Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.

IgA pemphigus reacting exclusively to desmoglein 3.

IgA pemphigus is a rare disease which is classified into two major types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN). The autoantigen of the SPD type was identified as desmocollin1 (Dsc1), while the antigen of the IEN type is still unknown. We report a case of IgA pemphigus possessing antibodies exclusively against desmoglein3 (Dsg3). The patient also had ulcerative colitis, clinically severe oral mucosal lesions with pustule formation, and the "sunflower-like" pustular skin lesions. Histopathology showed intraepidermal bullae with numerous neutrophils. Direct immunofluorescence showed IgA deposits in the keratinocyte cell surfaces only in the lower epidermis. Indirect immunofluorescence using normal human skin as a substrate showed circulating IgA anti-cell surface autoantibodies at a titer of 1:160. cDNA transfection test for Dsc1-3 was negative. IgA antibodies to Dsg3, but not Dsg1, were detected with IgA-ELISA for Dsgs. Addition of diaphenylsulfone (DDS) to prednisolone and cyclosporine A significantly improved the oral and skin lesions. There have been rare cases showing IgA antibodies to either Dsg1 or Dsg3. These cases can be designated as IgA pemphigus foliaceus or IgA pemphigus vulgaris, respectively, according to the autoantigens. We report here a case of IgA pemphigus vulgaris complicated by ulcerative colitis.

Papillon-Lefèvre syndrome and malignant melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma patients.

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.

Case of hypereosinophilic syndrome with cutaneous necrotizing vasculitis.

A 25-year-old male presented with pruritic papules over his trunk and extremities. The pruritic eruption had appeared on the arms 5 months before and gradually spread over the trunk. Blood tests showed a white blood cell count of 13 760/microL with 42.2% eosinophils. A skin biopsy from the leg revealed necrotizing vasculitis in the upper dermis with prominent eosinophil infiltration in the dermis and subcutis. Liver dysfunction in accordance with eosinophilia was also seen. The underlying disorder causing the eosinophilia was not detected. We diagnosed this case as hypereosinophilic syndrome. Although systemic corticosteroid therapy using prednisolone was effective, the symptoms recurred during a reduction of prednisolone. The addition of cyclosporine resulted in improvement of his symptoms. Both drugs were successfully tapered without relapsing symptoms. Hypereosinophilic syndrome with cutaneous necrotizing vasculitis is a rare condition, and this case suggests that cyclosporine may be a useful therapeutic adjunct in facilitating steroid tapering.

Six novel mutations of the ADAR1 gene in patients with dyschromatosis symmetrica hereditaria: histological observation and comparison of genotypes and clinical phenotypes.

Dyschromatosis symmetrica hereditaria (DSH), is a pigmentary genodermatosis of autosomal dominant inheritance. Since we clarified that the disease is caused by a mutation of the adenosine deaminase acting on the RNA 1 gene (ADAR1) in 2003, the molecular pathogenesis of a peculiar clinical feature of the disease has been expected to be clarified. We examined five familial cases and one sporadic case of Japanese families with DSH. The mutation analyses were done with single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and direct sequencing of ADAR1. The DNA analysis of each patient revealed one missense mutation (p.F1091S), two nonsense mutations (p.C893X, p.S581X) and three frame-shift mutations (p.E498fsX517, p.F1091fsX1092, p.L855fsX856). Visual and electron microscopic findings showed abundant melanin pigment deposited all over the basal layer, and enlarged melanocytes with long dendrites located in the pigmented lesions with small or immature melanosomes scattered sparsely in the cytoplasm, but in the adjacent keratinocytes many small melanosomes were singly dispersed or aggregated. The hypopigmented areas showed little melanin deposition and reduced numbers of melanocytes in which much degenerative cytoplasmic vacuole formation could be observed by electron microscopy. Herein, we report six cases of DSH with six novel mutations. The variety of their clinical phenotypes even in the pedigree may suggest the presence of factors other than the ADAR1 gene influencing the extent of the clinical skin lesion. Microscopic findings suggest that the clinical appearance must have developed directly by melanocyte variations mainly induced by the ADAR1 gene mutations.

Costello syndrome showing moyamoya-like vasculopathy.

This report describes a patient with Costello syndrome associated with moyamoya-like vasculopathy. His clinical findings were sparse, thin, and light-colored hair, bilateral ptosis, low-set ears, depressed nasal bridge, bulbous nose, short neck, loose pigmented skin with deep palmar and plantar creases, bilateral cryptorchidism, and delays in growth and development. Brain magnetic resonance imaging and cerebral angiography revealed moyamoya-like vasculopathy. A skin biopsy from the extensor surface of the right thigh revealed shortening and rupture of elastic fibers. Electron microscopy indicated reduced depositions of elastin. Formation of a stable elastic fiber system may be impaired in patients with Costello syndrome, and brain magnetic resonance imaging and magnetic resonance angiography would be recommended for these patients.

Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis.

