Masako Minami-Hori

Podoplanin expression in wound and hyperproliferative psoriatic epidermis: Regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22

BACKGROUND Podoplanin (PDPN)/T1α/aggrus/PA2.26 antigen, a transmembranous glycoprotein, is a well-known lymphatic endothelial marker. Recent evidence indicates that PDPN is also expressed in keratinocytes especially of sebaceous glands. OBJECTIVE To verify expression-pattern and the regulatory mechanism of PDPN in human epidermal keratinocytes. METHODS PDPN-expression pattern was analyzed in normal and psoriatic epidermis by immunostaining. The regulatory mechanism of PDPN-expression of keratinocytes by cytokines was analyzed using specific inhibitors, siRNA, and adenoviral shRNA of signaling pathways. RESULTS In normal skin, PDPN was expressed on the basal cell layer of sebaceous glands and on the outer root sheath of hair follicles. While no expression was detected in the normal interfollicular epidermis, PDPN was detected in the basal cell layer of wound and hyperproliferative psoriatic epidermis, where the granular layer is lacking. TGF-β1 and IFN-γ independently upregulated PDPN-expression of keratinocytes via TGF-β receptor-Smad pathway and JAK-STAT pathway, respectively. IL-6 and IL-22 also stimulated PDPN-expression of keratinocytes accompanied by STAT-3 phosphorylation. siRNA of STAT-1, inhibitors of STAT-3 signaling, AG490, STAT-3 inhibitor VI, and si/shRNA of STAT-3 inhibited the PDPN-expression of keratinocytes induced by IFN-γ, IL-6 and IL-22 but not by TGF-β1. CONCLUSION These results indicate that TGF-β1, IFN-γ, IL-6, and IL-22 induce PDPN-expression of keratinocytes, which might be significantly involved in the wound healing process as well as in the pathomechanism of hyperproliferative psoriatic epidermis.

Defective barrier function accompanied by structural changes of psoriatic stratum corneum

Although barrier function of psoriatic skin is shown to be decreased by measuring transepidermal water loss (TEWL), few reports exist examining other physical skin properties and components including stratum corneum hydration, natural moisturizing factor (NMF), free fatty acids (FFA), β‐sheet and α‐helix ratio of structural protein(s), and sebum content. We compared the skin properties and components of normal, involved and uninvolved skin of psoriasis. Using a corneometer and attenuated total reflection‐infrared spectrometer, we measured TEWL, stratum corneum hydration, NMF, FFA, β/α ratio and sebum in psoriasis vulgaris patients and healthy controls. TEWL and β/α ratio of involved psoriatic skin were significantly increased compared with uninvolved skin and normal control skin. In contrast, stratum corneum hydration, NMF and FFA, but not sebum, are significantly decreased in the involved skin compared with uninvolved skin and normal skin. TEWL and stratum corneum hydration returned to the normal levels following clinical improvement of the lesion. Barrier function and hydration of psoriatic skin are defective and secondary structure in stratum corneum protein is altered in the involved psoriatic skin.

IL36RN mutations underlie impetigo herpetiformis.

