Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases

Abstract

Summary Background Cutaneous mosaicism is an area of dermatology in which there has been an explosion of knowledge within the current decade. This has led to fundamental changes in the understanding of the conditions in this field, and to an ongoing paradigm shift in the approach to management of mosaic skin disorders. Objectives To lay out the general principles of mosaicism as they are currently understood, summarize the known cutaneous mosaic abnormalities of the skin with associated phenotypic and genotypic information, review the latest trials on targeted therapies and propose guidelines for the general approach to a patient with suspected mosaicism. Methods This was a consensus expert review as part of the European Reference Network project (ERN‐Skin). Conclusions This study provides clinicians with a practical approach to the patient with suspected mosaicism, redefines mosaicism for the modern genetic era, and proposes a new classification system based on genetic mechanism. What's already known about this topic? Cutaneous mosaicism is a complex field of dermatology that encompasses most birthmarks, and many rare syndromes. Some cutaneous patterns are known to be seen in mosaicism. Very few treatment options are available for most mosaic abnormalities of the skin. Recent high‐sensitivity genetic techniques have led to an explosion of knowledge about genotype and phenotype in the literature. What does this study add? Expert consensus from the European Reference Network project. Review of knowledge of confirmed mosaic abnormalities of the skin, including cutaneous phenotype, extracutaneous associated features and genotype. Proposed new classification of mosaic abnormalities of the skin by genetic mechanism and therefore inheritance potential. Practical tips on correct sample collection and genetic investigation. Review of trials of targeted therapies. Guidelines for a practical clinical approach to the patient with suspected mosaicism.

A decade of next‐generation sequencing in genodermatoses: the impact on gene discovery and clinical diagnostics*

“…This includes the identification of AKT1 mutations as the underlying genetic basis for Proteus syndrome, 29 and, more recently, mutations in RHOA underlying a novel mosaic neuroectodermal syndrome 30 . For the purposes of this review, we do not explore use of NGS for mosaic disorders, and for this information the reader is directed elsewhere 31 …”

Disorders Caused by Genetic Mosaicism

“…It is caused by an early embryonic NRAS mu-S tation in the neuroectoderm. The risk for melanoma depends on the extent of CMN and is around 1% in CMN in general compared to 12% in giant CMN (25). Neurocutaneous melanosis is also associated with an increased risk for CNS melanoma.…”

“…MEK inhibitors in particular have been tested in individual cases of mosaic disorders of the RAS/RAF signaling pathway (25), while a combination of MEK and AKT inhibitors has been investigated in large CMN in the preclinical phase (39). The need for etiological classification would appear to be particularly urgent in mosaic RASopathies, since these are often characterized by a cancer predisposition.…”

Genes and phenotypes in vascular malformations

“…2) have an impact on the phenotype of VM caused by somatic mutations, as shown below. 5,6 Timing The earlier during embryological development a mutation takes place, the more the tissues and cell lines are affected and the more extended is the clinical phenotype. There are many examples for the time-dependency of somatic mutations.…”