Enlightened therapy of the disorders of cornification

Abstract

Treatment of the inherited disorders of cornification (i.e., the ichthyoses, palmoplantar keratodermas, and related disorders in which a thickened or otherwise abnormal stratum corneum [SC] is a key component) has traditionally focused on the dual goals of 1) removing scale to improve appearance; and 2) enhancing hydration to improve pliability and comfort. For the most part, these treatments have been neither disease specific nor based upon disease pathogenesis, e.g., the same therapies are used in both retention hyperkeratoses, such as recessive X-linked ichthyosis, and in hyperproliferative disorders, such as nonbullous congenital ichthyosiform erythroderma. In addition to limited effectiveness, in some instances these therapies can even be counterproductive, i.e., treatments that peel off the SC may “overshoot the mark” and result in decreased function (e.g., a further impairment in permeability barrier function and/or decreased frictional resistance). The goal of treatment in an era of “enlightened therapeutics” is therapy based upon correction of the underlying defect; when that is neither possible nor practical, treatments should address the underlying pathophysiology of the disorder. Unfortunately, the first principle (i.e., correction of the primary or underlying genetic defect) remains an unattained goal because gene therapy is still in its infancy. Yet, it is possible to apply the current understanding of disease pathogenesis toward disease-specific therapy that will be both more appropriate and more effective. During the past two decades, the underlying genetic causes of the inherited disorders of cornification have been largely deciphered. The causative defects have been surprisingly broad and include not only inborn errors of lipid metabolism but also mutations that affect epidermal structural proteins, as well as primary defects in cellular communication, signaling and proliferation (Table 1). Because a wide variety of defects lead to a common, scaling phenotype, only a few, final common-pathways account for disease pathogenesis. In other words, the epidermis can either 1) fall apart (as it does in epidermolysis bullosa simplex, epidermolytic hyperkeratosis, and Netherton’s syndrome); 2) kill off a bad cell or apoptose (as it does in Darier disease); and/or 3) become hyperkeratotic (as it does by definition in almost all disorders of cornification, such as the ichthyoses and psoriasis). Hyperkeratosis, in turn, can arise through either a delay in desquamation and/or as a consequence of epidermal hyperplasia. In only a few instances is the hyperkeratosis caused by solely to a failure to desquamate (i.e., a retention hyperkeratosis). Most commonly, there is a component of epidermal hyperproliferation as well. Therefore, understanding the biology of both desquamation and epidermal hyperplasia, as well as their causes and consequences, is critical in designing enlightened therapies for these disorders. In addition, recent advances in knowledge of SC function and its metabolic regulation have offered additional insights into the pathogenesis of several scaling disorders, with potential therapeutic implications.