TO THE EDITOR Impetigo herpetiformis (IH) is a rare pustular dermatosis that typically occurs in pregnant women sporadically with unknown etiology (Sauer and Geha, 1961). Early diagnosis is essential, as IH is life-threatening and is associated with placental insufficiency and electrolyte abnormalities. IH appears to have the same clinical and histologic appearance as generalized pustular psoriasis (GPP), which is also a rare severe episodic pustular dermatosis that occurs repeatedly in both sexes at any age. However, some researchers have regarded IH as an entity distinct from GPP, because some patients are affected by IH only in the gestational period (Lotem et al., 1989). Recently, we reported that the majority of GPP that is not accompanied by psoriasis vulgaris (PV; GPP alone) is caused by homozygous or compound heterozygous mutations of IL36RN, which encodes IL-36 receptor antagonist (IL36RN), although only a small number of cases with GPP preceding or accompanied by PV (GPP with PV) were found to have IL36RN mutations (Sugiura et al., 2013). Very recently, we reported that CARD14 c.526G4C is a significant risk factor for GPP with PV, but not for GPP alone in the Japanese cohort, which further supports the idea that GPP with PV differs genetically from GPP alone (Sugiura et al., 2014a). However, to our knowledge, there have been no reports of IH with IL36RN mutations. Here we report two cases of IH with homozygous and heterozygous IL36RN mutations. Cases 1 and 2 were a 23-year-old woman and a 28-year-old Japanese woman who were admitted to our hospitals for pustular lesions in the 29 week and the 20 week of their first pregnancies, respectively (Figure 1a and b). There was no family history of GPP, no IH, and no consanguinity in their families. Case 1 had no previous history of GPP. Her pustular lesions had begun to develop at the 21 week of pregnancy, and she had been hospitalized in a maternity hospital. Oral prednisolone at a dose of 15 mg per day had been administered, but the eruptions had persisted. A skin biopsy from a pustular eruption on the trunk revealed a spongiform pustule of Kogoj in the epidermis consistent with IH (Figure 1c). Case 2 had suffered from GPP from the age of 8 to 18 years. Skin biopsies from pustular eruptions on the trunk revealed spongiform pustules of Kogoj in the epidermis at the age of 8 and 28 years (Figure 1d). She had been admitted to hospitals four times for GPP flare-ups. She had been treated with cyclosporine or etretinate. In the ten years leading up to her pregnancy, her GPP had been in remission without any treatment. Both cases had erythema with pustules over the whole body and fever of over 38 1C. Blood examinations from Cases 1 and 2, respectively, revealed white blood cell counts of 12,000ml 1 and 21,170ml , and C-reactive protein concentrations of 6.5 and 14.9 mg dl 1 (normal range: o0.3 mg dl ). Bacterial cultures of the pustules were negative. Thus, Cases 1 and 2 were, respectively, diagnosed as having IH and IH with a previous history of GPP. Following ethical approval, written informed consent was obtained in compliance with the Declaration of Helsinki Principles. The entire coding regions of IL36RN including the exon/intron boundaries were sequenced using genomic DNA samples from the patients. Case 1 had the homozygous mutation c.115þ6T4C, which was proven to result in p.Arg10ArgfsX1 in IL36RN by us previously, and Case 2 had the heterozygous mutation c.28C4T (p.Arg10X) in IL36RN. Both of these are GPP-causing founder mutations in the Japanese cohort (Sugiura et al., 2013, 2014b; Figure 1e and f, and Figure 2). A search for a second IL36RN mutation in all intron and putative promoter regions in Case 2 revealed no other IL36RN mutations (Supplementary Figure S1 online and Supplementary Table S1 online). However, there is still the possibility of a second unidentified IL36RN mutation in Case 2. More than 10 cases of GPP with heterozygous IL36RN mutations have been reported (Capon, 2013; Korber et al., 2013; Li et al., 2013; SettaKaffetzi et al., 2013; Sugiura et al., 2013). Moreover, in some patients, heterozygous IL36RN mutations are associated with palmoplantar pustulosis, a type of pustular psoriasis, and acute generalized exanthematous pustulosis, a severe cutaneous drug reaction (Navarini et al., 2013; SettaKaffetzi et al., 2013). IL-36 is absent in normal skin but is induced by inflammatory cytokines such as tumor necrosis factor-a, IL-17A, and IL-22 (Carrier et al., 2011). When functional IL-36RN is absent or underproduced, overexpressed IL-36 can induce neutrophilrich infiltration. Tumor necrosis factor-a is often elevated in the blood of pregnant women, whereby it induces various serious diseases (Mallmann et al., 1991). As for skin diseases, tumor necrosis factor-a sometimes causes exacerbation of PV lesions in pregnant women (Puig et al., 2010). Hence, it is very likely that a pregnant woman who has the IL36RN mutation occasionally cannot produce enough IL-36RN to adequately antagonize IL-36 excessively induced by inflammatory cytokines, and this imbalance results in IH. After longstanding controversy over whether IH is an independent disease Accepted article preview online 9 April 2014; published online 1 May 2014 Abbreviations: GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; IL-36RN, IL-36 receptor antagonist; PV, psoriasis vulgaris K Sugiura et al. IL36RN Mutations and IH

