Mosaicism and Skin Disease: A Fresh Look
Celia Moss, DM, FRCP, MRCPCH, Birmingham Children's Hospital, United Kingdom, discussed mosaicism in the skin, including the peculiar patterns in the skin known as Blaschko lines, and a broad set of diseases that display clinically important findings.
Dr. Moss traced the original concept of cutaneous mosaicism to Montgomery, in a paper published in the Journal of Cutaneous and Genitourinary Diseases in 1901. The concept of mosaicism is based on an understanding of cell development, with subpopulations of cells undergoing mutation and progeny cells continuing the mutation. One hundred years ago, Blaschko defined the cutaneous pattern of linear streaks and swirls, distinct from dermatomal lines, that is displayed in a broad set of syndromes and dermatologic diseases. For instance, in X-linked dominant disorders, such as incontinentia pigmenti, random inactivation of an X chromosome (Lyonisation) allows dominant lethal X-linked conditions to survive in an affected female. The linear pattern of vesicles, verrucous lesions, hyperpigmented streaks and swirls, and hypopigmented lines all may present in the "Blaschko pattern" as a physical sign of mosaicism.
Dr. Moss stressed that mosaicism is much more than "Blaschko lines" alone, and that Blaschko lines are of ectodermal origin. Cells derived from neural crest, including keratinocytes and melanocytes, follow Blaschko lines if mutations occur early enough in embryogenesis that cell migration is not yet complete. For instance, Dr. Moss proposed that melanocytes might migrate singly during development, creating linear, phylloid, or block patterns. Pigmentary conditions, both hyperpigmented and hypopigmented, may have a line of Blaschko pattern or a segmental pattern, reflecting variation in the timing and migration patterns of affected cells. The best experimental evidence for the mosaic basis of pigmentary patterns is the studies by Beatrice Mintz[6,7] on chimeric mice, showing clonal melanocyte origin of pigmented patterns.
Conditions that would otherwise be lethal in males are seen in mosaic form in X-linked dominant conditions such as incontinentia pigmenti, Goltz syndrome, CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea), Happle syndrome, and oral-facial digital syndrome type 1. X-linked recessive disorders with mosaicism displayed in carrier females include hypohydrotic ectodermal dysplasia, Menke syndrome, Partington cutaneous amyloidosis, and ectodermal dysplasia with immune deficiency. The precise cytogenetic or molecular event responsible for the mosaicism is known in only some of these conditions.
A broad set of somatic mutations may be mosaic, said Dr. Moss. Autosomal dominant single-gene disorders such as segmental neurofibromatosis type 1, linear bullous ichthyosiform erythroderma associated with keratin 10 anomalies, palmoplantar verrucous nevus associated with keratin 16 mutations, linear Darier disease, "segmental tuberous sclerosis" with angiofibromas in a segmental distribution, and comedone nevus may be such conditions. Dr. Moss related the case of a female patient who had unilateral freckling and Lisch nodules (iris hamartomas) who gave birth to a child with systemic neurofibromatosis type 1 (NF-1), implying that the mother had both somatic mosaicism and gonadic mutation for NF-1.
Other sets of conditions are presumed autosomal dominant lethal disorders "rescued" by mosaicism, in that they are never seen in a generalized form. These include McCune-Albright syndrome (associated with PTEN mutations), epidermal nevus syndrome, Proteus syndrome, and inflammatory linear verrucous epidermal nevus. She also speculated that there are multifactorial inflammatory disorders with autosomal dominant or polygenic inheritance, such as linear forms of psoriasis, morphea, lichen planus, lichen striatus, and lichen nitidus.
Some mosaic chromosomal disorders present with abnormal pigment, which may be due to chromosomal non-dysjunction. These include hypomelanosis of Ito, nevus depigmentosus, and linear and whorled nevoid hyperpigmentation. Segmental hyperpigmentation may be due to chimerism as well, stated Dr. Moss.
Dr. Moss stressed that the full clinical implications of cutaneous mosaicism are not completely explored. It is clear that the clinical correlation of abnormal cutaneous findings representing mosaicism is fascinating and enlightens our understanding of both skin disorders and normal skin development.
Medscape Dermatology. 2002;3(2) © 2002 Medscape
Cite this: Two Colleagues, Two Perspectives: Report From the Society for Pediatric Dermatology Annual Meeting, Part 2 - Medscape - Oct 01, 2002.