Toshinari Miyauchi

Warty intralymphatic histiocytosis successfully treated with topical tacrolimus.

References 1 Fujimoto M, Hamaguchi Y, Kaji K et al. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum 2012; 64: 513–522. 2 Kasuya A, Hamaguchi Y, Fujimoto M, Tokura Y. TIF1gamma-overexpressing, highly progressive endometrial carcinoma in a patient with dermato-myositis positive for malignancy-associated anti-p155/140 autoantibody. Acta Derm Venereol 2013; 93: 715–716. 3 Andrieux G, Fattet L, Le Borgne M, Rimokh R, Theret N. Dynamic regulation of Tgf-B signaling by Tif1gamma: a computational approach. PLoS ONE 2012; 7: e33761. 4 Beswick EJ, Pinchuk IV, Earley RB, Schmitt DA, Reyes VE. Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4 + T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun 2011; 79: 2737–2745. 5 Wahl SM, Hunt DA, Wong HL et al. Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation. J Immunol 1988; 140: 3026–3032. 6 Inman GJ. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev 2011; 21: 93–99. 7 Fleming NI, Jorissen RN, Mouradov D et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res 2013; 73: 725–735. 8 Zhang H, Yang P, Zhou H, Meng Q, Huang X. Involvement of Foxp3expressing CD4+ CD25+ regulatory T cells in the development of tolerance induced by transforming growth factor-beta2-treated antigenpresenting cells. Immunology 2008; 124: 304–314. 9 Kobie JJ, Wu RS, Kurt RA et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63: 1860–1864.

A severe case of X-linked ichthyosis showing palmar hyperlinearity without FLG mutations.

Editor A 57-year-old Japanese man was referred to us with generalised dry skin and dark brown, adherent scales on the trunk and extremities (Fig. 1a). Plate-like scales were also noted on the shins (Fig. 1b). His cutaneous manifestations had been present since soon after birth. He had a past medical history of squamous cell carcinoma of the gingiva, but was otherwise healthy. His unrelated parents and four sisters were all unaffected. Moreover, none of the male members in the maternal family were affected. A skin biopsy showed compact hyperkeratosis and basal melanosis without parakeratosis and/or acanthosis. Stratum granulosum was neither thickened nor diminished. From these findings, he was suspected of having X-linked ichthyosis (XLI). After obtaining approval for genetic study from the institutional review board and written informed consent from the patient, we performed fluorescence in situ hybridization using his white blood cells, which detected a genomic deletion at the STS locus on Xp22.3 (data not shown); this confirmed the diagnosis of XLI. Notably, he also manifested palmar and plantar hyperlinearity, with the former much more pronounced (Fig. 1c). Taken together with his severe skin conditions for XLI, this led us to suspect an additional mutation in the gene encoding filaggrin (FLG). We performed mutation analysis of the entire coding regions of FLG using the genomic DNA extracted from his peripheral blood as described previously; however, it identified no loss-of-function mutations. Our patient showed severe skin phenotypes for XLI. Liao et al. reported an association between FLG mutations and exacerbation of XLI phenotypes. In their study, two affected brothers showed different phenotypic severity, despite having a same STS genomic deletion. Notably, the more severely affected brother was found to be a heterozygous carrier of the nonsense mutation p.Arg501Ter in FLG, whereas the other was wild-type for the mutation. These findings, together with the fact that about 10% of the Japanese and British populations have loss-offunction mutations in FLG, indicate that FLG mutations can modify or exacerbate phenotypes of genodermatoses including XLI. However, our patient with XLI presented severe phenotypes without FLG mutations. Interestingly, Gruber et al. reported an XLI family in which two affected brothers carrying pathogenic mutations both in STS and FLG presented strikingly variable phenotypic severity, which indicates that hitherto unrecognised genes might contribute to phenotypic severity in XLI. This study provides further evidence for genetic and/or environmental modifiers exacerbating XLI other than FLG mutations. Palmar hyperlinearity is widely accepted as a useful clinical finding for the differential diagnosis of XLI and ichthyosis vulgaris (IV) because it has been reported to be specific to IV and/ or atopic dermatitis (AD). Nevertheless, our XLI patient showed palmar hyperlinearity without FLG mutations. CuevasCovarrubias et al. also reported a case of XLI presenting with palmar hyperlinearity with clinical signs of neither IV nor AD, although mutation analysis of FLG was not performed in their patient. These findings suggest that patients with XLI might exhibit palmar hyperlinearity even without FLG mutationrelated disorders, although a larger case study is warranted to validate this hypothesis.