Developmental alterations of physical properties and components of neonatal-infantile stratum corneum of upper thighs and diaper-covered buttocks during the 1st year of life.

BACKGROUND Although physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated. OBJECTIVE To determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults. METHODS Nineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS. RESULTS SC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the ω-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development. CONCLUSION Our results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development.

Novel postzygotic KRAS mutation in a Japanese case of epidermal nevus syndrome presenting with two distinct clinical features, keratinocytic epidermal nevi and sebaceous nevi.

Dear Editor, Epidermal nevus syndrome (ENS) is a heterogeneous congenital disorder characterized by the presence of epidermal nevi associated with systemic involvement. Keratinocytic epidermal nevus (KEN) syndrome and sebaceous nevus (SN) syndrome are included in ENS which share the same postzygotic HRAS and KRAS gene mutations that are relevant for cell proliferation. A HRAS mutation can induce nevus marginatus, a combined nevus of KEN and SN, and this suggests an identical genetic background of KEN and SN. Here, we report a case of ENS exhibiting both KEN and SN characteristics caused by a novel postzygotic KRAS mutation. A 3-year-old Japanese girl presented with multiple nevoid lesions along Blaschko lines on the left side of her body that she had had since birth. The skin lesions, which were light red at the neonatal stage (Fig. 1a), had transformed into two distinct types: yellowish plaques suggesting SN on the sebaceous gland-rich craniofacial area, and brownish verrucous lesions suggesting KEN on the trunk and extremities (Fig. 1b). Histological evaluation showed papillomatosis and acanthosis with overlying laminated hyperkeratosis (Fig. 1c,d).

Cornoid lamellae associated with follicular infundibulum and acrosyringium in porokeratosis

Skin lesions of porokeratosis consist of an atrophic center bordered by a peripheral grooved keratotic ridge that corresponds histopathologically to the cornoid lamella. Originally porokeratosis was named based on the assumption that the columns of parakeratosis emerge from the ostia of eccrine ducts. Despite this, it is generally accepted that the cornoid lamellae are rarely related to the acrosyringium. We recently encountered two cases of porokeratosis, where the cornoid lamellae were related to the follicular infundibulums. Therefore, we analyzed the location of the cornoid lamellae in 86 lesions of porokeratosis from 73 patients from our archives. We found that many cornoid lamellae are also detected at follicular infundibulum and acrosyringium. The existence of so many cornoid lamellae at follicular infundibulum and acrosyringium inside the plaques cannot be explained by pure coincidence and may be more than fortuitous.

Correlation of disease activity and serum level of carcinoembryonic antigen in acquired idiopathic generalized anhidrosis: A case report

Hypohidrosis and anhidrosis are congenital or acquired conditions which are characterized by inadequate sweating. Acquired idiopathic generalized hypohidrosis/anhidrosis (AIGA) includes idiopathic pure sudomotor failure (IPSF), which has the following distinct features: sudden onset in youth, increased serum immunoglobulin E and responds favorably to systemic corticosteroid. No clinical markers reflecting the disease severity or activity have been established. Here, we report a case of AIGA in a Japanese patient successfully treated with repeated methylprednisolone pulse therapy. In this case, serum carcinoembryonic antigen (CEA) levels increased up to 19.8 ng/mL along with aberrant CEA immunoreactivity of eccrine sweat glands. Interestingly, the serum CEA level normalized as sweating improved with repeated methylprednisolone pulse therapy. Therefore, serum CEA level may serve as a useful clinical marker of hypohidrosis or anhidrosis.

