Mosaicism In Skin Research Articles

Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

Verrucous epidermal nevi: some aspects of pathogenesis and clinical cases

Verrucous epidermal nevi ― hamartomas of keratinocyte or epidermal appendages, located on the skin or mucous membranes in the form of isolated birthmarks, less often have a linear localization. The pathogenesis of verrucous epidermal nevi has not been fully defined, probably the development of the disease is associated with genetic mutations during embryogenesis and represent a special form of skin mosaicism. Verrucous epidermal nevi are skin pathologies that require attention as potentially dangerous in terms of the development of malignant neoplasms of the skin and due to the possible difficulties in their diagnosis and differential diagnosis.
 Analysis of current data on the pathogenesis and differential diagnosis of various forms of verrucous epidermal nevi, presentation of clinical cases of verrucous epidermal nevi.
 The article considers two clinical cases of linear verrucous epidermal nevus. Studies of the pathogenesis of WEN have shown the presence of changes in expressed proteins by affected skin cells, such as OGN, NT5C3A, ADD1, OLFML1, DHRS1, CALML5, SAMHD1, SFRP2, SPRR1B and SERPINB13. This may indicate the participation in the development of verrucous epidermal nevi of changes in the p53 signaling pathway, the cellular response to a cytokine stimulus, and disturbances in cell adhesion and differentiation of Th1 and Th2 cells. The presented clinical cases describe linear verrucous epidermal nevus in order to study the diagnosis of the disease, based on the clinical picture. The need for differential diagnosis of various forms of verrucous epidermal nevi is due to their clinical and sometimes histological similarity with other skin formations. Immunohistochemical examination, genetic analysis using sequencing of the affected skin exome, and proteomic analysis of proteins expressed by affected skin cells help to carry out differential diagnosis.
 The study of the mechanisms of development of this disease will help not only in differential diagnosis with other skin diseases, but will also allow finding new approaches to its conservative therapy.

Four-dimensional, dynamic mosaicism is a hallmark of normal human skin that permits mapping of the organization and patterning of human epidermis during terminal differentiation

Recent findings of mosaicism (DNA sequence variation) challenge the dogma that each person has a stable genetic constitution. Copy number variations, point mutations and chromosome abnormalities in normal or diseased tissues have been described. We studied normal skin mosaicism of a single nucleotide polymorphism (SNP) [rs1426654, p.Thr111Ala] in SLC24A5, an ion transporter gene. This SNP is unusual in that more than 90% of people of European descent have homozygous germline A/A alleles, while more than 90% of East Asians and Blacks have homozygous germline G/G alleles. We found mosaicism in neonatal foreskins as well as in 69% of nearly 600 skin surface scraping samples from 114 donors of different ages. Strikingly, donors with germline (buccal or blood) A/A, A/G or G/G genotypes had all three sequences (A/A, A/G or G/G) in the skin surface scrapings. SNP sequence differences extended within the epidermis in the vertical dimension from basal cell layer to the stratum corneum at the surface, as well as across the two-dimensions of the skin surface. Furthermore, repeated scrapings in the same location revealed variation in the sequences in the same individuals over time, adding a fourth dimension to this variation. We then used this mosaicism to track the movement of epidermal cells during normal differentiation and characterize the patterning of epidermal cells during terminal differentiation. In this coordinated proliferation model of epidermal differentiation, the skin surface is alternatively populated by synchronous, cycling of waves of cells, with each group having a different DNA sequence. These groups of cells abruptly flatten into large sheets at the surface providing patches of uniform SNP sequence. This four-dimensional mosaicism is a normal, previously unrecognized form of dynamic mosaicism in human skin.

Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.

Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality. To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly. Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children's Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations. Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders. Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size. In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

Nevoid hypopigmentation as a manifestation of skin mosaicism

A case report of rare genetically specified dyschromia - nevoid hypopimentation - was described. This disease is considered as a manifestation of skin mosaicism with characteristics of clinical presentation. Literature data is given, differential diagnostics issues of this pathology are discussed.

Congenital vulnerability of cutaneous segments arising from skin mosaicism: A genetic basis for locus minoris resistentiae

Mosaicism is a biologic phenomenon that describes an individual who has two or more populations of cells with distinct genotypes and concomitant patterned phenotypes (eg, lines of Blaschko). It is distinguished from chimerism by its derivation from a single fertilized egg rather than multiple cell lineages derived from distinct fertilized eggs. With respect to dermatologic disorders, it is the strongest genetic example of how a cutaneous site, being populated by cells with distinct antigenic or immunologic properties, differs in its susceptibility or resistance to skin disorders, being preferentially affected in the former (ie, locus minoris resistentiae). We review patterns and mechanisms of skin mosaicism and discuss examples of segmental/mosaic dermatologic disorders that have been superimposed on a background of a nonsegmental eruption of the same disease or dermatologic disorders that have arisen secondarily on segmental cutaneous disorders.