Genetic analysis of a novel splice‐site mutation in TMC8 reveals the in vivo importance of the transmembrane channel‐like domain of TMC8

DEAR EDITOR, Epidermodysplasia verruciformis (EV, MIM 226400) is a rare autosomal recessive genodermatosis characterized by abnormal susceptibility to b-human papillomaviruses (b-HPVs). However, patients with EV are not vulnerable to other pathogens. Loss-of-function mutations in TMC6 and TMC8 have been identified as causes of EV. Seven mutations have been reported in each of TMC6 and TMC8. The transmembrane channel-like (TMC) family of proteins comprises eight members in mammals (TMC1–8), all of which possess a functionally important, conserved 120-aminoacid domain, known as the TMC domain. For TMC8, amino acids 418–537 correspond to this domain. Earlier in vitro studies demonstrated that the TMC domain of TMC8 binds to at least two proteins: zinc transporter-1 (ZnT-1) and tumour necrosis factor (TNF) receptor type 1-associated death domain protein (TRADD). The TMC8–ZnT-1 complex regulates intracellular distribution of free zinc and inhibits free zinc influx to nucleoli in keratinocytes, which eventually downregulates transcription factors including activator protein-1 (AP-1), a protein that plays a key role in the life cycle of HPVs. Moreover, the TMC8–TRADD complex promotes TNF-a-induced

Dermoscopic observation in adenoma of the nipple

1 Oiso N, Kawara S, Inui H, Kawada A. Pigmented spots as a sign of mammary Paget’s disease. Clin Exp Dermatol 2009; 34: 36–38. 2 Longo C, Fantini F, Cesinaro AM et al. Pigmented mammary Paget disease: dermoscopic, in vivo reflectance-mode confocal microscopic, and immunohistochemical study of a case. Arch Dermatol 2007; 143: 752–754. 3 Yanagishita T, Tamada Y, Tanaka M et al. Pigmented mammary Paget disease mimicking melanoma on dermatoscopy. J Am Acad Dermatol 2011; 64: e114–e116. 4 Hida T, Yoneta A, Nishizaka T et al. Pigmented mammary Paget’s disease mimicking melanoma: report of three cases. Eur J Dermatol 2012; 22: 121–124. 5 Lin J, Koga H, Takata M, Saida T. Dermoscopy of pigmented lesions on mucocutaneous junction and mucous membrane. Br J Dermatol 2009; 161: 1255–1261.

Warts in toe webs associated with human papillomavirus type 7: a specific cutaneous manifestation of this type?

regimens are needed. Cetuximab, in combination with paclitaxel, is an approved treatment for advanced SCC of the head and neck and has the highest disease control rate. Some recent reports have demonstrated that unresectable cutaneous SCCs have been successfully treated with cetuximab. Among these reports, a durable complete response using the combination therapy with cetuximab and paclitaxel was observed. Taking this evidence together, there is a possibility that the combination therapy with cetuximab and paclitaxel could be useful for various kinds of SCCs other than just head and neck. This case strongly implies that the combination therapy with cetuximab and paclitaxel is also effective for cutaneous SCCs, including vulvar SCC, and therefore randomized clinical studies for SCC of the skin and mucosa would be desirable.

Sweet syndrome-like eruption with prominent dermal leukocytoclasis associated with systemic lupus erythematosus

Dear Editor, Sweet syndrome-like eruption associated with lupus erythematosus (LE) is a rare disorder, with only approximately 50 similar cases reported in the published work. From the first report by Goette, various names have been used, including “non-bullous neutrophilic dermatosis”, “Sweet’s syndrome associated with SLE” and “SLE-associated neutrophilic dermatosis”. In addition to the clinical manifestation of Sweet syndrome-like eruptions, histopathologically, dermal infiltration of neutrophils is commonly observed. However, the extent of neutrophilic infiltration is highly variable, and even cases with scant neutrophilic infiltration have been reported. Here, we report a case of Sweet syndrome-like eruption with prominent dermal leukocytoclasis in a patient with systemic LE (SLE). A 46-year-old Japanese woman with SLE presented with a 6-week history of malaise and fever, and 2-week history of eruptions. She was diagnosed with SLE at the age of 29 years, and 4 mg/day of oral prednisolone had been taken at presentation. On physical examination, asymptomatic, 2–3-cmdiameter, indurated, erythematous, partially annular macules and nodules were scattered over the whole body (Fig. 1a,b). There were no blistering lesions. Her body temperature was 37–38°C. Laboratory investigations showed leukopenia (3.3 9 10/lL), increased C-reactive protein (3.32 mg/dL) and liver dysfunction. Reduced C4 was observed, but C3 and CH50 were both within normal limits. Antinuclear antibody was elevated (9320), and anti-dsDNA, anti-Sm and anti-RNP antibodies were positive. Skin biopsy taken from a back lesion

Identification of SERPINB7 mutations in Korean patients with Nagashima-type palmoplantar keratosis.

