re. risk of spontaneous bacterial peritonitis)
  • Consideration of liver transplantation, where appropriate
  • Nutritional support


Extended Family - consider retrospective diagnosis / genetic screening / couselling of family members.


Follow-up

  • Monitor renal function
  • Screen for hepatocellular carcinoma at intervals
  • Monitor all of the above.


Prognosis

  • Not requiring liver transplant: estimated 20 year survival 80%
  • Requiring liver transplant: estimated 20 year survival 60%
  • Associated serious cardiac malformation likely to require cardiac surgery: predicted 20 year survival 40%


References

  • Emedicine article
  • Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. Jan 1975;86(1):63-71.


Patient Support Information

Personal tools
Recommend