1 de septiembre de 2014

MPI Liliana Alejandra Reynoso Garca

Cdigo: 207594984
Hospital Civil de Guadalajara Dr. Juan I. Menchaca
Pediatra

Alagille Syndrome

Definition. Alagille Syndrome is a multisystemic autosomal dominant disorder of variable
expression that was described more than 35 years ago. The prevalence is approximately 1/70,000.
Etiology. Is caused by mutations in JAGGED1 located in chromosome 20 band p12 (more than
90%) and in NOTCH2. The frequency of detectable deletions of 20p12 is low (less than 7%). Is
most commonly due to JAG1 (20p12) gene mutations (AGS type 1), encoding a Notch signaling
pathway ligand. AGS type 2 is due to NOTCH2 gene mutations (1p12). Transmission is autosomal
dominant, but reduced penetrance (up to 50% of cases) and somatic mosaicism (~8%) are
common.
Manifestations. Clinically, it appears with intermitent episodes of cholestasis, due to anomalies of
the intrahepatic biliary ducts wich manifests by conjugated hyperbilirubinemia,
hepatosplenomegaly, hypercholesterolemia, hypertriglyceridemia, and coagulopathy. Pruritus and
xanthomas may occur. Malformations associated with the syndrome include a characteristic facial
phenotype include prominent forehead, deep-set eyes, upslanting palpebral fissures, hypertelorism,
flat nasal root, and pointed chin; minor skeletal abnormalities include butterfly hemivertebrae
(around 50% of cases), and shortening of the radius, ulna, and phalanges; ophthalmic anomalies
include posterior embryotoxon (75% of cases), pigmentary retinopathy, papillary and optic disc
anomalies; and cardiovascular anomalies: pulmonary artery condition that causes different degrees
of peripheral pulmonary stenosis, atrial and/or ventricular septal defects, tetralogy of Fallot, and
patent ductus arteriosus. Small and dysplastic kidneys (common in AGS type 2), and
hypothyroidism may be present. Growth delay, fat malabsorption, and sometimes developmental
delay occur.
Diagnosis. Based on the clinical picture and liver biopsy revealing chronic cholestasis and paucity
of interlobular bile ducts. Imaging (abdominal ultrasonography, cholangiography) helps to identify
biliary anatomy. Screening for ophthalmic, skeletal, vascular and endocrine (thyroid) abnormalities
should be performed. DNA sequencing may confirm the diagnosis. If a pathogenic mutation has
been identified, prenatal genetic diagnosis is possible on DNA from chorionic villous tissue or
cultured amniocytes. Detailed fetal ultrasonography may identify cardiac and/or renal anomalies if
present.
Treatment. Is non-specific and includes high-carbohydrates and high-medium chain triglyceride
diets and vitamin supplementation. Cholestasis, pruritus and xanthomas have been successfully
treated with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine,
rifampin, naltrexone). In certain cases, partial external biliary diversion has also proved successful
and iver transplantation may be necessary for patients with refractory disease (cirrhosis and liver
failure). Cardiac or vascular procedures may be required for significant symptomatic lesions.
Prognosis. Usually favorable, but complications such as cirrhosis, variceal hemorrhage, refractory
ascites, and spontaneous bacterial peritonitis may occur. It has long been said to have a relative
good prognosis but overall survival at twenty years averages 70%. The disease usually stabilizes
between ages 4 and 10 years. When hepatic failure and/or cardiac lesions are present, mortality
risk is increased.
Differential diagnosis. It includes: infections, genetic-metabolic diseases, biliary atresia, congenital
hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial
intrahepatic cholestasis, and tyrosinemia.

Bibliography.
Alagille syndrome. Hadchouel M. Indian J Pediatr. 2002 Sep; 69(9):815-8.
Alagille syndrome. Ciocca M1, Alvarez F. Arch Argent Pediatr. 2012 Dec; 110(6):509-15.
Alagille syndrome. I D Krantz, D A Piccoli, N B Spinner. J Med Genet 1997; 34:152-157
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