Alagille syndrome (AGS)

Last reviewed 01/2018

Alagille syndrome (AGS)

• AGS
  • autosomal dominant disorder first described in 1969 by Alagille et al
  • prevalence of 1 in 70,000 to 100,000 newborns 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 arteriohepatic dysplasia
• criteria include histologic bile duct paucity on liver biopsy in association with 3 of 5 major clinical features (1):
  • (1) chronic cholestasis
  • (2) congenital cardiac disease
  • (3) skeletal malformation
  • (4) ocular posterior embryotoxon
  • (5) characteristic facies
  • gene defect associated with AGS localized to the human Jag1 gene on the short arm of chromosome 20 (20p12) (2)
• 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 ophthalomogological 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 diabilities, 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 (3)
            • 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 levesl 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 indicatedin severe cases
    • successful treatment of AGS-associated xanthomas can occur after a few weeks of ursodeoxycholic acid
• Prognosis
  • depends on its severity
  • a report of 92 cases with AGS, the predicted probability of attaining the age of 20 years was 75% for all patients (4)
  • without liver transplantation, there is a 50% probability of long-term survival
  • neonatal cholestastic jaundice is associated with poorer survival in patients without transplantation

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) Oda T et al. Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12, Genomics 1997;43: 376–379.
• (3) Tomeh C, Sulman CG. Laryngeal xanthomas in alagille syndrome: A new physical finding? International Journal of Pediatric Otorhinolaryngology Extra 2007; 2 (2): 88-91
• (4) Hoffenberg EJ et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;27:20–224