Olmsted syndrome: immunodysregulation with TRPV3 mutation

Introduction: Olmsted syndrome (OS) is a rare congenital skin disorder presenting with a combination of hyperkeratotic lesions and palmoplantar keratoderma severe enough to result in spontaneous digit amputation. It is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of OS. Objective: This study was aimed at exploring the immunological component of Olmsted syndrome. Methods: Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of OS. Genetic assessment of the case was performed by exome sequencing and common polymorphisms were filtered out. Confirmation and frequency testing of candidate mutation was performed via Sequenom using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyzer (Sequenom Inc., CA, USA). Multi-color flow cytometry was used to profile the peripheral immune system after staining for specific surface and intracellular cell markers. All major cell types and their subsets from peripheral blood mononuclear cells were considered including B cells, T cells, and dendritic cells subsets. Results: The sequencing results revealed the OS patient to harbor a previously undescribed 1718G-C transversion in TRPV3, causing a G573A mutation. Detailed clinical and immunological analysis identified indicators suggestive of immune dysregulation: frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood. Conclusion: The presence of systemic phenotype of hyper IgE and persistent eosinophilia provides strong evidence for the involvement of immunological processes in the pathogenesis of OS. Being the first comprehensive assessment of the immunological features of OS, the results have important clinical consequences with regard to the treatment of OS patients.status: publishe