Pathogenesis of the permeability barrier abnormality in epidermolytic hyperkeratosis

Epidermolytic hyperkeratosis is a dominantly inherited ichthyosis, frequent ly associated with mutations in keratin 1 or 10 that result in disruption o f the keratin filament cytoskeleton leading to keratinocyte fragility. In a ddition to blistering and a severe disorder of cornification, patients typi cally display an abnormality in permeability barrier function. The nature a nd pathogenesis of the barrier abnormality in epidermolytic hyperkeratosis are unknown, however. We assessed here, first, baseline transepidermal wate r loss and barrier recovery kinetics in patients with epidermolytic hyperke ratosis. Whereas baseline transepidermal water loss rates were elevated by approximately 3-fold, recovery rates were faster in epidermolytic hyperkera tosis than in age-matched controls. Electron microscopy showed no defect in either the cornified envelope or the adjacent cornified-bound lipid envelo pe, i.e., a corneocyte scaffold abnormality does not explain the barrier ab normality. Using the water-soluble tracer, colloidal lanthanum, there was n o evidence of tracer accumulation in corneocytes, despite the fragility of nucleated keratinocytes. Instead, tracer, which was excluded in normal skin , moved through the extracellular stratum corneum domains. Increasing inter cellular permeability correlated with decreased quantities and defective or ganization of extracellular lamellar bilayers. The decreased lamellar mater ial, in turn, could be attributed to incompletely secreted lamellar bodies within granular cells, demonstrable not only by several morphologic finding s, but also by decreased delivery of a lamellar body content marker, acid l ipase, to the stratum corneum interstices. Yet, after acute barrier disrupt ion a rapid release of preformed lamellar body contents was observed togeth er with increased organelle contents in the extracellular spaces, accountin g for the accelerated recovery kinetics in epidermolytic hyperkeratosis. Ac celerated recovery, in turn, correlated with a restoration in calcium in ou ter stratum granulosum cells in epidermolytic hyperkeratosis after barrier disruption. Thus, the baseline permeability barrier abnormality in epidermo lytic hyperkeratosis can be attributed to abnormal lamellar body secretion, rather than to corneocyte fragility or an abnormal cornified envelope/corn ified-bound lipid envelope scaffold, a defect that can be overcome by exter nal applications of stimuli for barrier repair.