Transient perforating folliculitis induced by sorafenib

Figure 1. Isolated, dark-red papules with central coneshaped keratotic plugging surrounded by erythema. Dear Editor, Sorafenib is an oral multikinase inhibitor originally developed as a Raf-1 kinase inhibiting agent, but has been demonstrated to inhibit other kinases such as vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, plateletderived growth factor receptor-b, and FLT3, as well. Cutaneous side-effects (including hand–foot syndrome, facial erythema, alopecia, xerosis, pruritus and subungual splinter hemorrhages) are frequently associated with sorafenib. Rarely, the drug induces perforating folliculitis (PF), keratosis pilaris-like eruption and follicular hyperplasia. Herein, we present a case of PF associated with sorafenib. To our knowledge, this is the first report of sorafenib-associated PF in Japan. A 77-year-old Japanese man was treated with sorafenib (two doses of 400 mg ⁄day) for metastatic renal cell carcinoma. Two weeks after the onset of the therapy, he noticed hair loss, which was followed by typical hand–foot syndrome with symmetrical red palms and soles and patchy hyperkeratosis on plantar pressure areas. Sorafenib was continued without lowering the dose and 7 weeks after the beginning of the therapy asymptomatic, solitary dark-red papules of up to 6 mm surrounded by erythema developed on the extensor side of the lower extremities, on buttocks and lumbar area (Fig. 1). Each papule contained a central cone-shaped keratotic plug. Histopathological examination disclosed prominent keratotic plugging, and dilated follicular infundibula filled with compact parakeratotic cornified cells, an example of which can be seen in Figure 2a. Neutrophils were infiltrating into the cornified cells. Upper follicular epithelial cells showed marked vacuolization (Fig. 2b) and dyskeratosis. Perifollicular lymphocytic infiltration and vascular proliferation were also noticed. The patient was diagnosed with PF associated with sorafenib. Although topical corticosteroid therapy

Serum carcinoembryonic antigen (CEA) as a clinical marker in acquired idiopathic generalized anhidrosis: a close correlation between serum CEA level and disease activity

Hypohidrosis/anhidrosis are congenital or acquired sweating impairments. Among them, acquired idiopathic generalized anhidrosis/hypohidrosis (AIGA) is the most common, and characterized by favourable response to systemic corticosteroid, however, no clinical markers for disease severity or activity have been developed.

Olanzapine‐induced limb edema simulating episodic angioedema with eosinophilia

fragments on and around the left orbital region (Fig. 1a). The fragments had slightly injured the left cornea. Dermoscopy revealed tiny dust and metal particles (arrows) mostly on or partly inside the skin (Fig. 1b), which we removed through careful and intensive brushing with a toothbrush. The brushing was performed after wiping off the gels. The left cornea was carefully washed and the particles were removed. On 22 July, we used dermoscopy to evaluate the treatment (Fig. 1c) and confirmed that most of the particles had been eliminated (Fig. 1d). A second dermoscopic evaluation on 3 August showed similar results, with the remaining particles forming a traumatic tattoo (Fig. 1e,f). Dermoscopy was useful for evaluating the precise appearance of particles on and within the skin. It could be used as a guide for brushing with a toothbrush before treatment, because the distribution of metal particles is the most important point of treatment. It was also a useful tool for assessment after treatment. Using dermoscopy, we were able to brush the affected lesion sufficiently and eliminate almost all of the metal particles, even though some particles remained as a tattoo. Qswitched ruby laser, Q-switched alexandrite laser and Qswitched 1064-nm neodymium:yttrium–aluminum–garnet laser would be useful for the residual fragments. Future victims may benefit from dermoscopic evaluation of their treatments.