Fumiko Sakamoto

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

Fabry disease is an X‐linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme α‐galactosidase A (EC 3.2.1.22). The causative mutations are diverse, include both large rearrangements and single‐base substitutions, and are dispersed throughout the 7 exons of the α‐galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1‐deoxygalactonojirimycin (DGJ), an inhibitor of α‐galactosidase A, at subinhibitory concentrations. We transfected COS‐7 cells with the 24 mutant GLAs and analyzed the α‐galactosidase A activities. We then treated the transfected COS‐7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease.

CD2-, CD4+, CD56+ agranular natural killer cell lymphoma of the skin.

We present a case of CD56-positive cutaneous lymphoma with a clinical appearance resembling angiosarcoma. The biopsy specimen showed angiocentric infiltrates of small to medium-sized cells positive for CD4, CD45, and CD56 but negative for CD2, surface and cytoplasmic CD3, CD8, CD20, and CD57. There was no detectable clonal rearrangement of either TCRbeta or TCRgamma genes and no dense core granules in the cytoplasm. Epstein-Barr virus was not detected. The patient died of an unrelated disease 20 months after initial biopsy, although there was some response to interleukin-2, radiotherapy, and VP-16. The results suggest that our case does not precisely match the recently proposed variants of CD56-positive lymphoma, namely nasal T/natural killer cell lymphoma and blastic natural killer cell lymphoma. Agranular natural killer cell lymphomas similar to our case in the immunophenotype have been reported to be indolent and occur in the skin. These lymphomas may be a distinct subtype and have a predilection for involving the skin.

Human parvovirus B19 infection: Immunohistochemical and electron microscopic studies of skin lesions

Erythema infectiosum is known to be caused by human parvovirus B19 and shows characteristic clinical skin manifestations in children, although adult cases of human parvovirus B19 infection do not always show such characteristic features. Recently, we experienced an epidemic adult cases of human parvovirus B19 infection and examined the erythematous skin lesion by immunohistochemistry and electron microscopy to clarify the pathogenesis of the skin manifestations. Light microscopic examination showed slightly irregular‐shaped vessels in the dermis. By immunohistochemistry, using anti‐human parvovirus B19 monoclonal antibody, positive reactions were found in endothelial cells. No immunoglobulins were found, but C3 deposits were present in the perivascular areas. By electron microscopy, virus particles were found in the cytoplasm of endothelial cells. An inflammatory reaction due to the direct human parvovirus B19 infection in dermal vessels seems to be an important factor in the pathogenesis of the skin manifestations.

Barrier Abnormality Due to Ceramide Deficiency Leads to Psoriasiform Inflammation in a Mouse Model

It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and β-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of γδ T cells that produced IL-17 (γδ-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of γδ-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing γδ-17 cells.

Pathogenesis of pili annulati

SummaryPlucked scalp hairs and hair roots of pili annulati were examined to understand their pathogenesis. Stereoscopic examinations of hairs in transmitted light and/or reflected light and light microscopic surveys of the cross-sections of hairs confirmed that the cortical empty spaces appeared to be responsible to the unique dotted shiny appearance of the hairs seen by the unaided eyes under a refracted light. By transmission electron microscope, small vacuoles and dense bodies were observed in the cytoplasm of the differentiating cortical cells; subsequently, with increasing number of tonofilaments, an uneven distribution of free ribosomes occurred and abnormal spaces containing fine granular substances were formed in the cytoplasm of the cortical cells. Occasionally, extremely large cortical trichohyaline granules were found. In the keratinized hair, irregular empty spaces were present in the cortex of the abnormal hair segments. Histochemically, the keratinized cortex of the affected hairs always had more residual SH groups than the controls. Pili annulati may be a disorder of protein metabolism involving a partial dysfunction of cytoplasmic ribosomes, resulting in a lack of cortical keratin formation.

Basal cell tumor with apocrine differentiation: Apocrine epithelioma

A locally invasive tumor developed in a 71-year-old woman on the right retroauricular skin, involving cartilage and parotid glands. Histologically, the tumor displayed characteristic features of basal cell epithelioma accompanied by stromal fibrosis. Histochemically, an apocrine pattern in enzyme reactions was detected in tumor cells. Ultrastructurally, the tumor cells showed the features of apocrine-type secretory cells and ductlike structures, and the peripheral cells revealed the characteristics of myoepithelial cells. A large number of myofibroblasts was observed in the connective tissue surrounding the tumor nests. From these findings, the womans tumor was considered to represent a basal cell tumor with apocrine differentiation.

Cutaneous ciliated cyst: a case report and histochemical, immunohistochemical, and ultrastructural study

A 19‐year‐old woman with a cutaneous ciliated cyst on her buttock is reported. Histological, histochemical, and electron microscopic studies revealed ciliated cells, mucinous cells showing merocrine secretion, and areas of squamous metaplasia in the cyst wall. This is the first case of cutaneous ciliated cyst that contained non‐ciliated mucinous cells as a component.

Proliferating trichilemmal cyst with apocrine-acrosyringeal and sebaceous differentiation

An adnexal tumor on the scalp of a 74‐year‐old woman is described. Histologically, the tumor was composed of cystic structures showing typical trichilemmal keratinization. The tumor cells in the cyst walls often formed duct‐like or squamous eddy‐like structures and occasionally showed vacuolation or poromalike change. Ultrastructurally, some tumor cells showed differentiation either toward the acrosyringium or sebaceous cells. From these findings, the present tumor is considered to differentiate toward various parts of the hair follicle including infundibulo‐isthmus epithelium, apocrine acrosyringium, and sebaceous cells.

A case of localized follicular hamartoma: an ultrastructural and immunohistochemical study

We report the case of a 22‐year‐old woman with a nevoid plaque that we termed localized follicular hamartoma. The plaque was noticed at puberty on a unilateral site of the face and scalp. Clinically, it revealed numerous, skin‐colored to light brown papules alone and in groups, occasionally bearing a single hair. Histologically, branched epithelial nests of squamoid and/or basaloid cells were revealed in connection with the interfollicular epidermis and the upper portions of hair follicles, of which the lower portions showed normal structures. Immunohistochemically, the epithelial nests showed the keratin expression consisted with that of the infundibular epithelium. S‐100‐positive cells were found in the epithelial nests and the stroma. Factor XIIIa‐positive dendritic cells were numerous in adjacent to the epithelial nests. Ultrastructurally, immature melanocytes with a small number of premelanosomes and Merkel cells were found in the nests. Stromal dendritic cells showed the adherent features of the cytoplasmic processes to anchoring fibrils or basal lamina of the epithelial nests. From these findings, our case is a hamartoma, which seems to be an abortive growth of secondary hair germs with a limited differentiation to the upper follicular portion.

Angiolymphoid hyperplasia with eosinophilia presenting multinucleated cells in histology: an ultrastructural study

A case of angiolymphoid hyperplasia with eosinophilia arising on the face of a woman is reported. Histologically, the uniqueness of this case is the presence of multinucleated cells (MNCs), besides the conventional dermal changes. Electron microscopy showed that some of the apparent MNCs are clusters of endothelial cells forming immature vascular lumens with numerous microvilli, and the other MNCs displayed the recognized features of fibrohistiocytic or myofibroblastic cells. Immunohistochemically, some MNCs were positive for Ulex europaeus agglutinin and Factor VIII‐related antigen. From these findings, some of the MNCs are histologically endothelial sprouts, and the others are fibrohistiocytic cells in the present case.