Takayuki Aizu

Papillon-Lefèvre Syndrome and Malignant Melanoma

Papillon-Lefèvre syndrome (PLS) is a rare autosomal-recessive genodermatosis characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The development of malignant cutaneous neoplasms within the hyperkeratotic lesions of the syndrome is quite rare. Here, we report on a 51-year-old Japanese woman with PLS associated with recurrent malignant melanoma (MM). Mutation analysis of the cathepsin C gene revealed that the proband was homozygous for a missense mutation, c.415G→A, which is predicted to result in the amino acid substitution p.G139R. Including our case, 4 families have been described as having PLS with MM, 3 of which are Japanese, implying a high incidence of melanoma development in Japanese PLS patients. We suggest that hereditary palmoplantar keratoderma (PPK) in Japanese patients might be predisposed to MM. A literature review revealed that in 18 cases of MM-associated PPK, 13 (76%) were Japanese, suggesting a high incidence of MM in Japanese PPK patients. This tendency might be attributable to the high frequency of acral lentiginous melanoma in Japanese subjects, in contrast to a lower frequency of this subtype in Caucasians.

Significance of sentinel node biopsy in the management of squamous cell carcinoma arising from recessive dystrophic epidermolysis bullosa

The most life‐threatening complication developing in patients with recessive dystrophic epidermolysis bullosa (RDEB) is squamous cell carcinoma (SCC). To improve patient prognosis, early detection of regional lymph node metastasis is required. Herein, we report a patient diagnosed with non‐Hallopeau–Siemens RDEB who developed SCC on the left foot with inguinal lymph node swelling. Use of the sentinel node biopsy (SNB) technique favorably minimized defective damage to the inguinal region in this case. Genetic analysis identified one novel COL7A1 mutation, a maternal c.238G > C (p.A80P) and one previously reported mutation, a paternal c.3631C > T (p.Q1211X). A published work review demonstrated that no COL7A1 mutations specific for SCC development in RDEB have previously been identified. It remains unclear if SNB in combination with gene diagnosis is beneficial for the management of SCC in RDEB patients, however, because of the limited number of case reports. To address this issue, COL7A1 mutational analysis should be performed in as many cases of RDEB as possible.

A case of bullous dermatitis artefacta possibly induced by a deodorant spray

Dermatitis artefacta is one of a spectrum of factitious diseases etiologically responsible for skin lesions denied by patients. These factors often make it difficult to identify the causative agents of the condition. Herein, we report a case of bullous dermatitis artefacta in a 12‐year‐old girl, for which a deodorant spray was suspected as the probable cause. Pathological examination revealed subepidermal blistering with full‐thickness necrosis of the epidermis, suggesting a thermo‐ or cryo‐induced injury. Psychological testing demonstrated her immaturity and dependence. In searching for the causative agent, we suspected a deodorant spray as a blister‐inducing agent. We succeeded in reproducing a similar blister lesion on the volunteers healthy skin using the same spray. Psychiatric involvement significantly complicates the treatment of factitious diseases, including dermatitis artefacta. Cooperation among dermatologists, psychiatrists and the patients family members is required for ensuring a favorable prognosis.

Dermoscopy of eccrine poroma with calcification.

BACKGROUND Eccrine poromas are relatively common slow-growing benign solitary adnexal tumors originating from the intraepidermal portion of the eccrine sweat duct (acrosyringium). Dystrophic calcification is rarely found in lesions of eccrine poroma, and only 2 cases of eccrine poroma with calcification have been reported thus far. In the present report, we describe another case of eccrine poroma with calcification occurring in the palm of the hand. Also, we show dermoscopic features of this case. MAIN OBSERVATIONS A 73-year-old man with hemiparesis, who had a 10-year history of tumor on his right palm, which was occasionally injured by a walking crutch, causing bleeding and ulceration. Physical examination revealed a pigmented dome-shaped tumor. Dermoscopic analysis revealed glomerular vessels, multiple pink-white structureless areas, and lacunae. Histological examination revealed that the tumor was composed of cords of tumor cells extending from the epidermis into the dermis. These were uniformly cuboidal cells with round, basophilic nuclei and dense vascular stromas with telangiectasia. The tumor showed cystic structures and calcification. The patient was diagnosed with Pinkus-type eccrine poroma on the basis of histological findings. CONCLUSIONS Although cutaneous neoplasms commonly associated with calcification are of follicular origin, it is known that dystrophic calcification may be triggered also in tumors of eccrine origin by multiple factors, including mechanical injury. Dermoscopy may be helpful in establishing clinical diagnosis of calcified eccrine poromas.

Calcineurin/NFAT-dependent regulation of 230-kDa bullous pemphigoid antigen (BPAG1) gene expression in normal human epidermal keratinocytes

