Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy

Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing for consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages, and predominantly palmoplantar skin involvement (nonsyndromic and syndromic). sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counselling and the initiation of therapy. All sEDDs are rare; the most common are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise and variable clinical features of sEDDs, the natural history of the diseases with advancing age and genotype-phenotype relationships are poorly defined. Of the 51 sEDDs, associated neurological (n = 36; 71%) and/or ophthalmological (n = 25; 49%) findings are most common, and 39% (n = 20) have associated hair abnormalities. The widespread use of topical lovastatin for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with the pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment of SPINK5-sEDD with kallikrein inhibitors. Many sEDDs may be amenable to gene editing or the introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryological development.