Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis. Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of human keratinization disorders mainly characterized by generalized abnormal scaling of the skin. To date, positional cloning and homozygosity mapping of families with ARCI have identified disease-associated mutations in seven genes: ABCA12, ALOX12B, ALOXE3, CYP4F22, ICHTHYIN, PNPLA1, and TGM1. The reported molecular mechanisms underlying disease development are related to defects in epidermal lipid pathways that interfere with terminal keratinocyte differentiation and skin barrier function. In this study we used genome-wide SNP mapping, which identified homozygous mutations in the CERS3 (ceramide synthase 3) gene that cause a new type of ARCI. Functional analysis of a skin sample and in vitro differentiated keratinocytes from one patient demonstrated that mutated CERS3 impairs the synthesis of ceramides with very long-chain acyl moieties. The defect in sphingolipid metabolism disturbs the epidermal lipid profile, which leads to an abnormal terminal differentiation process. In summary, mutations in CERS3 are causative for ARCI and illustrate the important role of ceramide synthesis in human skin physiology.

Epidermal differentiation disorders (EDDs) encompass inherited conditions characterized by abnormal epidermal differentiation, including nonsyndromic and syndromic subtypes with more extensive cutaneous involvement or palmoplantar keratoderma. Nonsyndromic EDDs (nEDDs) are defined as disorders that primarily affect large areas of skin and adnexal structures without alterations in extracutaneous tissues resulting from the underlying genetic change. To facilitate the development of targeted therapies and to provide clinicians with clearer therapeutic guidance, we have developed a new nomenclature for EDDs that includes the causative altered gene and the nEDD subgroup designation, sometimes with a clinical or histological descriptor or acronym. Historically, many nEDDs have been named on the basis of phenotypic characteristics or associations that are now considered outdated or inappropriate. For example, the term ‘harlequin ichthyosis’ evokes potentially stigmatizing images. Similarly, the word ‘ichthyosis’ is derived from the Greek ichthys, meaning fish, and the Greek hystrix, meaning porcupine, further emphasizing the need to abandon derogatory terminology. As a result, the clinical relevance of the previous classification, which included eponymous and/or descriptive titles, has diminished. In the new, gene-based classification, old terms considered pejorative, such as ichthyosis, vulgaris, hystrix and harlequin have been eliminated and eponyms have been replaced. Among the 53 genetically distinct nEDDs are conditions formerly known as autosomal recessive congenital ichthyosis, erythrokeratodermia variabilis et progressiva, Hailey–Hailey disease and Darier–White disease. This review outlines the updated nomenclature and classifications of nEDDs, linked to detailed clinical descriptions and representative photographs to guide practitioners.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defin...

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.