Trichophyton indotineae sp. nov.: A New Highly Terbinafine-Resistant Anthropophilic Dermatophyte Species.

In this report, we describe the first isolation of two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with tinea corporis in Japan. These strains (designated NUBS19006 and NUBS19007) exhibited a TRF minimal inhibitory concentration (MIC) of > 32 mg/L and contained a missense mutation (Phe397Leu) in squalene epoxidase (SQLE) gene. The internal transcribed spacer (ITS) region sequences amplified from the isolates (NUBS19006 and NUBS19007) were 99.5% identical to Japanese isolates of T. interdigitale and T. interdigitale strain CBS 428.63. The homology of region sequences were also 97.6% identical to T. mentagrophytes strain CBS 318.56. Moreover, the ITS sequences amplified from the isolates were 100% identical to highly TRF-resistant strains of T. interdigitale, which were isolated in Delhi, India, and harbored mutations in SQLE. The urease test on Christensen's urease agar was positive for T. mentagrophytes and T. interdigitale after 7 days of incubation. On the other hand, the type strain of T. rubrum CBS 100081 T and highly TRF-resistant strains (NUBS19006 and NUBS19007) were negative on Christensen urease agar after 7 and 14 days of incubation. Moreover, NUBS19006 and NUBS19007 were also negative reaction on the hair perforation test. To avoid confusion in the taxonomy of the T. mentagrophytes/T. interdigitale complex, we suggest that the highly TRF-resistant Indian strains be considered a new species independent of T. interdigitale, according to clinical and mycological features.

Dupilumab Alters Both the Bacterial and Fungal Skin Microbiomes of Patients with Atopic Dermatitis.

The skin microbiome at lesion sites in patients with atopic dermatitis (AD) is characterized by dysbiosis. Although the administration of dupilumab, an IL-4Rα inhibitor, improves dysbiosis in the bacterial microbiome, information regarding the fungal microbiome remains limited. This study administered dupilumab to 30 patients with moderate-to-severe AD and analyzed changes in both fungal and bacterial skin microbiomes over a 12-week period. Malassezia restricta and M. globosa dominated the fungal microbiome, whereas non-Malassezia yeast species increased in abundance, leading to greater microbial diversity. A qPCR analysis revealed a decrease in Malassezia colonization following administration, with a higher reduction rate observed where the pretreatment degree of colonization was higher. A correlation was found between the group classified by the Eczema Area and Severity Index, the group categorized by the concentration of Thymus and activation-regulated chemokine, and the degree of skin colonization by Malassezia. Furthermore, an analysis of the bacterial microbiome also confirmed a decrease in the degree of skin colonization by the exacerbating factor Staphylococcus aureus and an increase in the microbial diversity of the bacterial microbiome. Our study is the first to show that dupilumab changes the community structure of the bacterial microbiome and affects the fungal microbiome in patients with AD.

Neutrophilic, urticaria-like erythema associated with immunoglobulin A monoclonal gammopathy of undetermined significance.

A 70-year-old-male had suffered from non-pruritic, erythematous eruptions on the trunk for 3 months without any general symptoms. The individual lesions lasted for several days. Laboratory investigation showed marked elevation of serum immunoglobulin A (2235 mg/dL) with monoclonal gammopathy (IgA k-type). Monoclonal gammopathy of undetermined significance was diagnosed. Histopathological examination of the eruption revealed diffuse neutrophilic infiltration with leukocytoclasia in the dermis. There was no vasculitis. Treatment with antihistamines alone was not effective. Diaphenyl sulfone (DDS) at 75 mg/day dramatically improved the skin lesions. A similar case of urticarial erythema associated with IgA myeloma has been previously reported. We suggest that neutrophilic, urticaria-like erythema associated with IgA monoclonal gammopathy may be regarded as a new entity.

Dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in a patient with acquired reactive perforating collagenosis.

Bullous pemphigoid (BP) is a common autoimmune blistering disorder with unknown etiology. Recently, increasing numbers of BP cases which developed under the medication with dipeptidyl peptidase-4 inhibitors (DPP4i), widely used antihyperglycemic drugs, have been reported in published works. Here, we report a case of DPP4i (teneligliptin)-associated BP that developed in a 70-year-old Japanese man. Interestingly, the patient had acquired reactive perforating collagenosis (ARPC), which is also known to be associated with the onset of BP. In the present case, clinical, histopathological and immunological findings suggested that DPP4i rather than ARPC was associated with the onset of BP.

Paraneoplastic pemphigus mimicking erosive mucosal lichen planus associated with primary hepatocellular carcinoma.

