Genetic diagnosis of Hailey-Hailey disease in two Chinese families: novel mutations in the ATP2C1 gene.

Hailey-Hailey disease (HHD; OMIM 169600), is an autosomal dominantly inherited disorder characterized by suprabasal cell separation of the epidermis. Mutations in ATP2C1, which encodes the human secretory pathway Ca(2+)/ Mn(2) +/- ATPase protein 1 (hSPCA1), have been identified as the pathogenic gene of HHD without evidence of genetic heterogeneity. In this study, the ATP2C1 gene was screened in two typical Chinese pedigrees with HHD, and two specific novel mutations of the ATP2CL gene were identified. Family 1 had a 16-base deletion mutation c.1068-1083del16 and family 2 had a substitution mutation c.1982T>G (p.Met661Arg). DNA sequencing of the three descendants of the probands revealed that they all had the normal genotype, indicating that there had been no transmission of the mutation.

Comparative histochemical study of Bowen's disease and actinic keratosis: preserved normal basal cells in Bowen's disease.

The degree of DNA-instability as revealed by immunohistochemical staining with anti-cytidine antibody after acid hydrolysis (DNA-instability test) has been recently used as a marker of malignancy. This technique was applied to examine 17 skin tissue samples of Bowen's disease, 47 of actinic keratosis, 15 of squamous cell carcinoma, 5 of seborrheic keratosis, and 10 of normal skin. All benign neoplastic cells of seborrheic keratosis and normal epidermal cells were negative. On the other hand, all cancer cells were positive with the DNA-instability test, indicating their malignancy, but all basal cells in Bowen's disease were completely negative. Compatible with this result, the basal cells in Bowen's disease were characteristically normal as evident in other histochemical examinations. Thus, they were negative with p53 immunohistochemistry, with normal signals of chromosome 17 in situ hybridisation and argyrophilic nucleolar organiser region, and showed slightly enhanced proliferative activity as revealed by proliferating cell nuclear antigen immunohistochemistry. Immunohistochemical staining with 34 beta E12 (monoclonal antibody against cytokeratins 1, 5, 10, and 14), which stains all normal epidermal keratinocytes including basal cells, showed that only the basal cells of Bowen's disease stained strongly and homogeneously, while all cancer cells in the upper layers of Bowen's disease and all layers of actinic keratosis were only sporadically or weakly stained. Staining with 34 beta B4 (monoclonal antibody against cytokeratin 1), which recognises the whole epidermis except for the basal layer in the normal epidermis, showed that the basal cells in the Bowen's disease were completely negative, and lower layer cells in the actinic keratosis and upper layer cells in Bowen's disease were only sporadically stained positive, although the superficial layer cells in actinic keratosis stained strongly and homogeneously. Our findings clearly indicate that the basal cells in Bowen's disease are normal. In support of this conclusion, the same cells showed normal morphology on electron microscopy with preserved basement membrane, although the latter was often damaged in actinic keratosis.

Hair follicle nevus occurring in frontonasal dysplasia: an electron microscopic observation.

We report a rare hair follicle nevus that occurred in a three-month-old Japanese boy with mild frontonasal dysplasia. It had been present since birth. Histologically, numerous tiny vellus hair follicles were found within the dermis. The constituent cells of these follicles showed the features of follicular germ cells under the electron microscope. The fibroblasts around the follicles were active and merged with the colloid substance. Many myofibroblasts were found in a collagenous stroma in the atrophic lesion of the frontonasal dysplasia.

Volar melanotic macules in a Japanese man with histopathological postinflammatory pigmentation: the volar counterpart of mucosal melanotic macules.

BACKGROUND: Volar melanotic macules are asymptomatic light-brown or tannish-grey macules usually found on the palms and/or soles of blacks, although they have also been reported on the volar surfaces of whites. Similar lesions have not been reported before in Japanese people. Since the cause is as yet unknown, it remains to be discussed whether they are a distinct entity. METHODS: In this report, a 52-year-old Japanese man with volar melanotic macules is reported with the clinical and histopathological findings. RESULTS: A 52-year-old Japanese man presented with many light-brown macules on his bilateral soles. He had a 20-year history of tinea pedis. Histopathological examination revealed melanophages and inflammatory infiltrates in the superficial dermis. There was a slight increase in melanin granules around the acrosyringium. Fontana-Masson stain revealed a slight increase in melanin granules in the basal layer including the acrosyringium and superficial dermis. These changes corresponded with postinflammatory pigmentation. CONCLUSIONS: This is the first report of volar melanotic macules in Japanese people. We suggest that volar melanotic macules is not an independent entity but a clinicopathological one that includes postinflammatory pigmentation, and that the condition is the volar counterpart of mucosal melanotic macules.

Expression of granulocyte colony-stimulating factor and its receptor in epithelial skin tumors.

