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A rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys.
ORPHA:52Classification level: Disorder
The prevalence is approximately 1/70,000.
The disease may manifest in newborns by prolonged jaundice due to conjugated hyperbilirubinemia, and/or cardiac signs and symptoms. Cardiac abnormalities include pulmonary atresia or stenosis, atrial and/or ventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus (see these terms). Cholestasis manifests by conjugated hyperbilirubinemia, hepatosplenomegaly, hypercholesterolemia, hypertriglyceridemia, and coagulopathy. Pruritus and xanthomas may occur. Minor skeletal abnormalities include butterfly hemivertebrae (around 50% of cases), and shortening of the radius, ulna, and phalanges. Characteristic facial features, if present, are usually apparent from childhood and include prominent forehead, deep-set eyes, upslanting palpebral fissures, hypertelorism, flat nasal root, and pointed chin. Ophthalmic anomalies include posterior embryotoxon (75% of cases), Axenfeld anomaly (see this term), pigmentary retinopathy, papillary and optic disc anomalies. Growth delay, fat malabsorption (rickets may occur), and sometimes developmental delay occur. Small and dysplastic kidneys (common in AGS type 2), and hypothyroidism may be present.
AGS 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).
The diagnosis is 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.
Differential diagnoses include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia (see these terms).
If a pathogenic mutation has been identified, prenatal genetic diagnosis is possible on DNA from chorionic villous tissue or cultured amniocytes. Otherwise, detailed fetal ultrasonography may identify cardiac and/or renal anomalies if present.
Transmission is autosomal dominant, but reduced penetrance (up to 50% of cases) and somatic mosaicism (~8%) are common.
Management and treatment
Treatment is non-specific and includes high-carbohydrates and high-medium chain triglyceride diets and vitamin supplementation. Pruritus may be reduced by cholestyramine or rifampin. Liver transplantation may be necessary for patients with refractory disease. Cardiac or vascular procedures may be required for significant symptomatic lesions.
The prognosis is usually favorable, but complications such as cirrhosis, variceal hemorrhage, refractory ascites, and spontaneous bacterial peritonitis may occur. The disease usually stabilizes between ages 4 and 10 years. When hepatic failure and/or cardiac lesions are present, mortality risk is increased.