Vitamin D3 ointments containing active forms of vitamin D3 are widely used to treat inflammatory keratotic dermatoses such as psoriasis. Senile wart or seborrheic keratosis is a benign tumor which occurs mainly in the elderly. It has traditionally been treated with surgical procedures, freezing with liquid nitrogen, or laser therapy. We treated senile warts with topical vitamin D3 ointments (tacalcitol, calcipotriol or maxacalcitol). Out of 116 cases treated for 3 to 12 months, 35 (30.2%) showed complete disappearance or more than an 80% decrease in the volume of the tumor, 54 cases (46.6%) showed a decrease in the volume between 40 and 80%, and no remarkable changes or decreases of less than 40% were seen in 27 cases (23.3%). The tumors faded without any inflammatory changes such as erythema or swelling. An organ culture experiment using senile wart as a material with several concentrations of tacalcitol revealed that tacalcitol induced apoptosis in the tissue. On the other hand, only sporadic apoptotic cells were seen in the controls (p<0.001). Vitamin D3 may affect senile warts by inducing apoptosis. Clearance of senile warts, especially on exposed areas without pain, may improve the quality of life (QOL) of the elderly.

Erythema Dyschromicum Perstans: Identical to Ashy Dermatosis or Not?

Erythema dyschromicum perstans (EDP) and ashy dermatosis (AD) are pigmentary disorders of unknown etiology. EDP is usually considered to be identical to AD; however, a new clinical classification for EDP was proposed in the recent literature. Herein, we report a typical case of EDP observed in an African-American man. Interestingly, the late skin lesions in this case fit the criteria of AD as well. While there appear to be a few clinical cases that can be diagnosed as both EDP and AD based on the clinical course, the preponderance of the evidence in the published reports of EDP and AD and the clinical findings reported here strongly suggest that they are two distinct entities in terms of the extent of the inflammation, albeit on the same spectrum of pigment disorders.

Family with Legius syndrome (neurofibromatosis type 1-like syndrome).

Legius syndrome (Online Mendelian Inheritance in Man no. 611431) or neurofibromatosis type 1 (NF1)-like syndrome was first reported by Legius et al. in 2007. We herein report the first instance of Legius syndrome occurring in two female siblings in Japan. Both individuals presented cafe-au-lait macules and freckling. Mutation analysis revealed a mutation of c.349C>T resulting in p.Arg117* in the SPRED1 gene as the cause of the Legius syndrome. The National Institutes of Health criteria for NF1 are insufficient to rule out the condition. For this reason, and because the clinical course of each condition is quite different, we stress the need to differentiate Legius syndrome from NF1 clearly.

Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families.

Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing. We identified 18 mutations, of which 13 were novel and seven (39%) were recurrent. The majority of the mutations were clustered between exons 1-8 and exons 21-26. They comprised four nonsense mutations (22%), eight frameshift insertions or deletions (44%), and six splice-site defects (33%). All mutations predict the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes, and five were heterozygotes with only one identifiable SPINK5 mutation. Five mutations, one of which resulted in perinatal lethal disease in three families, were associated with certain ethnic groups. We also describe 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals and ichthyosis linearis circumflexa was seen in 12 out of 24 patients. Interfamilial and intrafamilial variation in disease severity was observed, with no clear correlation between mutations and phenotype, suggesting that the degree of severity may be affected by other factors.

Genetic abnormalities and clinical classification of epidermolysis bullosa.

Genetic abnormalities for different subtypes of epidermolysis bullosa (EB) have been described. In dominant simplex type EB, mutations of the K5 or K14 gene lead to disruption of basal cells and the formation of bullae. The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations. In junctional EB, mutations of the laminin 5, type XVII collagen, and alpha 6 beta 4 integrin genes have been reported. Dystrophic type EB is associated with various abnormalities of the type VII collagen gene. A new classification of EB based on these genetic abnormalities has been proposed. However, some concern has been voiced regarding the clinical utility of a classification based solely on genetic abnormalities. Although the reasons are unclear, identical genetic abnormalities have been known to be associated with different clinical features. A classification including a component based on clinical features would therefore be preferable. This article describes recently discovered genetic abnormalities and offers a new classification scheme for EB.

Iatrogenic hypercalcemia due to vitamin D3 ointment (1,24(OH)2D3) combined with thiazide diuretics in a case of psoriasis.

Tacalcitol is a synthetic vitamin D3 analogue developed for topical treatment of inflammatory skin diseases such as psoriasis. Hypercalcemia has not been previously reported during treatment with topical tacalcitol. We experienced a male patient with psoriasis and hypertension whose conditions were treated with tacalcitol ointment and thiazide, respectively, resulting in hypercalciuria and hypercalcemia. After initiation of topical vitamin D3 ointment (20 micro g/g of tacalcitol) 10 g/day for the skin lesions, both the serum level of calcium and urinary excretion of calcium increased gradually. On day 28 of the treatment, his serum calcium levels had reached 3.55 mmol/l, and his urinary calcium excretion had also increased from 0.008 g/day to 0.475 g/day. The tacalcitol treatment was terminated, seven days later, the serum calcium level had returned to the reference range without any specific treatment. The present case is the first report of hypercalcemia induced by vitamin D3 ointment and thiazide simultaneously.

