New Aspects of Cutaneous Mosaicism

The Journal of Dermatology Vol. 29: 681–692, 2002 Dohi Memorial Lecture New Aspects of Cutaneous Mosaicism Rudolf Happle Abstract The concept of cutaneous mosaicism has today been proven at the cellular level in at least fifteen different skin disorders. We can distinguish five different patterns of mosaicism, including the phylloid pattern and the lateralization pattern. Etiologically, cutaneous mosaics can be divided into two large categories, epigenetic mosaicism and genomic mosaicism. All forms of epigenetic mosaicism known so far, including the various patterns of X-inactivation, appear to be caused by the action of retrotransposons. A new concept is functional autosomal mosaicism transmittable through the action of retrotransposons, which has been described in mice and dogs and may explain, for example, the familial occurrence of pigmentary mosaicism along the Blaschko lines in human skin. Among the examples of mosaicism of autosomal lethal mutations, phylloid hypomelanosis is a recently recognized neurocutaneous entity caused by mosaic trisomy 13. Possible examples of a type 2 segmental manifestation now include at least fifteen different autosomally dominant skin disorders. This phenomenon is most frequently found in gloman- giomatosis, cutaneous leiomyomatosis, and disseminated superficial actinic porokeratosis. Recently proposed examples of didymosis (twin spotting) include cutis tricolor, paired patches of excessive or absent involvement in Darier disease, and didymosis aplasticose- bacea characterized by coexistent aplasia cutis congenita and nevus sebaceus. To the list of possible examples of paradominant inheritance, cutis marmorata telangiectatica congenita and speckled lentiginous nevus syndrome have now been added. Revertant mosaicism giving rise to unaffected skin areas in autosomally recessive cutaneous traits will certainly likewise be recognized more often when clinicians are bearing this concept in mind. Such cases can be taken as examples of “natural gene therapy”. Key words: epigenetic mosaicism; retrotransposons; transposable elements; X- inactivation; genomic mosaicism; phylloid hypomelanosis; type 2 segmental manifestation of autosomal dominant skin disorders; didymosis; paradominant inheritance; revertant mosaicism In the medical sciences, a mosaic is de- saicism began with speculations and hy- fined as an organism composed of two or potheses. Presently, however, many of these more genetically different populations of ideas have been proven at the cytogenetic or cells originating from a genetically homoge- molecular level. Today we distinguish two neous zygote. Dermatologists are in a privi- large groups in the forms of epigenetic mo- leged position because the various states of saicism and genomic mosaicism. mosaicism can be recognized most easily in Where is the evidence for cutaneous mosaicism? the skin. The concept of cutaneous mosaicism was The history of research on cutaneous mo- first proven in 1983 in a case of linear hy- perpigmentation reflecting a trisomy 18 mo- By Invitation: Presented as the 42nd Dohi Memor- saic (1). Further cytogenetic and, more re- ial International Exchange Lecture, Kumamoto, cently, molecular research have provided Japan, June 8, 2002. Reprint requests to: Rudolf Happle, M.D., Depart- proof of mosaicism in many different cuta- ment of Dermatology, Philipp University of Marburg, neous traits (Table 1). Deutschhausstrasse 9, D-35033 Marburg, Germany. All nevi are mosaics 682 Happle Table 1. Skin disorders in which mosai- According to a recently proposed defini- cism has been proven at the cellular level tion, all nevi can be taken as lesions originating from mosaicism (2). For obvious rea- 1983 Hypermelanotic mosaicism sons, however, the converse is not true. Cu- along Blaschko lines taneous mosaicism does not always result in 1988 Hypomelanotic mosaicism nevi because otherwise, malignant melano- along Blaschko lines (“hypome- ma and basal cell carcinoma should likewise lanosis of Ito”) be categorized as nevi. 1991 McCune-Albright syndrome 1994 Epidermal nevus, 5 different patterns of mosaicism nonepidermolytic type Cutaneous mosaics can manifest them- 1995 Epidermal nevus, epidermolytic selves in various patterns (3). Today we can type distinguish five well-established archetypes Tuberous sclerosis (Fig. 1), but the number of different mosaic 1996 Acquired melanocytic nevi patterns is certainly even higher. 