Alagille syndrome (AGS)

Alagille syndrome (AGS) (1,2,3)

• AGS
  • autosomal dominant disorder first described in 1969 by Alagille et al
  • prevalence of 1 in 70,000 to 100,000 new borns with variable expression and no sex preference
  • AGS is characterized by intrahepatic bile duct paucity with cholestasis and is also known as paucity of interlobular ducts (PBID), intrahepatic bile atresia, intrahepatic bile hypoplasia, and arterio-hepatic dysplasia
  • criteria include histologic bile duct paucity on liver biopsy in association with 3 of 5 major clinical features:
• chronic cholestasis
• congenital cardiac disease
• skeletal malformation
• ocular posterior embryotoxon
• characteristic facies
  • gene defect associated with AGS localized to the human Jag1 gene on the short arm of chromosome 20 (20p12)
• Clinical features
  • characteristic facies of AGS may not be evident in the first months of life
    • AGS facies - broad forehead, deep-set eyes, mild hypertelorism, straight nose, small pointed chin
    • distinctive cardiovascular anomaly is moderate ventricular hypertrophy with hypoplasia or stenosis of the pulmonary artery - tetralogy of Fallot may also occur
    • failure to thrive may occur
    • cholestasis appears typically during the first 2 years of life and may be severe enough to produce pale stools, dark urine, and malabsorption
    • posterior embryotoxon mentioned in the clinical criteria is the most common ophthalmogological finding
      • an abnormal prominence of Schwalbe's lines in the anterior chamber
    • skeletal malformation
      • classic skeletal malformation is a “butterfly wing” vertebra
        • due to failed fusion of the anterior arch
    • other possible minor clinical features of AGS include renal disease, endocrinopathies, learning disabilities, vascular anomalies, high pitched voice, and dermatologic manifestation
      • cutaneous findings can be an important aid in clinical suspicion of AGS
        • include xanthomas - most common location is on the extensor surface of fingers
          • xanthomas are associated with prolonged and severe cholestasis levels
            • appear progressively from age 4 years and decrease after age 10 years, along with decreased cholesterol levels from reduced cholestasis
          • supernumerary digital flexion creases, which can be observed in some patients
            • almost always located on the middle phalanges and can be present on single or multiple fingers
          • laryngeal xanthomas have also been reported - aetiology of these xanthomas can be presumed to be similar to the cause of cutaneous xanthomas, namely hypercholesterolemia
            • may also be a genetic predisposition which determines the location of xanthomas
          • less common dermatological findings include lymphoedema of the extremities and palmar erythema
          • excoriations and lichenification can be observed that are due to intense pruritus
• Investigations
  • suggestive of cholestasis - increased levels of conjugated (direct) bilirubin, alkaline phosphatase, gamma-glutamyltransferase and aspartate aminotransferase levels
  • hypercholesterolaemia and hypertriglyceridemia
  • liver biopsy can be performed to confirm diagnosis
• Management
  • depends on severity
    • may include nutritional support, low fat diet, antihistamines, ursodeoxycholic acid, cardiac surgery
    • liver transplantation may be indicated in severe cases
    • successful treatment of AGS-associated xanthomas can occur after a few weeks of ursodeoxycholic acid
• Prognosis
  • depends on its severity
  • without liver transplantation, there is a 50% probability of long-term survival
  • the GALA study results reported native liver survival of 54% at 10 years and 40% at 18 years, with a total bilirubin less than 5 mg/dL at 6 to 12 months associated with improved long-term outcomes (4)

Reference

1. Alagille D et al. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur.J Pediatr 1975;86: 63–71.
2. Kohut TJ, Gilbert MA, Loomes KM. Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment. Semin Liver Dis. 2021 Nov;41(4):525-537.
3. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012 Mar;20(3):251-7
4. Vandriel SM et al. Global ALagille Alliance (GALA) Study Group. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology. 2023 Feb 01;77(2):512-529.