The immunocompromised district in dermatology: A unifying pathogenic view of the regional immune dysregulation

Besides the systemic immune deficiency, a sectorial default in immune control may occur in immunocompetent subjects. This regional immune defect can appear and remain confined to differently damaged skin areas, lately labeled immunocompromised districts (ICDs).An ICD is a skin area more vulnerable than the rest of the body for genetic or acquired reasons. Its vulnerability mainly consists in a local dysregulation of the immune control, which often facilitates (but sometimes hinders) the local onset of immunity-related eruptions or skin disorders.The factors responsible for localized immune dysregulation are multifarious, being represented by chronic lymphatic stasis, herpetic infections, ionizing or ultraviolet (UV) radiations, burns, all sorts of trauma (especially amputation), tattooing, intradermal vaccinations, and others of disparate nature (eg, paralytic stroke, poliomyelitis). Whatever the cause, in time an ICD may become a vulnerable site, prone to developing opportunistic infections, tumors, or dysimmune reactions (often of granulomatous type), strictly confined to the district itself; however, the opposite may also occur with systemic immune disorders or malignancies that selectively spare the district. In any case, the immunologic behavior of an ICD is different from that of the rest of the body. The pathomechanisms involved in this sectorial immune destabilization may reside in locally hampered lymph drainage that hinders the normal trafficking of immunocompetent cells (eg, chronic lymphedema, posttraumatic lymph stasis) or in a damage to sensory nerve fibers that release immunity-related peptides (eg, herpetic infections, carpal tunnel syndrome), or in both conditions (eg, amputation stump, radiation dermatitis).The ICD is a conceptual entity with no definite shape or dimension. It may take an extremely variable form and extent depending on the causative agent, ranging from a minimal area (eg, intradermal vaccination) or a small area (eg, herpes simplex infection), through a wide area (eg, radiotherapy), a bandlike segment (eg, skin mosaicism, herpes zoster infection), or an acral area (eg, carpal tunnel syndrome), up to a whole limb (eg, Stewart-Treves syndrome) or even an entire half body (eg, brain stroke).Varied newly coined terminology can be used to indicate the specific cause each time that it is responsible for a regional immune dysregulation. The advantage of the umbrella term ICD is that it encompasses all the possible causes involved in a local immune destabilization.An ICD may have a congenital or a postnatal origin, and interesting similarities between the two forms exist. An ICD may also take place in patients with a preexisting systemic immune deficiency, thus creating a more vulnerable site in an already vulnerable patient.Identifying a cutaneous ICD in a given patient is an important standpoint for both diagnostic and prevention purposes. This can be proven by the educative clinical examples that are reported here.

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

Superimposed Segmental Dermatomyositis

I read with great interest the paper by Takahashi et al.1 reporting on a child affected by juvenile dermatomyositis (JDM). The peculiarity of the case was the presence of erythema and violaceous papules following a Blaschko’s line over the posterior aspect of the right thigh. The authors speculate that such lesion is an expression of flagellate erythema. However, flagellate erythema of DM is transient, not infiltrated, typically occurs in multiple streaks on the trunk and does not follow Blaschko’s lines. I rather suggest herein that the reported case actually represents a remarkable example of superimposed segmental dermatomyositis. Two types of skin mosaicism are currently recognized with regard to monogenic skin disorders, i.e. type 1 (segments of heterozygous skin in the setting of nonmutant skin) and type 2 (segments of homozygous skin in the setting of heterozygous skin). Segmental manifestations can also be observed in many acquired polygenic skin disorders. In this case, the terms suggested as equivalents of type 1 and type 2 are “isolated” (segmental lesions as the sole manifestation of a dermatosis) and “superimposed” (segmental lesions coexisting with nonsegmental, otherwise typical manifestations of a dermatosis), respectively.2 Many polygenic skin disorders have been already shown to present, albeit very rarely, with a superimposed segmental manifestation. JDM has been recently included in the list3 after the publication of 3 cases featuring segmental calcinosis.4-6 The case by Takahashi et al. 1 is likely to represent the first reported one in which the segmental manifestation is represented by the pathognomonic findings of DM, i.e. Gottron’s sign and papules.

Evidence for the Clonal Origin of Chronic Myeloid Leukemia From a Sex Chromosome Mosaic: Clinical, Cytogenetic, and Marrow Culture Studies

Abstract Cytogenetic studies on a 7½-yr-old child presenting with clinical and hematological features of chronic myeloid leukemia (CML) revealed a constitutional 46 XY/47 XYY mosaicism in skin, blood, and marrow. A third 46 XY, Ph1 cell line predominated in the marrow on initial presentation and in subsequent acute transformation. Assessment of granulocytic colony-forming capacity in agar culture revealed that colony-forming cells (CFCs) were greatly increased in the circulation and possessed the abnormal light buoyant density and low susceptibility to tritiated thymidine killing which distinguishes leukemic CFCs from normal. During acute transformation colony-forming capacity was lost but small, poorly differentiated cell clusters persisted in culture. Only 46 XY, Ph1 metaphase were obtained following cytogenetic analysis of in vitro colonies and clusters displaying leukemic growth characteristics in agar culture. The coexistence of CML and sex chromosome mosaicism in this patient provides further support for the uniclonal origin of CML and indicates that cytogenetic instability implicated in mosaicism may carry an increased risk of further cytogenetic evolution with emergence of the Ph1 chromosome.

Blood group and tissue mosaicism in a Natal Indian woman.

A normal 46, XX karyotype was demonstrated in an Indian woman who has 2 approximately equal populations of red cells and of leucocytes. She also has skin mosaicism. She is a normal female and has borne 4 healthy children. The ABO, Ss, Rh and Fy groups of her 2 red cell populations differed, but both were Le(a+b-) although she is a secretor of B and H substances. The relationship between this and the 7 examples of dispermywith blood group mosaicism reported in the literature is discussed briefly