Clinical characteristics and VPS33B mutations in patients with ARC syndrome.
OBJECTIVE
ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is a rare, fatal cause of neonatal intrahepatic cholestasis without known treatment modalities and has recently been ascribed to a mutation in the VPS33B gene. We assessed the clinical characteristics and investigated the VPS33B mutations in Korean patients with ARC syndrome.


METHODS
We reviewed the medical records of 6 patients with ARC syndrome among 90 patients with neonatal cholestasis from 2000 to 2005 and assessed the relative incidence rate ratio, clinical symptoms, laboratory findings, and pathological findings. DNA samples from 5 patients, 4 parents, and 2 fetuses were analyzed for VPS33B mutations.


RESULTS
The relative incidence rate ratio was 1/7 that of biliary atresia (95% CI 0.33-0.06). All 6 patients presented with ichthyosis and recurrent infection, and failed to thrive with the 3 main symptoms. All of the patients died within the age of 12 months. They had various severities of cholestasis, metabolic acidosis, nephrogenic diabetes insipidus, chronic diarrhea, platelet abnormalities, and central nervous system anomalies. We identified 1 novel c.403+2T>A splice-site mutation, 2 frame-shift mutations (c.1509_1510insG, c.790_791del), 1 nonsense mutation (c.661C>A), and 1 known nonsense mutation (c.1518C>T) in the VPS33B gene. Prenatal diagnosis was performed in 2 different families.


CONCLUSIONS
This study indicates that the incidence of ARC syndrome is not as rare as has been thought. We found 4 novel and 1 known mutations in ARC syndrome patients and performed prenatal diagnosis in 2 families, which will facilitate genetic diagnosis and counseling for affected families.
Jang
Joo Young
JY
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kim
Kyung Mo
KM
Kim
Gu-Hwan
GH
Yu
Eunsil
E
Lee
Jin-Joo
JJ
Park
Young Seo
YS
Yoo
Han-Wook
HW
D000015:Abnormalities, Multiple / Q000235:genetics*; D001176:Arthrogryposis / Q000235:genetics*; D001656:Biliary Atresia / Q000235:genetics; D002779:Cholestasis / Q000235:genetics*; D005183:Failure to Thrive / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000453:epidemiology / Q000235:genetics; D015994:Incidence; D007223:Infant; D007239:Infections / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D007674:Kidney Diseases / Q000235:genetics*; D007723:Korea / Q000453:epidemiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics*
C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins