High intrafamilial variability in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: a case study.

Autoimmune polyendocrinopathy- candidiasis-ectodermal-dystrophy syndrome (APECED) is a monogenic disease whose phenotype may reveal wide heterogeneity. The reasons of this variability still remain obscure. Two APECED siblings with identical genotype and extremely different phenotype were compared with regard to exposure to infectious triggers, autoantibodies' profile, mechanisms of peripheral tolerance, and human leukocyte antigen (HLA) haplotype. The following infectious markers were evaluated: rubella, Epstein Barr virus, cytomegalovirus, toxoplasma, varicella zoster virus, parvovirus B19, herpes simplex virus, and parainfluenza virus. APECED-related autoantibodies were detected by indirect immunofluorescence or complement fixation or enzyme- linked immunosorbent assay or radioimmunoassay. Resistance to Fas-induced apoptosis was evaluated on peripheral blood mononuclear cells (PBMC) activated with phytohemoagglutinin, the number of TCD4+CD25+ regulatory cells (Treg) was evaluated through flow-cytometry and natural killer (NK) activity through Wallac method. Perforin (PRF1) was amplified by PCR and sequenced. No difference was observed between the siblings in common infectious triggers, extent of Fas-induced apoptosis, NK-cell activity and PRF1 sequence, the number of Tregs and HLA haplotypes. Although APECED is a monogenic disease, its expressivity may be extremely different even in the same family. This variability cannot be explained by common triggering infectious agents or functional alterations of mechanisms governing peripheral tolerance.