Yoshihiko Mitsuhashi

Localization of the Netherton Syndrome Gene to Chromosome 5q32, by Linkage Analysis and Homozygosity Mapping

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.

Genotype-phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin 1

Abstract: We report a 42‐year‐old Japanese man with an unusual autosomal recessive genodermatosis. The clinical features comprised normal skin at birth, loss of scalp hair at 3‐months of age after a febrile illness, progressive nail dystrophy during infancy, palmoplantar keratoderma starting around the age of 18u2003years and trauma‐induced skin fragility and blisters noted from the age of 20u2003years. Skin biopsy of rubbed non‐lesional skin revealed widening of spaces between adjacent keratinocytes from the suprabasal layer upwards. Electron microscopy demonstrated a reduced number of hypoplastic desmosomes. Immunohistochemical labeling showed a reduction in intercellular staining for the desmosome component plakophilin 1. Mutation analysis revealed a homozygous intron 11 donor splice site mutation in the plakophilin 1 gene, 2021+1 G>A (GenBank no. Z34974). RT‐PCR, using RNA extracted from the skin biopsy, provided evidence for residual low levels of the full‐length wild‐type transcript (∼8%) as well as multiple other near full‐length transcripts, one of which was in frame leading to deletion of 17 amino acids from the 9th arm‐repeat unit of the plakophilin 1 tail domain. Thus, the molecular findings help explain the clinical features in the patient, who has a similar but milder phenotype to previously reported patients with skin fragility‐ectodermal dysplasia syndrome associated with complete ablation of plakophilin 1 (OMIM 604536). This new ‘mitis’ phenotype provides further clinicopathological evidence for the role of plakophilin 1 in keratinocyte cell–cell adhesion and ectodermal development.

Overexpression of tumour necrosis factor‐α‐converting enzyme in psoriasis

Backgroundu2002 Tumour necrosis factor (TNF)‐α‐converting enzyme (TACE) is a metalloproteinase‐disintegrin that releases soluble TNF‐α from cells by cleaving within the extracellular domain of membrane‐bound pro‐TNF‐α. It was proposed that TNF‐α is involved in the pathogenesis of psoriasis, and it is therefore suggested that TACE has important roles in psoriasis. However, it is unclear whether TACE is expressed in psoriatic tissue.

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 α6β4 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.

An immunohistochemical study of E-cadherin expression in human squamous cell carcinoma of the skin: relationship between decreased expression of E-cadherin in the primary lesion and regional lymph node metastasis.

E‐cadherin is a Ca2+‐dependent, intercellular adhesion molecule that is specifically expressed in epithelial tissues and is essential for maintaining intercellular connections. It has been reported that E‐cadherin expression of tumor cells is often decreased in some types of metastasizing carcinomas as compared with those without metastasis.

Multiple squamous cell carcinomas in situ in vitiligo lesions after long-term PUVA therapy

2. Berman A, Winkelmann R. Appearance in course of exfoliative erythroderma and regression associated with histologic mononuclear cell inflammation. Arch Dermatol 1982;118:615-8. 3. Schwengle L, Rampen F. Eruptive seborrheic keratoses associated with erythrodermic pityriasis rubra pilaris. Acta Derm Venereol (Stockh) 1988;68:443-5. 4. Holdiness M. The sign of Leser-Trelat. Int J Dermatol 1986;25:564-72. 5. Williams N. Acanthoma appearing after eczema. Br J Dermatol 1956;68:268-71. orrheic keratoses were localized and occurred several months postoperatively. Therefore this appears to be a case of eruptive, confluent seborrheic keratoses associated with a graft site. We might hypothesize that in this case, the growth factors being induced by the healing graft site stimulated appearance of the seborrheic keratoses locally. To our knowledge, this is the first reported case of postoperative eruptive seborrheic keratoses.

C2-ceramide induces apoptosis in a human squamous cell carcinoma cell line

Backgroundu2003Previous studies have demonstrated that synthetic cell‐permeable analogues of ceramide promote differentiation and inhibit proliferation of keratinocytes, and that the vitamin D3 inducible sphingomyelin cycle generates ceramide in keratinocytes. Although it has been suggested that exogenous ceramide induces apoptosis of keratinocytes, which is similar to their effect on other cell types, such as leukaemia cells, only a few studies have reported ceramide‐induced apoptosis of keratinocytes.

A Case of Infantile Digital Fibromatosis with Spontaneous Regression

We reported a fourteen‐month‐old boy with infantile digital fibromatosis. At the age of seven months, a nodule appeared on the back of the left third toe, and developed into a slight red tumor divided into five hemispherical nodules. Histopathologically, spindle‐shaped tumor cells with an eosinophilic inclusion body in the cytoplasm were seen in the dermis. Electron microscopy showed a dense body in the cytoplasm of the tumor cells. One year and two months after the first visit, the tumor regressed without any aggressive treatment. Japanese cases of infantile digital fibromatosis were reviewed. The literature review and our case suggest that the tumor should be observed without any aggressive treatment unless it causes mobile dysfunction of the affected finger or toe.

Toxic Epidermal Necrolysis Possibly Linked to Hyperacute Graft‐versus‐Host Disease after Allogeneic Bone Marrow Transplantation

Toxic epidermal necrolysis (TEN) is a severe blistering skin disease of high mortality. TEN may occur after bone marrow transplantation (BMT). In such cases, TEN have been attributed to graft‐versus‐host disease (GVHD) or an adverse drug reaction. It is very difficult to distinguish the causes of TEN after BMT. We report a 21‐year‐old Japanese man who developed TEN eight days after BMT, evaluate the differential diagnosis of hyperacute GVHD and an adverse drug reaction, and deduce that hyperacute GVHD was the more likely pathogenesis of TEN in this patient.

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.