Nevus Sebaceus Is a Mosaic RASopathy

The recent discovery that nevus sebaceus is a mosaic RASopathy represents a major breakthrough in research on epidermal nevi. In this issue, both Levinsohn et al. and Sun et al. confirm this advancement with results obtained through whole-exome sequencing. Further molecular studies will almost certainly show that sebaceous and keratinocytic nevi are different disorders, although there is some clinical overlap

Interleukin-1β-Induced Inhibition of Hair Growth In Vitro Is Mediated by Cyclic AMP

Interleukin (IL)-1 has been shown to be a potent inhibitor of hair growth in vitro. We hypothesized that this cytokine might be a decisive factor causing hair loss during the lymphocytic attack in alopecia areata. Neither the intracellular pathways involved in hair growth inhibition mediated by IL-1β nor the signal transduction processes within hair follicles in general are known. We therefore investigated the intracellular signals involved in human hair growth in vitro. Hair follicles were isolated from scalp biopsies by microdissection and hair growth was measured daily by image analysis. We assessed intracellular signal transducing elements using specific inhibitors or activators either alone or in combination with IL-1β. The calcium ionophore A 23187 induced a rapid and complete arrest of hair growth and phorbol-12-myristate-13-acetate (PMA), genistein, or IL-1β decreased hair growth by approximately 60%-80%. IL-1β-elicited hair growth arrest was not antagonized by calphostin C, a specific inhibitor of protein kinase C. In contrast, coincubation of IL-1β with pertussis toxin or H 1004 neutralized the effect of IL-1β and dibutyryl-cAMP and cholera toxin, an activator of adenylate cyclase, inhibited hair growth. These data suggest that cAMP acts as a second messenger for IL-1β-induced inhibition of hair growth. Moreover, our data indicate that in vitro hair growth is dependent on intracellular Ca2+ levels and activation of tyrosine kinase as well as protein kinase C. We were unable to detect a signal transducing element responsible for enhanced hair growth in vitro

Alopecia Areata: Treatment of Today and Tomorrow

It is the aim of this article to review and appraise available data on treatments for alopecia areata (AA) according to the demands of evidence based medicine. Studies evaluating the efficacy of a treatment for AA should include appropriate controls, use cosmetically acceptable hair regrowth as a parameter for treatment success, include patients with AA totalis, universalis or extensive patchy AA, and exclude patients suffering from AA for less than 3 months. Moreover, the treatment must be safe over a prolonged period of time. Among the various therapeutic approaches presently available for AA, only treatment with contact sensitizers such as diphenylcyclopropenone or squaric acid dibutylester has been shown to be effective in studies that fulfill these criteria.Improved future treatments may be immunosup-pressive or immunomodulatory targeting of the autoimmune pathogenesis of AA, or they may otherwise protect hair follicles from the injurious effects of inflammation. Such possible future therapeutic approaches include the incorporation of immunomodulatory agents into liposomes as an improved vehicle; inhibition of apoptosis mediated by the Fas-FasL system; inhibition of the lymphocyte homing receptor CD44v10; induction of tolerance

Treatment with an Anti-CD44v10-Specific Antibody Inhibits the Onset of Alopecia Areata in C3H/HeJ Mice

