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Reticulate pigmentary disorders are a group of disorders characterized by hyper- and/or hypopigmented macules with varying sizes and amounts of pigment. Some of the disorders are heritable, such as Dowling-Degos disease, dyschromatosis universalis hereditaria, dyschromatosis symmetrica hereditaria, reticulate acropigmentation of Kitamura and X-linked reticulate pigmentary disorder. Although each condition possesses unique phenotypic characteristics and the prognosis for each is somewhat different, there is a large degree of overlap between the disorders and therefore they are difficult to differentiate in the clinical setting. This updated review provides a clinical and molecular delineation of these genetic reticulate pigmentary disorders and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis, as well as to provide useful information for clinical and genetic counselling., (© 2017 British Association of Dermatologists.)

This review assesses molecular aspects of the rescue of disease-causing mutations in genodermatoses by means of naturally occurring secondary genetic phenomena. Such data have important implications for the design of gene therapy approaches for inherited skin diseases. Reversal of the phenotype depends on three elements: the number of cells involved; the degree of gene reversal; and the specific timing of the reversion. If reversion occurs in somatic cells, revertant mosaicism may occur. This is the situation in which a patient's skin is generally affected by the genodermatosis, but islands of normal skin stand out. These reflect the presence of revertant cells that are sufficient to restore a normal local skin phenotype. Reversion of the original mutation may also be partial, in which case the phenotype may display no, or only limited, improvement. Nevertheless, the phenotype may ameliorate with age if the reverted cells preferentially expand in time or if the time of onset of reversion is after birth. In essence, the complexities of naturally occurring rescue processes are important to understand because the inherent mechanisms may provide clues and insight into optimal therapeutic gene manipulation, and the possibility of mimicking nature in the management of patients with diverse genodermatoses.

The Human Genome Mapping Project and allied rapid advances in genetic technology over the past decade have facilitated accurate association of allelic variations in several genes with specific skin phenotypes. Currently the genetic bases of the majority of the more common genodermatoses have been elucidated. In scientific terms this work has been extraordinarily successful and has yielded many new biological insights. These advances, although exciting, have yet to be translated into direct benefit for patients with these diseases. Genetic counselling has been greatly aided by gene identification, by the better understanding of genotype-phenotype correlation and by the disclosure of unexpected genetic mechanisms in some families. Knowledge of the molecular basis of these disorders has also been vital in enabling DNA-based prenatal diagnosis in several conditions and DNA-based preimplantation diagnosis has been used in a selected few. While this successful period of gene mapping is now nearing completion, progress towards the next goal, that of developing therapeutic strategies based on the knowledge of these underlying genetic mechanisms, has proven frustratingly slow. Despite the ready access to the skin compared with solid internal organs, the challenges of cutaneous gene therapy are legion and many technical issues need to be surmounted to enable gene replacement or modification of gene expression to have a useful role in these disorders. In this article we make a comprehensive review of progress to date in gene identification, genotype-phenotype correlation, prenatal diagnosis and cutaneous gene therapy, and we examine future directions for research in this field.