Rudolf Happle - Mosaicism in Human Skin: Understanding Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia

Springer-Verlag Berlin Heidelberg 2014

Rudolf Happle 1

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Abstract

In biology, the term mosaic means an organism that is composed of two or more genetically different cell lines originating from one homogeneous zygote. Mosaicism can occur in all pluricellular living organisms. Molecular genetics has provided evidence that every human being represents, to some degree, a mosaic. In dermatology, the concept of mosaicism has helped solving the following problems: How to find a workable definition of the term nevus; why different types of nevi may sometimes occur as twin spots; why the arrangement of nevi can neither be called "dermatomal" nor "zosteriform"; why we can discriminate, in autosomal dominant skin disorders, three different categories of postzygotic mosaicism; why some segmentally arranged skin disorders are heritable whereas others are not; why a segmental distribution of autosomal dominant skin disorders implies an increased risk for the next generation; why patients born with a severe Mendelian skin disorder may develop, later in life, patchy areas of healthy skin; why common skin disorders such as atopic dermatitis or lichen planus are sometimes superimposed by a rather pronounced linear or otherwise segmental involvement; and why all types of skin cancer reflect mosaicsm.

Since ancient times, a mosaic denotes a piece of artwork made by placing colored squares in a pattern creating a picture. In modern biology, the term mosaic is used in a metaphoric way. It means an organism that is composed of two or more genetically different cell lines originating from one homogeneous zygote. Mosaicism can occur in all pluricellular living organisms. In human genetics, a well-known example is functional mosaicism in women because one of the X chromosomes is randomly inactivated at an early developmental stage. Mosaicism can involve all organs but is most easily noted in the skin because this organ is right before our eyes.

During the past decades, the concept of mosaicism in human skin has gained increasing importance and awareness because in many cutaneous disorders a mixture of normal and aberrant cells, giving rise to alternating segments of affected and unaffected skin, has now been documented at the molecular level. Today, it is clear that every human being represents, to some degree, a mosaic. For example, evidence has been provided that all nevi reflect mosaicism and that epigenetic mosaicism involves a large number of genes in both male and female individuals.

In dermatology, the concept of mosaicism has been shown to exert explanatory power to understand the etiology and pathogenesis of both rare and common diseases. Combined clinical and molecular research on mosaic skin disorders has helped understanding the following problems:

If an organism originates from the fusion of two different zygotes, the result will not be a mosaic but a chimera. In order to clarify the similarities and differences between mosaicism and chimerism, the reader will find in this book also a chapter on chimerism in human skin.

Springer-Verlag Berlin Heidelberg 2014

Rudolf Happle 1

(1)

2.1

2.2

2.3

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Abstract

Shortly after 1901, when the rules of Mendelian inheritance had been rediscovered, the concept of mosaicism was developed in both plants and animals. Mosaic patterns were described first in maize and citrus fruits, and subsequently in apple and pineapple. Between 1925 and 1940, twin spots were documented in maize and apple, and they were induced by x-rays in Drosophila. In the second half of the 20th century, twin spotting was reported in other plants such as tomato and tobacco, and it was experimentally induced in soybean and snapdragon. During the fifties, Barbara McClintock developed the concept of epigenetic mosaicism by studying ears of maize. In 1961, Mary Lyon discovered the mechanism of X inactivation that represents a particular form of epigenetic mosaicism. During the seventies, the lines that Alfred Blaschko had described in 1901 were rediscovered and gained general recognition as a possible pattern of mosaicism in human skin. Several other mosaic patterns of cutaneous mosaicism were delineated during the nineties of the past century. From a clinical point of view, it is difficult but important to discriminate mosaic phenotypes from similar segmental patterns reflecting chimerism. A mosaic originates from one zygote, whereas a chimera originates from the fusion of two or more different zygotes.

Virtually all human skin disorders, including common diseases such as psoriasis, drug eruptions, or acne, sometimes display mosaicism. It is important to realize, however, that mosaicism also occurs as a physiological phenomenon. All human beings represent, to some degree, mosaics because today we know that mutual monoallelic expression of genes gives rise to functional mosaicism in both women and men. In other words, humans always display epigenetic mosaicism. On the other hand, all mammalian organisms will develop, during their lifetime, various forms of genomic mosaicism that may originate from diverse mechanisms such as postzygotic new mutation, mitotic recombination resulting in loss of heterozygosity, or other forms of allelic loss. Most of these mechanisms have first been studied in plants or animals. Conversely, some forms of mosaicism such as the superimposed segmental manifestation of both autosomal dominant and polygenic traits have initially been recognized in human disorders.