Ikue Nemoto-Hasebe

Clinical Severity Correlates with Impaired Barrier in Filaggrin-Related Eczema

Mutations in the gene-encoding filaggrin (FLG), a key molecule involved in skin barrier function, have been shown to be a major predisposing factor for atopic dermatitis (AD; eczema). To elucidate the pathomechanisms underlying filaggrin-related AD, we investigated stratum corneum (SC) hydration and transepidermal water loss (TEWL) as parameters of barrier function in AD patients harboring FLG mutations compared to AD patients without any FLG mutation. In filaggrin-related AD, SC hydration was both significantly reduced (P<0.01-0.05) and thicker (P<0.01-0.05) than that in healthy controls. TEWL was demonstrably increased in non-filaggrin AD compared to healthy controls (P<0.01-0.05). The objective score of atopic dermatitis (OSCORAD), a disease clinical severity index, significantly correlated with TEWL (r=0.81, P<0.005), SC hydration (r=-0.65, P<0.05), and SC thickness (r=0.59, P<0.05) in filaggrin-related AD. On the contrary, there was no correlation between these parameters and the OSCORAD in non-filaggrin AD. Furthermore, a significant correlation was obtained between the OSCORAD and specific IgE for house dust (r=0.66, P<0.05), mite allergen (r=0.53, P<0.05), and cat dander (r=0.64, P<0.05) in filaggrin-related AD, but not in non-filaggrin AD. All these data suggest that experimentally demonstrable skin barrier defects due to FLG mutations may play a crucial role in the pathogenesis of AD.

Specific Filaggrin Mutations Cause Ichthyosis Vulgaris and Are Significantly Associated with Atopic Dermatitis in Japan

Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and shown to be major predisposing factors for atopic dermatitis (AD). However, these studies have been mainly carried out in European populations. In early 2007, we identified two Oriental-specific FLG mutations in four Japanese families with IV and reported that filaggrin mutations were also significant predisposing factors for AD in Japan. However, the frequency of FLG mutations observed in our Japanese AD cohort (5.6%), was much lower than that seen in Europeans (up to 48%). Here, we studied a further seven Japanese families with IV and identified two additional nonsense mutations in FLG, S2889X, and S3296X. We found that more than 20% of patients in our Japanese AD case series carry FLG mutations, and there is significant statistical association between the four mutations and AD (chi(2) P=8.4 x 10(-6); heterozygote odds ratio 7.57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan.

FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema

Background  Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE).

Prevalent and Rare Mutations in the Gene Encoding Filaggrin in Japanese Patients with Ichthyosis Vulgaris and Atopic Dermatitis

CXCL8 in the NOD1 shRNA-expressingcells is mediated by such receptors.In summary, to our knowledge this isthe first report demonstrating that theintracellular receptor NOD1 is func-tional expressed in human keratino-cytes, suggesting that NOD1 may beinvolved in cutaneous innate immunity.Further studies are needed to under-stand the contribution of intracellularinnate immune receptors to cutaneoushost defense.

Analysis of Taiwanese ichthyosis vulgaris families further demonstrates differences in FLG mutations between European and Asian populations

Background  Mutations in the gene encoding filaggrin (FLG) were identified to underlie ichthyosis vulgaris (IV) and also shown to predispose to atopic eczema. Until now, no FLG mutations have been described in the Taiwanese population.

Circumscribed palmar hypokeratosis: correlation between histopathological patterns and dermoscopic findings

acknowledgments within their content, authorship disclosure within advertising material was highly inconsistent and often made it difficult to determine if medical professionals were involved. In other specialities, reports have observed a similar low level of professional medical involvement in app design, and have found content containing misleading claims and a lack of academic reference. Certain apps, such as one that uses an automated system of photographic analysis to stratify a patient’s skin lesions as low, medium or high risk, provide many potential diagnostic risks. While such apps may promote beneficial skin-monitoring behaviour, the use and interpretation of an unknown, unvalidated risk stratification system by the untrained user is inadvisable and could lead to false reassurance. Other concerns include confidentiality and data storage. Some teledermatology apps use online forums where a large number of unknown users can view an individual’s clinical information. More general concerns include the risk of cross-contamination, where using mobile phones during clinical encounters could interfere with hand hygiene and provide a reservoir for pathogenic bacteria. In February 2011, the U.S. Food and Drug Administration published draft guidelines specifying that some apps constitute a ‘medical device’ and require regulation. Additionally, the U.S. Federal Trade Commission has addressed misleading marketing, in one case by outlawing an app claiming to provide a cure for acne. As some apps cross the divide from entertainment into a capacity as a medical device, increasing regulation is welcome; however, the future extent of regulation of medical apps is currently unknown. We propose that simple measures to improve accountability of app content, such as insistence by app providers of full authorship disclosure, listing of regulatory approval, recognized quality marks and external review, may lead to improvements in the reliability and quality of the content offered.

Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss

Background  Connexins, components of the gap junction, are expressed in several organs including the skin and the cochlea. Mutations in connexin genes including GJB2 (Cx26), GJB3 (Cx31), GJB4 (Cx30.3), GJB6 (Cx30) and GJA1 (Cx43) are responsible for various dermatological syndromes and/or inherited hearing loss, frequently showing overlapping phenotypes.

Extremely severe palmoplantar hyperkeratosis in a generalized epidermolytic hyperkeratosis patient with a keratin 1 gene mutation

To the Editor: Epidermolytic hyperkeratosis (EHK; OMIM#113800), also called bullous congenital ichthyosiform erythroderma, is a rare genetic disorder of keratinization. We report a patient with generalized EHK showing extremely severe palmoplantar hyperkeratosis with digital contractures. A 45-year-old Japanese man had erythroderma at birth. He exhibited skin blistering, erosions, and hyperkeratosis on the erythrodermic skin since infancy. The blistering and erosions gradually diminished with age. He developed severe palmoplantar hyperkeratosis and digital contractures at 7 years of age. At 24 years of age, surgery was performed to improve the contraction of his toes. A physical examination revealed hyperkeratosis of the entire body, especially at the ankles, elbows, and knees, and erosions were observed on the inner side of the elbows and knees (Fig 1, A-D). Palmoplantar hyperkeratosis was severe with digital contractures. The

Wells' Syndrome Associated with Chronic Myeloid Leukaemia

© 2013 The Authors. doi: 10.2340/00015555-1483 Journal Compilation

CD30-positive primary cutaneous anaplastic large-cell lymphoma and definite squamous cell carcinoma

CD30-positive primary cutaneous anaplastic large cell lymphoma (PCALCL) is one of several primary cutaneous CD30-positive lymphoproliferative disorders. The overlying epidermis often shows epidermal hyperplasia with ulceration, and pseudocarcinomatous hyperplasia has been reported in a small number of CD30-positive PCALCL cases. However, separate and distinct squamous cell carcinoma (SCC) has rarely been seen in CD30-positive PCALCL, and only one SCC (keratoacanthoma type) was reported by Cespedes et al. We report a rare case of CD30positive PCALCL with SCC that infiltrated the deep dermis. A 20-year-old woman presented with a 3-month history of an enlarging hyperkeratotic tumour (50 mm in diameter) on the left thigh. Histological examination of a biopsy from the tumour showed infiltrative proliferation of atypical keratinocytes (Figs 1 and 2a) as well as a diffuse and dense background infiltrate of large atypical lymphoid cells mixed with many eosinophils in the dermis (Fig. 2c). The atypical keratinocytes were well differentiated (Fig. 2b). Large atypical lymphoid cells strongly expressed CD30 (Fig. 2d) and CD3, but were negative for ALK-1. There was no evidence of extracutaneous involvement of the tumour based on the findings from chest and abdominal computed tomography and 67-Ga scintigraphy. The diagnosis of PCALCL with well-differentiated SCC was made. The lesion was completely excised and has not recurred in > 11 years. Some reports have described epidermal hyperplasia together with CD30-positive PCALCL. The pathogenesis of prominent epidermal hyperplasia in association with CD30-positive PCALCL has been attributed to a variety of mediators including epidermal growth factor (EGF), transforming growth factor (TGF)-a and epidermal growth factor receptor (EGFR). Courville et al. reported stronger expression of EGF and TGF-a in T cells and stronger epidermal expression of EGFR in cutaneous T-cell lymphoma (CTCL) with pseudocarcinomatous hyperplasia than in control cases of CTCL without pseudocarcinomatous hyperplasia. EGF causes epidermal proliferation and TGF-a is an important factor in wound healing and carcinogenesis. EGFR is the receptor for both EGF and TGF-a, and amplification or overexpression of EGFR has been seen in SCC of the skin. It is currently thought that EGFR is important in squamous cell carcinogenesis, and anti-EGFR antibody (cetuximab) has been used to treat cutaneous SCC. From the common association of CD30positive PCALCL with epidermal hyperplasia and less commonly, with SCC, we speculate that these mediators may play a role in epidermal proliferation and tumorigenesis. Treatment for SCC or epidermal hyperplasia overlying CD30-positive PCALC should be carefully planned. Scarisbrick et al. reported that epidermal hyperplasia in CD30positive PCALCL may be mistakenly diagnosed as SCC, thereby leading to inappropriate overtreatment. We agree with this assessment and that epidermal hyperplasia with CD30-positive PCALCL need not to be treated with wide local excision, but definite SCC such as in our case does need wide local excision. In conclusion, our case of CD30-positive PCALCL coexisting with SCC is very rare. It suggests that CD30positive PCALCL may induce not only epidermal hyperplasia but also SCC in specific cases. Figure 1 A skin biopsy taken from the hyperkeratotic plaque on the left thigh showed deep infiltrative proliferation of atypical keratinocytes in the reticular dermis near the subcutaneous tissue (haematoxylin and eosin, original magnification · 10). Viewpoints in dermatology • Correspondence