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
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
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