Velocardiofacial Syndrome (VCF): Presentation with and Management of Immune Cytopenias.

Background: VCF is a 22q deletion syndrome which occurs in 1:4000 live births. It consists of dysmorphic facies, cleft palate, neurodevelopmental disorders and conotruncal cardiac defects. In addition to 22q11.2 deletion, other loci, e.g.10p4, have been implicated. Autoimmune cytopenias are prominent in this condition and present specific issues in diagnosis and therapy. Method: With IRB approval, we retrospectively reviewed patients referred to our center for evaluation of thrombocytopenia between 1999 and the present. Five children were suspected to have the VCF phenotype.

Results: Two of the 5 patients were confirmed to have 22q11.2 deletion by genetic testing (Table1). The other 3 also tested negative for the 10p4 defect. The universal features were immune cytopenias and neuropsychiatric disorders manifesting as developmental delay and/or abnormal behavior. Three patients had cardiac defects, of which 2 were right sided aortic arches; 3 had plastic repair of cleft palates. All had 2 or 3 immune cytopenias, including Evans syndrome, presented between ages 2 to 8 years, and were difficult to treat. Prolonged steroid therapy was avoided and Rituximab was generally effective. Patient 1 was evaluated on the basis of cytopenias with coexisting psychiatric disease but had no cardiac or palatal findings, leaving the diagnosis uncertain. His subsequent genetic testing was negative. Patient 2 presented with Evans syndrome, and, on review of chest xrays, a previously unreported right aortic arch was noted. This patient developed acute deterioration in preexisting behavioral features during an initial steroid course for ITP.

Discussion: In view of the implications for treatment of the immune cytopenias, it is important to suspect VCF, but how many phenotypic features of VCF are required to make the diagnosis is uncertain. The adverse impact of prolonged steroid therapy on neuropsychiatric disease warrants earlier use of Rituximab, especially in autoimmune hemolysis. Rituximab therapy avoids T cell immunosuppression in patients who may have concurrent immunologic defects and it is now accepted that splenectomy should be avoided in children with Evans syndrome. In patients 2 and 5, Rituximab therapy was implemented early in the course; patient 4 presented prior to its availability. All our patients manifested thrombocytopenia without giant platelet morphology. An individual with 22q11.2 deletion is haploinsufficient for Gp1bβ, also carried at this locus, and is therefore a Bernard Soulier syndrome heterozygote. A patient not responding to standard therapy for ITP may have thrombocytopenia related to this rare condition. In summary, VCF patients without significant cardiac or palatal disease may be undiagnosed at the time a cytopenia manifests. Pitfalls in diagnosis may occur with inadequate history, good cosmetic repair of a palatal defect, and missed right aortic arches. Prolonged steroid therapy often exacerbates coexisting neuropsychiatric disorders and immunosuppression and is not recommended in these difficult to treat patients. Rituximab is a useful treatment, especially for autoimmune hemolysis.