1997 Generalized atrophic benign Type 1: Lines of Blaschko epidermolysis bullosa Most nevoid skin disorders follow the 1998 Apert syndrome well-known lines of Blaschko (Fig. 2). It 2000 Neurofibromatosis 1 should be noted that this pattern is rather Darier disease variable. From a recent study of 186 figures Incontinentia pigmenti showing skin lesions following Blaschko’s CHILD syndrome lines on the head and neck, we have con- Phylloid hypomelanosis cluded that, in several areas of the face, 2001 Spitz nevus these lines intersect at an angle of almost Fig. 1. Five patterns of cutaneous mosaicism. Type 1a: lines of Blaschko, narrow bands; type 1b: lines of Blaschko, broad bands; type 2: checkerboard pattern; type 3: phylloid pattern; type 4: patchy pattern without midline separation; type 5: lateralization Cutaneous Mosaicism 683 Fig. 2. Tentative explanation of the lines of Blaschko: At an early developmental stage precursor cells start to proliferate transversally from the primitive streak. This proliferation interferes with the longitudinal growth and increasing flexion of the embryo, resulting in a fountain-like pattern on the back. 90° (Fig. 3) (4). Type 1a is characterized by narrow bands, as found in incontinentia pigmenti, whereas Fig. 3. Lines of Blaschko on the face and neck type 1b is defined by broad bands, as ob- (4). Note definite crossing of lines. served in the McCune-Albright syndrome. For the time being, it seems reasonable to separate these two subtypes, although future Type 5: Lateralization pattern clinical research may show that more sub- In the CHILD syndrome, a unique pat- types can be distinguished. tern becomes manifest in the associated Type 2: Checkerboard pattern CHILD nevus that tends to involve one half This pattern is characterized by flag-like of the body with a strict midline separation. areas with a clear-cut midline separation. A mosaic origin has been proven by molecu- Clinical examples are speckled lentiginous lar analysis (5). nevus and Becker nevus. Perhaps, the Why not “zosteriform nevi”? portwine stains as observed in Klippel-Tre- When dealing with nevoid dermatoses, naunay-Sturge-Weber syndrome may like- the term “zosteriform” is almost always out wise be arranged in this pattern. of place. This term refers to the system of Type 3: Phylloid pattern dermatomes visualized in a zoster eruption. This type is characterized by peculiar leaf- Nevi that are described as “zosteriform” are like or oblong macules. A strict midline sep- usually not dermatomal but follow the lines aration is not always present. This pattern is of Blaschko, which is why the term “zosteri- characteristic, although not pathognomon- form” should be avoided in such cases (6). ic, of phylloid hypomelanosis (see below). Epigenetic versus genomic mosaicism Type 4: Large patches without midline We can divide the various mosaics into separation two large categories, epigenetic mosaicism This pattern is observed in congenital and genomic mosaicism. Phenotypes re- giant melanocytic nevi, for which a mosaic flecting epigenetic mosaicism can be inher- origin has so far not been proven but is very ited from one generation to the next. By likely. contrast, genomic mosaics are generally not 684 Happle Fig. 4. Incontinentia pigmenti. A similar linear pigmentary disorder is found in women het- Fig. 5. MIDAS syndrome in a 2-year-old girl erozygous for ectodermal dysplasia of Zonana. (courtesy of Dr. J. Mücke, Hamburg, Ger- many) (18) aggregation. Epigenetic mosaicism and retrotransposons: A new perspective Transposable elements or retrotransposons are particles of retroviral origin. They are interspersed in large amounts in the genome of both plants and animals, including man (7, 8). They tend to affect the activity of neighboring genes by methylation Fig. 6. Dermal aplasia heralding MIDAS syn- or demethylation, giving rise to silencing or drome in the mother of the girl shown in Fig- activation of gene expression. Remarkably, a ure 5 (courtesy of Dr. J. Mücke, Hamburg, variegated coat pattern reminiscent of the Germany) (18) lines of Blaschko is observed in the murine mutant viable yellow agouti (8). This linear and patchy pattern is caused by a retrotransposon, and the same is true for the brindled inheritable, with the exception of paradom- trait of dogs (9). inant traits that sometimes show a familial Generally speaking, modern molecular Cutaneous Mosaicism 685 Fig. 7. CHILD nevus showing a lateralization pattern Fig. 8. CHILD nevus arranged along the lines of Blaschko Fig. 9. Brindled trait in a boxer. The ebr muta- Fig. 10. Pigmentary mosaicism in human skin tion causes a variegated pattern following the may sometimes show a familial aggregation, lines of Blaschko. (courtesy of Dr. M. Bittar, and this may likewise reflect the action of a San Rafael, Mendoza, Argentina) retrotransposon. 686 Happle Table 2. X-inactivation patterns Table 3. Proposed examples of autosomal lethal mutations surviving • Lines of Blaschko (many phenotypes) by mosaicism • Checkerboard pattern (X-linked hyper- trichosis) Pigmentary mosaicism of the Ito

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