Mosaic disorders affecting pigmentation - part 1: how to make a clinical diagnosis

Mosaic disorders affecting pigmentation are a large group of different rare diseases that present with hypo- and/or hyperpigmented birthmarks. These can have associated risks such as involvement of other organ systems, a predisposition to cancer and the possibility of transmission to future offspring as germline disease. However, clinical diagnosis of these conditions has been notoriously difficult, owing to the rarity of the conditions, the similarity of their cutaneous signs and the massive intradisease variability intrinsic to their pathogenetic mechanism. This review draws on the genetic and clinical discoveries of the last decade to introduce key concepts such as how to define a mosaic disorder, the relevance of small single pigmentary birthmarks, the occurrence of 'postnatal birthmarks' and the defining clinical features of mosaic disorders affecting pigmentation. It then lays out a modular classification for use in clinical practice and research studies, based on two independently variable features of the cutaneous signs: the developmental pattern and the lesion type. For the first time, the classification brings together macular lesions as well as naevi, epidermal as well as dermal lesions and hyper- and hypopigmented lesions, reflecting this unifying overview of aetiology. A companion smartphone iOS app for the clinical classification has been designed for use in clinic and is freely available online at 'What'sThatSpot'. The clinical importance of distinguishing mosaic disorders from germline disorders presenting with the same developmental patterns is discussed in the context of differential diagnoses. The third modular component of the classification (genotype) is addressed in the second part of this review.