Syndromic epidermal differentiation disorders: New classification towards pathogenesis-based therapy

Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing 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 (nEDD), and predominantly palmoplantar skin involvement (pEDD, nonsyndromic and syndromic). The 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 counseling, and initiation of therapy. All sEDDs are rare, the most common of which 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, their disease natural history with advancing age and genotype-phenotype relationships are poorly defined. Among the 51 sEDDs, associated neurologic (71%) and/or ophthalmologic (49%) findings are most common, and 39% have hair abnormalities. The widespread use of topical lovastatin-cholesterol for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with 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 with kallikrein inhibitors for SPINK5-sEDD. Many sEDDs may be amenable to gene editing or introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryologic development.