Dear Editor, Nagashima-type palmoplantar keratoderma (NPPK) is a relatively new entity of hereditary PPK. NPPK is an autosomal recessive disorder characterized by diffuse palmoplantar hyperkeratosis and erythema of the inner wrist, ankle, Achilles tendon and dorsum of the hands and feet. SERPINB7 has been identified as a causative gene of NPPK. Recently, NPPK has been established as a common type of hereditary PPK in Asian populations; however, there have been no previous reports of SERPINB7 mutations in the Korean population, with all reported patients being of Japanese or Chinese origin. Herein, we report three Korean patients with NPPK and two underlying SERPINB7 mutations. Three unrelated patients (two males and one female) of Korean ethnicity with diffuse and non-epidermolytic PPK were enrolled. The diagnosis of NPPK was clinically determined by two experienced dermatologists. All patients presented with diffuse, erythematous palmoplantar hyperkeratosis of the wrist, Achilles tendon and dorsum of the hands/feet with an onset age ranging from birth to 3 years and reported aquagenic wrinkling after a shower. In one case, there was a family history involving the patient’s sister. Mild hyperhidrosis of the palms and soles and skin maceration were noted in all patients (Fig. 1a–c). Two patients reported recurrent tinea pedis. A biopsy specimen from the erythematous dorsum of the hand revealed orthokeratosis, hyperkeratosis with

The identification of autoantigens in mucous membrane pemphigoid using immortalized oral mucosal keratinocytes

BACKGROUND Mucous membrane pemphigoid (MMP) is a rare chronic autoimmune subepithelial blistering disorder, targeting multiple basement membrane zone (BMZ) proteins including collagen XVII (COL17). Circulating autoantibodies of MMP are often undetected due to their lower titers. The oral mucosa is a valuable substrate for the detection of autoantibodies in MMP patients. However, obtaining normal human oral mucosa is more difficult than obtaining normal human skin. We established immortalized normal human oral mucosal keratinocytes (OMKs) and performed immunoblotting using immortalized OMK lysate for detecting autoantigens in MMP. METHODS Immortalized OMKs were generated from primary OMKs using E6/E7 proteins of HPV. We compared the protein expression levels of major BMZ proteins between primary OMKs and immortalized OMKs. We performed immunoblotting to detect autoantigens using cell lysates from immortalized OMKs in 30 MMP patients. RESULTS There were no significant differences between primary OMKs and immortalized OMKs in terms of protein expression levels of the BMZ proteins, including COL17, laminin 332, integrin α6/β4, collagen VII, and collagen IV. Cell lysates of immortalized OMKs effectively identified MMP autoantigens in 60% (18/30) of MMP sera. We found an interesting case of MMP whose autoantibodies preferentially reacted to the 120-kD protein that is an ectodomain of COL17. CONCLUSION We demonstrated that a cell lysate of immortalized OMKs is a reliable substrate for the detection of MMP autoantigens. This newly developed immunoblotting analysis method promises to contribute to the diagnosis of MMP.

Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis

TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22‐year‐old Japanese man presented with large, dark brown, plate‐like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype–phenotype correlations and pathogenesis in lamellar ichthyosis.

Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes

Heterozygous chromosomal inversions suppress recombination. Therefore, they may potentially influence recombination-associated phenotypes of human diseases, but no studies have verified this hypothesis. Here, we describe a 35-year-old man with severe congenital ichthyosis. Mutation analysis revealed a heterozygous splice-site mutation, c.1374-2A>G (p.Ser458Argfs*120), in KRT10 on 17q21.2. This mutation was previously reported in patients with ichthyosis with confetti type I (IWC-I), a prominent skin disease characterized by the frequent occurrence of recombination-induced reversion of pathogenic mutations. Intriguingly, the number of revertant skin areas in this patient is considerably reduced compared with typical IWC-I cases. G-banded karyotyping revealed that the patient harbors a heterozygous nonpathogenic inversion, inv(17)(p13q12), whose long-arm breakpoint was subsequently refined to chromosomal positions (chr17: 36,544,407-36,639,830) via FISH. Collectively, the only chance of revertant mosaicism through somatic recombination appears to involve recombination between the KRT10 mutation and the inversion breakpoint. Indeed, in the examined revertant spot, the KRT10 mutation was diminished by somatic recombination starting from chromosomal positions (chr17: 36,915,505-37,060,285) on 17q12. This study provides the first evidence to our knowledge implicating chromosomal inversions as a potential modifier of clinical phenotypes. Furthermore, the reduced occurrence of revertant spots in the recombination-suppressed patient suggests that somatic recombination is the main mechanism of revertant mosaicism in IWC-I.