BACKGROUND AND OBJECTIVE Cyclosporin A (CsA) is utilized widely for treatment of inflammatory skin diseases, such as psoriasis vulgaris. The therapeutic effects of CsA are thought to be mediated by its immunosuppressive action on infiltrating lymphocytes in the lesional skin. CsA also inhibits epidermal keratinocyte proliferation, suggesting a direct biological action on keratinocytes. Here we tested the hypothesis that CsA can modulate the expression of the nuclear factor of activated T-cell (NFAT) in epidermal keratinocytes. We also investigated whether the keratinocyte-specific gene expression is modified by CsA through NFAT activity in association with differentiation induction. METHODS RT-PCR was performed using total RNAs extracted from cultured normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF), and normal human epidermal melanocytes (NHEM) for detecting NFAT isomolecules. Transient transfections of NHEK with a 230-kDa bullous pemphigoid antigen (BPAG1) promoter/luciferase reporter gene and the luciferase assay were conducted for examining the effect of CsA on the promoter activity of the BPAG1 gene. Electrophoretic gel mobility shift assays (EMSA) with probes containing NFAT consensus sequences for analyzing the binding activities of the nuclear proteins extracted from NHEK. RESULTS RT-PCR revealed expression of all of the five isoforms of NFAT in the cell lines examined. The mRNA expression levels of NFAT1, NFAT2, BPAG1, and involucrin were downregulated by CsA treatment in NHEK. The luciferase assay indicated suppression of the promoter activity by CsA. EMSA with NFAT consensus probes identified in the BPAG1 promoter region demonstrated specific binding activity in the nuclear proteins of epidermal keratinocytes. CONCLUSION As reported previously, our results indicate that epidermal keratinocytes possess calcineurin/NFAT system, which is suppressed by CsA. In addition, the data suggest that CsA can downregulate the BPAG1 gene expression perhaps via the NFAT consensus cis-elements in the BPAG1 promoter region. Such transcriptional regulatory system might be involved in the regulation of keratinocyte differentiation and proliferation.

Treatment of acquired reactive perforating collagenosis with 308-nm excimer laser.

A.L. Tatu, V.Clatici and V. Cristea Department of Dermatology, Faculty of Medicine and Pharmacy, University Dunarea de Jos, Galati, Romania; Department of Dermatology, Elias Emergency Hospital, Bucharest, Romania; and Department of Laboratory Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania E-mail: dralin_tatu@yahoo.com Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 5 November 2015

Novel and recurrent nonsense mutation of the SLC39A4 gene in Japanese patients with acrodermatitis enteropathica

Acrodermatitis enteropathica (AE, OMIM 201100) is a rare autosomal recessive disease characterized by hypozincaemia derived from the inability to absorb intestinal zinc. The clinical manifestations of AE include growth retardation, diarrhoea, alopecia, repeated infections due to immune dysfunction, and characteristic skin lesions on acral and periorificial areas. The hypozincaemia in AE is believed to be caused by a defect in a zinc transporting protein. Recently, the gene encoding this zinc transporting protein was identified on chromosomal region 8q24.3, and subsequently SLC39A4 located on the chromosome was identified as the AE gene. SLC39A4 encodes the ZIP4 zinc transporter, which transports zinc into the cytoplasm, mainly in the intestine. Here, we report two Japanese families with AE, in which a novel nonsense mutation in the SCL39A4 gene was identified.

Giant pilomatricoma associated with hypercalcaemia and elevated levels of parathyroid hormone-related protein

Background  Pseudoxanthoma elasticum (PXE) is a genetic disorder due to mutations in the gene encoding the transmembrane transporter protein adenosine triphosphate binding cassette (ABC)‐C6, resulting in calcification of elastic fibres in the skin, eyes and cardiovascular system.

Oral lichen planus with antibodies to desmogleins 1 and 3

Lichen planus (LP) is a chronic inflammatory disorder involving the skin or mucous membranes. Previous studies have demonstrated that some LP patients showed positive enzyme‐linked immunosorbent assay (ELISA) for desmoglein (DSG) antibodies. We report a case with intractable painful oral lesions. ELISA indices for DSG1 and 3 antibodies were increased by 49 and 36, respectively. Histopathological analysis revealed irregular acanthosis and band‐like infiltration of lymphocytes at the dermal–epidermal interface. Direct immunofluorescence revealed negative deposits of immunoglobulin G and C3 in intracellular spaces of the epidermis. Indirect immunofluorescence of normal skin also did not detect any antibodies. Consequently, we made a final diagnosis of oral LP. The previous two LP cases with positive ELISA for DSG antibodies and our case manifested the erosive form, the most advanced oral LP. Therefore, it is a possibility that severe damage of keratinocytes may induce generation of DSG antibodies. However, negative results of immunofluorescence and no relation between disease severity and titers of antibodies make the possibility unlikely. We should measure titers of DSG antibodies in LP patients and accumulate data to establish a valid conclusion.

Functional analysis of the nuclear localization signal of the POU transcription factor Skn‑1a in epidermal keratinocytes

POU domain proteins are a family of critical regulators of development and differentiation due to their transcriptional activity in the nucleus. Skn‑1a, a member of the POU domain protein family, appears to be expressed predominantly in epidermal keratinocytes and is thought to play a critical role in keratinocyte differentiation and proliferation. In this study, we examined the mechanisms involved in the nuclear localization of Skn‑1a. We transiently expressed enhanced green fluorescent protein (EGFP) reporter constructs encoding EGFP fusions with Skn‑1a deletion and mutation proteins in normal human epidermal keratinocytes (NHEKs). The experiments clearly demonstrated that Skn‑1a contained a functional nuclear localization signal (NLS) domain, and that the smallest domain necessary for Skn‑1a nuclear transport was the GRKRKKR sequence located within amino acids 279‑285. Previous studies have shown that the phosphorylation of specific amino acids neighboring the NLS may regulate nuclear transport and that the amino acid residues threonine (Thr) and serine (Ser) have the potential to undergo phosphorylation. We examined whether the amino acids Thr286 and Ser287, which reside adjacent to the NLS at the carboxy‑terminal side, play a role in Skn‑1a nuclear localization. For this purpose, we generated three EGFP‑Skn‑1a mutation constructs, in which Thr286, Ser287, or both Thr286 and Ser287 residues were replaced with alanine, respectively. The results showed that the Thr286 and Ser287 residues were involved in the regulation of nuclear localization as well as epidermal differentiation. These results suggested that the epidermal differentiation signaling pathway, involving kinase and phosphatase activation, may regulate the NLS activity of Skn‑1a in keratinocytes. Collectively, these data contribute to understanding the mechanisms of nuclear translocation of POU domain proteins and epidermal differentiation.