Cholestasis and growth failure: indicators of a complex syndrome

A.L., chronological age: 6.5 years old (bone age: 3.5 years old). Dysmorphic facies with hypertelorism, saddle nose, broad forehead, pointed chin. Only child, born at 41 weeks of regular pregnancy, eutocic delivery, small for gestational age (weight: 2030 g), left preauricolar appendage. At birth: direct hyperbilirubinemia, elevated serum GGT, pulmonary artery branches stenosis. Falling rate of bilirubin until normalisation after 6 months, with lab evidence of cholestasis (elevated serum GGT, bile acids and cholesterol) and hypertransaminasemia. At 4 years and 2 months old, because of a growth failure (weight and height are less than the 3rd percentile, bone age of 2 years and 9 months, non-responder to arginine-clonidine provocative test, normal female karyotype), undergo hormonal therapy for 12 months, with a catch-up growth. Clinical examination: spleen palpable 2 cm below the costal margin, mesocardiac 1/6 systolic murmur. Hypertransaminasemia (AST 100 U/L, ALT 125 U/L), lab evidence of cholestasis (serum GGT 261 U/L, cholesterol 227 mg/dl and bile acids 24.8 µmol/l), mild conjugated hyperbilirubinemia (0.45 mg/dl), elevated serum alkaline phosphatase (900 U/L) and alpha-amylase (131 U/L). Abdominal US: dilated intrahepatic bile ducts under Glisson’s capsule. Distended gallbladder. Splenomegaly (11 cm interpolar diameter). Cardiac US: patent arterial duct. Ophthalmological examination: incomplete posterior embryotoxon. Fundus oculi examination: persistent myelination, excavation of the optic disk. No vertebral anomalies. Possible diagnosis: Alagille Syndrome, confirmed by genetic testing and liver biopsy (cholestasis and paucity of the interlobular biliary ducts). The estimated incidence of Alagille syndrome is 1 in 70 000 newborns per year. A diagnosis of Alagille Syndrome may be suspected when 3 of 5 major clinical signs are present (distinctive facial features, intrahepatic cholestasis, pulmonary artery branches stenosis, posterior embryotoxon, butterfly shaped vertebrae or hemivertebra). Treatment is non-specific and includes carbohydrates, medium-chain triglycerides and vitamin supplementation. The disease usually stabilises between ages 4 and 10 years. Liver transplantation may be necessary for patients with refractory disease.