Granulocyte colony-stimulating factor receptors (G-CSFR) have been observed on the surface of not only hematopoietic cells but also several cancer cells. In the present study, we investigated the expression of G-CSFR or G-CSF in epithelial skin tumors by immunohistochemical staining. The assessments were defined by the percentage of G-CSFR or G-CSF positive cells and expressed as G-CSFR and G-CSF scores. The G-CSFR score in SCC (77.6+/-20.0%) was significantly higher than that in Bowen's disease (BD) (51.0+/-35.6%), actinic keratosis (AK) (49.3+/-34.6%) or normal skin (30.0+/-32.1%) (P=0.0004, P=0.0003, P<0.0001, respectively). The mean G-CSF score in SCC (56.7+/-27.4%) or in BD (44.1+/-31.4%) was higher than that in normal skin (24.9+/-25.8%) (P=0.0075, P<0.001, respectively). G-CSF expression in AK (29.8+/-31.2%) was lower than that in SCC (P=0.0037). There was significant positive correlation between the G-CSFR score and the G-CSF score (gamma=0.274, P=0.0107) in skin tumors. These findings suggested that the assessment of G-CSFR expression might be associated with carcinogenesis of skin tumors.

Sub-populations of melanocytes in pigmented basal cell carcinoma: a quantitative, ultrastructural investigation.

BACKGROUND: Pigmentation is a characteristic clinical feature of basal cell carcinomas (BCCs) in Japanese patients. The pathogenesis of melanin pigment in pigmented BCCs is poorly understood. METHODS: We have combined the techniques of morphometric analysis and electron microscopy to assess accurately the morphologic aspects of melanocytes that occurred in pigmented and non-pigmented areas of pigmented BCCs. RESULTS: In the pigmented areas melanocytes were not only located along the basal membrane but also interspersed between tumor cells in the central parts of the tumor nest, and had large and numerous dendrites. Those in a supra-basal location displayed some degree of degeneration due to mitochondrion and melanosome swelling. In the non-pigmented areas melanocytes were only basally located, showed fewer dendrites, and frequently showed abortive melanosomes. However, melanocytes in these two different portions were in the active state of melanogenesis and proliferation. Ultrastructural cytomorphometric analysis also showed significant differences in most of the nuclear and cell parameters including nuclear and cell area, the nuclear/cell area ratio, cell perimeter and cell form factor between these two types of melanocytes. Particularly melanocytes in the pigmented areas were twice the cell size of the latter. In addition, the melanosomes remained almost completely in the apoptotic tumor cells, and the phagocytosis of the melanosome-containing apoptotic cells by the neighboring tumor cells appeared to be followed by the formation of the melanosome complexes. CONCLUSIONS: These findings suggest that different populations of melanocytes are probably present in pigmented BCCs, and repeated cycles of phagocytosis of melanosome-containing apoptotic cells may represent the predominant way of forming large melanosome complexes. The present morphological observation and quantitative analysis provide a morphological basis for further studies to interpret other pathologic changes in pigmented BCCs.

Atrophic dermatofibroma. Elastophagocytosis by the tumor cells.

A 55-year-old woman presented with an asymptomatic red plaque on the left upper back for 6 or 7 years. The lesion was depressed in response to finger pressure. The clinical diagnosis was anetoderma. Histopathologically, the characteristic cells of cellular dermatofibroma proliferated within the thinned dermis, which showed atrophy of about 60 or 70%. The proliferated cells were positive for factor XIIIa and negative for CD34. The involved dermis showed the loss of elastic fibers on elastica van Gieson stain. Electron microscopically, the proliferating cells phagocytized the elastic fibers. We report a typical case of atrophic dermatofibroma and show the possibility that the cause of this disease might be elastophagocytosis between the collagen fibers by the dermatofibroma cells.

The ultrastructural characteristics of eccrine sweat glands in a Fabry disease patient with hypohidrosis.

As an investigation of the pathogenetic mechanism of diminished sweating in Fabry disease, an electron microscopy ultrastructural study was conducted on specimens of eccrine sweat glands from a typical patient with Fabry disease who had hypohidrosis, a low skin moisture content, and diminished thermoregulation ability. Numerous characteristic cytoplasmic inclusions were observed in the eccrine sweat glands, the lamellar pattern of which was considerably variable in various types of gland cells. Large vacuolar inclusions predominated in clear cells of secretory coil; lesser vacuoles were also seen in the coiled duct, and the basal cells of the straight duct toward the coiled duct displayed mulberry-like figures. There were some clear cells showing cell damage and necrosis in the secretory coil. Lamellated inclusions were noted in the unmyelinated axons innervating the eccrine sweat glands. The small blood vessels around the eccrine glands were narrowed by swollen endothelial cells with heavy inclusions. These intracytoplasmic deposits may be responsible for the decreased sweating ability in Fabry disease. The factors related to hypohidrosis are also discussed.

The ultrastructural findings of Charcot-Leyden crystals in stroma of mastocytoma.

Charcot-Leyden crystals (CLCs) have been found in many conditions associated with eosinophilia, but their occurrence in skin diseases is very rare. We report ultrastructural observations on the presence of CLCs in the cutaneous lesions of two cases of mastocytoma. Electron microscopy documented CLCs located in phagosomes of morphologically activated macrophages as well as free CLCs in the stromal tissue, close association between CLCs formation and damaged and lysed eosinophils was present. These findings provided evidence that the formation of CLCs in mastocytoma implicated the individual and interrelated biology of mast cells, eosinophils and macrophages. Phagosomes probably acted as the site of CLCs formation. The clinic and pathologic role of CLCs in mastocytoma deserves further investigation.