A murine CD44v10-neutralizing antibody has been reported to impair delayed-type hypersensitivity reactions. Because alopecia areata is characterized by a delayed-type hypersensitivity-like T cell mediated immune response, we addressed the question whether an anti-CD44v10-antibody influences the onset of alopecia areata. Therefore, we used the C3H/HeJ mouse model with the induction of alopecia areata in unaffected mice by the grafting of lesional alopecia areata mouse skin. Six grafted mice were injected (intraperitoneally) with anti-CD44v10, six grafted mice with anti-CD44standard, and six with phosphate-buffered saline only. After 11 wk phosphate-buffered saline injected animals on average had developed alopecia areata on 36.8% of their body. The onset of hair loss was slightly delayed and its extent reduced to 17.2% of their body in anti-CD44standard-treated mice. By contrast, five of six anti-CD44v10-treated mice did not show any hair loss and one mouse developed alopecia areata on only 1% of the body. Immunohistochemical examination revealed a marked reduction of perifollicular CD8+ lymphocytes and, to a lesser degree, CD4+ cells as well as a decreased expression of major histocompatibility complex class I on hair follicle epithelium in anti-CD44v10-treated mice as compared with phosphate-buffered saline or anti-CD44 standard-treated mice. Our data show that anti-CD44v10 is able to inhibit the onset of alopecia areata in C3H/HeJ mice. This might be accomplished by an anti-CD44v10-triggered impairment of immune cell homing (e.g., CD8+ T cells), resulting in a decrease of their number in target tissues

A Case of Linear Porokeratosis Superimposed on Disseminated Superficial Actinic Porokeratosis

We present a female patient with linear porokeratosis of her right arm since childhood. At the age of 67 years she additionally developed disseminated superficial actinic porokeratosis (DSAP) involving both lower legs. This uncommon coexistence of two different types of porokeratosis fulfils the clinical criteria of a type 2 segmental manifestation of an autosomal dominant skin disorder, being superimposed on the ordinary nonsegmental lesions and reflecting loss of heterozygosity that occurred at an early developmental stage. In DSAP molecular evidence of this concept is so far lacking, but such proof has already been provided in several other autosomal dominant skin disorders. Molecular analysis of cases of type 2 segmental involvement may help elucidate the genetic defect causing DSAP

PTPN11 mosaicism causes a spectrum of pigmentary and vascular neurocutaneous disorders and predisposes to melanoma

Phakomatosis pigmentovascularis (PPV) is a diagnosis which denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement including central nervous system disease, asymmetrical growth and a predisposition to malignancy. Using a tightly phenotyped group and high depth next generation sequencing of affected tissues we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of PPV type III or spilorosea. Within an individual the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to demonstrate that the same variants can cause either the specific pigmentary or vascular phenotypes alone, as well as driving melanoma development within the pigmentary lesion. Protein conformational modelling highlights that while variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modelling of the missense variants confirms downstream MAPK pathway overactivation, and widespread disruption of human endothelial cell angiogenesis. Importantly, PTPN11-mosaic patients theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of naevus spilus and capillary malformation syndromes, paving the way for better clinical management

Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis.

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities

What is in a name-Perifollicular fibroma or fibrofolliculoma?

So far, confusion exists regarding the question of whether hereditary perifollicular fibromas and fibrofolliculomas can be distinguished from each other. Here, histopathological arguments are presented to clarify this terminological problem. In 1977, Birt et al. described a large kindred affected with hereditary multiple "fibrofolliculomas," which they thought were "a hitherto unrecognized pilar hamartoma," but they never claimed the fibrofolliculomas were part of a syndrome. A careful microscopic comparison shows, however, that the tumors are clinically and histopathologically identical to perifollicular fibromas, as first described by Burnier and Rejšek in 1925. Their familial occurrence was discovered in 1971 by Civatte and Le Tréguilly. Before 1977, the term "perifollicular fibroma" was used for these skin tumors. By contrast, Hornstein and Knickenberg described in 1975 perifollicular fibromas as a cutaneous marker of a syndrome characterized by a predisposition to colon cancer and pneumothorax. Later, two French groups erroneously proposed the term "Birt-Hogg-Dubé syndrome" to describe the co-occurrence of fibrofolliculomas, trichodiscomas, and acrochordons, which was contrary to what Birt et al. had in mind. Hence, today, we should discriminate between the hereditary nonsyndromic perifollicular fibromas, as documented by Civatte and Le Tréguilly and later by Birt et al., and the syndromic perifollicular fibromas, as delineated by Hornstein and Knickenberg