ARC syndrome is a severe autosomal recessive multisystem disorder characterized by arthrogryposis, neonatal cholestatic jaundice, renal tubular acidosis, failure to thrive, dysmorphic features, congenital heart disease, cerebral malformation, hypotonia, recurrent febrile illness and a bleeding disorder. It is associated with consanguinity and most patients do not survive beyond the first year of life. ARC syndrome is linked to loss of function in either VPS33B or VIPAS39, respectively encoding VPS33B and VPS16B, which we have shown to be interaction partners within a multiprotein complex involved in intracellular vesicular trafficking (Urban et al, Blood. 2012 Dec 13;120(25):5032-40). Earlier we determined that bleeding problems in ARC syndrome patients (where platelet aggregation abnormalities have been observed) arise from abnormal function of normally abundant platelets lacking α-granules (Lo et al, Blood. 2005;106(13):4159-66). Detailed studies of ARC syndrome platelets have been hampered by limited availability.A term 4-month old boy was observed to have significant epistaxis and petechiae requiring multiple transfusions of plasma, packed red blood cells, tranexamic acid, vitamin K and nasal packing twice, with final success over control of bleeding. INR was 1.8 and PTT was 40 with a normal platelet count of 319 during this episode. Intermittent episodes of bleeding continued throughout his course, with difficulty in stopping the bleeding. The patient was found to have jaundice with scleral icterus, cholestasis and giant cell hepatitis seen on liver biopsy. A metabolic work-up revealed significant aminoaciduria and proximal tubular acidosis. He also had failure to thrive, feeding intolerance, severe bilateral sensorineural hearing loss, limb contractures, right rocker bottom foot and clubbed left foot. MRI of the brain showed abnormal corpus callosum with non-visualization of the anterior commissure. On abdominal ultrasound, the liver was enlarged and mildly echogenic with no evidence of portal hypertension and patent vessels. Echogenic kidneys were present with nephrocalcinosis. He was referred for evaluation and possible liver transplantation.Blood film examination revealed pale-appearing platelets and transmission electron microscopy confirmed the complete absence of α-granules, making a diagnosis of ARC syndrome highly probable. Immunofluorescence confocal microscopy detected abnormalities in patient platelets with regards to: 1) size (larger than normal); 2) morphology of the tubulin ring cytoskeleton (loosely organized compared to normal); and 3) intracellular distribution of CD63 (more abundant and widely dispersed than normal). Sequencing of patient DNA detected normal VIPAS39 and apparent homozygosity for a single base pair deletion (c.1531delT, p.Tyr511ThrfsStop10) in exon 20 of VPS33B, predicted to cause a frame shift and premature translation stop codon. Gene sequencing of the parents detected the identical VPS33B mutation in the mother heterozygous to a normal allele; no mutation was found in the father. Array comparative genomic hybridization (aCGH) – which allows detection of deletions and amplification mutations of one or more exons within a given gene – uncovered an approximately 140 kb deletion mutation encompassing the entire VPS33B gene in our patient (g.91,478,004 – proximal to g.91,618.247 – distal), confirming compound heterozygosity. According to the online locus-specific ARC database (https://grenada.lumc.nl/LOVD2/ARC), this is the first association of this mutation combination with ARC syndrome.Unusually for ARC syndrome, bleeding indicative of platelet dysfunction was a major presenting symptom in this patient. While the genetic profile is unusual, the pathological platelet hallmarks of ARC syndrome were present: hypogranular platelets on blood film and absence of α-granules via electron microscopy. We were also able to detect other platelet abnormalities via immunofluorescence microscopy. These observations lead us to suspect that ARC syndrome may represent the most severe class within a possible spectrum of platelet function disorders associated with mutations in VPS33B and/or VIPAS39, a possibility that requires further study. Disclosures:No relevant conflicts of interest to declare.
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Oct 1, 2015
F Chiatto + 6
Open Access