Immunohistochemical differentiation of extra-ocular sebaceous carcinoma from other skin cancers.

We performed an immunohistochemical study using routinely processed formalin-fixed and paraffin-embedded tissue specimens from 26 cases of extra-ocular sebaceous carcinoma (EOSC) and eight easily available antibodies. They were polyclonal anti-carcinoembryonic antigen (CEA) antibody, monoclonal anti-CEA antibody, anti-breast carcinoma associated antigen-225 antibody (CU18), anti-CA15.3 antibody (CA15.3), anti-CD15 antibody (CD15), anti-breast carcinoma associated antigen antibody (B6.2), anti-gross cystic disease fluid antigen-15 antibody (GCDFP15) and anti-Thomsen-Friedenreich antigen antibody (TFA). Squamous cell carcinoma, porocarcinoma, syringomatous carcinoma, malignant clear cell hidradenoma, apocrine adenocarcinoma, and extramammary Paget's disease with underlying adenocarcinoma were used as controls. EOSC was positive for CU18 and CA15.3 in most cases, and for CD15 in a few cases. Squamous cell carcinoma of the skin was positive for CA15.3 in only one case. Porocarcinoma, syringomatous carcinoma and malignant clear cell hidradenoma were positive for CEA, CU18, CA15.3, and B6.2 in most cases. Apocrine adenocarcinoma and extramammary Paget's disease with underlying adenocarcinoma were positive for CEA, CU18, CD15, GCDFP15, CA15.3, and B6.2 in most cases. TFA was positive not only in EOSC but also in other skin cancers. Immunohistochemical examinations using these seven of eight antibodies except for TFA and routinely processed formalin-fixed and paraffin-embedded tissue specimens are beneficial in differentiating EOSC from other skin cancers.

Hydroa vacciniforme-like eruptions in a patient with chronic active EB virus infection.

We report a case of chronic active Epstein-Barr (EB) virus infection (CAEBV) associated with skin eruptions mimicking hydroa vacciniforme (HV) in a 4-year-old boy. The patient had repeated episodes of vesiculo-necrotic eruptions on the face, scalp, and bilateral forearms one year before the first visit to our department. General symptoms including fever, hepatosplenomegaly, abnormal liver function, and cervical lymph node swelling were noted three months before the first visit. At the first visit, small, bean-sized, erythemic papules with central necrosis were observed on the face and anterior chest wall. Thumb-sized ulcers with crust were present on the bilateral forearms. Histopathological examination of an erythematous lesion in the submandibular area revealed parakeratosis with a thick crust, mild spongiosis in the epidermis, and a dense infiltration of lymphoid cells into the dermis and perivascular space. Laboratory examination showed EBNA x 40, EBV VCA IgG x 1,280, and EBV DNA (PCR) 8 x 10(4). EBV-encoded small nuclear RNA (EBER) positive cells were detected in the dermis by an in situ hybridization (ISH) method. Large granular lymphocytes (65%) with the NK cell phenotype were found in the peripheral blood. A real time PCR method showed 171,741 copies/ micro g DNA in CD 16 positive cells. Although latent EBV infection-associated eruptions have been documented, detailed skin manifestations in CAEBV are less well known.

A case of labial adhesion due to lichen sclerosus et atrophicus.

A 67-year-old Japanese woman first visited to the hospital in regard to episodes of a 6 months history of difficulty on urination. Her perineum was mild whitish, and labia majorae were all adhered with only a pinhole-sized opening. A labial incision was performed under a spinal anesthesia. Pathological finding of the skin biopsy specimen was lichen sclerosus et atrophicus (LSA). In view of that LSA occasionally develops into squamous cell carcinoma, urologists should be care of LSA in labial adhesion case.

[New aspects on vitamin D3 ointment; treatment of senile warts with topical application of active forms of vitamin D3].

Vitamin D(3) ointment is widely used for the therapy of inflammatory keratotic dermatoses such as psoriasis. Senile wart (seborrheic keratosis) is a benign tumor, which occurs mainly in the elderly. It has been treated with surgical procedures, freezing with liquid nitrogen, or laser therapy. We tried to treat senile wart with active forms of topical vitamin D(3) (tacalcitol, calcipotriol or maxacalcitol). These topical vitamin D(3) ointments were applied on senile warts once or twice a day. Out of 116 cases those were treated for more than three months, 35 cases (30.2%) showed excellent response that means more than 80% of decreasing of tumor volume, 54 cases (46.6%) showed moderate response that means 40 to 80% of decreasing, 27 cases (23.2%) showed no remarkable changes or decreasing less than 40%. The tumor disappeared without any inflammatory change such as erythema or swelling. Any of side effects were not observed on all patients whose senile warts were treated with topical vitamin D(3).