A 58-year-old Japanese male visited us with painful lesions on the lower lip, oral mucosa and genital region of an 8-month duration. Histological features of the genital lesion were almost consistent with lichenoid tissue reaction. A few intraepidermal acantholytic keratinocytes were also seen in the suprabasal clefts. Direct immunofluorescence exhibited cell surface immunoglobulin (Ig)G deposition and linear deposition of fibrinogen at the dermoepidermal junction. IgG anti-desmoglein (Dsg)3 antibody, but not anti-Dsg1 antibody, was detected in the patient's serum by enzyme-linked immunosorbent assay. Immunoblotting using normal human epidermal extract detected the 210-kD envoplakin, 190-kD periplakin and 130-kD Dsg3. The diagnosis of paraneoplastic pemphigus (PNP) was made. Subsequent investigation revealed a large space-occupying lesion in the liver. Histological findings from liver biopsy specimen were consistent with hepatocellular carcinoma. The patient has been alive 38 months after the diagnosis of PNP was made, although the liver mass has slowly enlarged. Our case is clinically and histologically similar to erosive mucosal lichen planus. Immunological studies confirmed the diagnosis of PNP. The results of negative Dsg1 and positive Dsg3 were consistent with clinical features showing severe mucosal involvement without cutaneous erosion. In PNP, the association with non-hematological solid tumor is extremely rare.

Possible paraneoplastic syndrome case of bullous pemphigoid with immunoglobulin G anti-BP180 C-terminal domain antibodies associated with psoriasis and primary macroglobulinemia.

A 61-year-old Japanese man developed bullous skin lesions during topical therapy for psoriasis vulgaris. Physical examination demonstrated numerous tense bullae and scaly erythemas on the trunk and extremities. Histopathology of the skin biopsy demonstrated subepidermal bullae and lymphocytic infiltration with eosinophils in the dermis. Direct immunofluorescence revealed linear deposits of immunoglobulin (Ig)G, IgA and C3 along the basement membrane zone. Indirect immunofluorescence of 1 mol/L NaCl-split skin showed IgG reactivity with both epidermal and the dermal sides. IgM reactivity with both the epidermal and dermal sides was also detected. Enzyme-linked immunosorbent assays showed negative results for both BP180 and BP230. Immunoelectrophoresis of serum and bone marrow aspiration revealed underlying primary macroglobulinemia with M-proteinemia of IgM-κ type. Immunoblot analysis revealed IgG, but not IgM, antibodies to recombinant protein of BP180 C-terminal domain. We diagnosed the present case as bullous pemphigoid with IgG anti-BP180 C-terminal domain autoantibodies associated with primary macroglobulinemia and psoriasis vulgaris. Systemic administration of prednisolone 30 mg/day resulted in dramatic improvement of both bullous and psoriatic skin lesions. When the bullous and psoriatic lesions relapsed, DRC chemotherapy (dexamethasone, rituximab and cyclophosphamide) for macroglobulinemia was performed. Then, the psoriatic lesions improved and the bullous lesions disappeared. We suggested that the present case may be paraneoplastic syndrome of bullous pemphigoid associated with primary macroglobulinemia and psoriasis vulgaris.

Disseminated extrafacial rosacea with papulonecrotic lesions.

BACKGROUND: Rosacea is a common skin disease and predominantly affects on the face of middle-aged women. It exceptionally occurs on the extrafacial areas such as ear, neck, axilla, and upper extremities, and has been reported as disseminated rosacea. MAIN OBSERVATION: A 40-year-old Japanese female presented with one-month history of erythematous skin eruption with burning sensation on the face, neck, and upper limbs. Physical examination showed rosacea-like eruption on the face as well as multiple papules disseminated on the neck, forearms, and hands. These extrafacial lesions demonstrated papulonecrotic appearance. Bilateral conjunctiva showed marked hyperemic which was consistent with ocular rosacea. Corneal opacity was also seen. Histology of the umbilicated papule on the neck revealed necrobiotic granulomas around the hair follicle with transepidermal elimination. Another tiny solid papule on the forearm suggesting early lesion also demonstrated necrobiosis with palisading granuloma but no transepidermal elimination. Systemic administration of minocycline and topical tacrolimus therapy promptly improved the skin lesions. Topical application of fluorometholone in temporary addition with levofloxacin improved ocular involvement 12 weeks after her 1st visit. The clinical course of the skin lesion and ocular symptoms mostly correlated. Then, the skin lesion and ocular symptoms often relapsed. Rosacea uncommonly associates with the extrafacial involvement as disseminated rosacea. The present case is characterized by the disseminated papulonecrotic lesions of the extrafacial areas histologically showing transepidermal elimination of necrobiotic granulomas. CONCLUSIONS: Dermatologists should recognize that papulonecrotic lesions of the neck and upper extremities might be extrafacial rosacea when the patient has rosacea on the face.

Cheek and periorbital peculiar discoid lupus erythematosus: rare clinical presentation mimicking tinea faciei, cutaneous granulomatous disease or blepharitis.

We present clinically peculiar facial discoid lupus erythematosus (DLE) that mimicked tinea faciei. Although DLE is a chronic autoimmune dermatosis, it has a variety of rare clinical presentations, including periorbital DLE, comedonic DLE and hypertrophic DLE recently. In this case, a scaly, erythematous lesion on the eyelid and the central healed, mildly elevated, annularly distributed facial DLE mimicked tinea faciei, complicating our diagnosis.

Vasoactive intestinal peptide and cytokines enhance stem cell factor production from epidermal keratinocytes DJM-1.

Stem cell factor can induce mast cell proliferation and melanocyte activation. Vasoactive intestinal peptide has been suggested to play a part in inflammatory dermatoses, such as atopic dermatitis. The aim of this study was to investigate the possible role of stem cell factor in atopic dermatitis by analyzing epidermal stem cell factor production induced by vasoactive intestinal peptide and cytokines. Full-length type stem cell factor transcript was detected in normal human epidermal keratinocytes, and a human epidermal keratinocyte cell line DJM-1, as well as normal human dermal fibroblasts, using reverse transcription-polymerase chain reaction. Spliced-type stem cell factor transcript was detected in both DJM-1 cells and normal human epidermal keratinocytes. Western blot analysis with stem cell factor antibody revealed a protein of the known molecular size of membrane-bound stem cell factor in the lysates of all three cell types. Stem cell factor immunoreactivity was found in the cytoplasm and the membrane of both DJM-1 cells and normal human epidermal keratinocytes using confocal laser scanning microscope. We examined the effects of vasoactive intestinal peptide and cytokines on stem cell factor production of DJM-1 cells using enzyme-linked immunosorbent assays. Stem cell factor contents significantly increased in culture supernatants of DJM-1 cells treated with 1000 nm vasoactive intestinal peptide and/or cytokines, including interleukins 4 and 13, tumor necrosis factor-alpha, and interferon-gamma. Overall, these results suggest that several inflammatory cytokines (T helper 1 and 2) and vasoactive intestinal peptide from mast cells and nerve endings are capable of inducing stem cell factor production from epidermal keratinocytes in atopic dermatitis.

Serum levels of vasoactive intestinal peptide are elevated in patients with atopic dermatitis.

Vasoactive intestinal peptide (VIP) has been suggested to play some roles in atopic dermatitis. Tissue of VIP levels has been reported to increase in chronic lichenified lesions of atopic dermatitis (AD). To analyze whether serum levels of VIP in AD patients are elevated compared with normal controls and correlated with the disease severity, we measured serum levels of VIP using enzyme-linked immunosorbent assay in 53 patients with AD and 21 healthy individuals. The results showed that serum levels of VIP in AD patients (345.8+/-71.5 microg/ml) were significantly higher than those in healthy individuals (307.1+/-42.6 microg/ml). However, a correlation was not found between serum VIP levels and disease severity, other markers including serum LDH levels, total serum IgE levels, and peripheral blood eosinophil counts in patients with AD. This indicates that VIP levels in AD patients were elevated not only in the skin but also in the serum, suggesting that increased serum VIP levels in the patients with AD might be involved in its pathogenesis.

Activation of mast cells within a tumor of angiosarcoma: ultrastructural study of five cases.

The accumulation of mast cells around tumors is a well-recognized phenomenon in a number of malignancies, including basal cell carcinoma, melanoma, and breast cancer. However, little information exists regarding mast cells within tumor nests. To clarify the role of mast cells infiltrating in skin cancers, we examined the morphological features of mast cells within tumors of five cases of angiosarcoma, including two patients with Stewart-Treves syndrome, by electron microscopy. In light microscopy, mast cells were observed within tumor nests at various densities and exhibited weak staining intensity with toluidine blue. By electron microscopy, most of the tumor-infiltrating mast cells exhibited anaphylactic or piecemeal degranulation, indicating that the mast cells had been activated in situ. Some mast cells were noted in close apposition to tumor cells, suggesting the existence of direct cell-to-cell interactions. Tumor cells adjacent to mast cells showed no degenerative changes. In conclusion, these results suggest that careful histologic examination in combination with electron microscopy should enable us to identify more mast cells within cancer lesions with greater sensitivity than in a number of prior reports. Furthermore, the close proximity of mast cells and surrounding tumor cells suggests some biologically significant role of mast cells in the development of angiosarcoma, including tumor growth as well as host immunity and stromal reaction.