[Skin Lesion in Fabry Disease].

Fabry disease is an inborn error metabolisms caused by deficiency of α-galactosidase A activity, and results in glycolipid accumulation of in multiple tissues or organs. Skin lesions occurred in Fabry disease are characterized by angiokeratoma, including acroparesthesia or hypohydrosis, among others. There are important characteristics for the diagnosis of Fabry disease.

Therapeutic Efficacy of Etretinate on Cutaneous-type Adult T-cell Leukemia-Lymphoma.

Cutaneous-type adult T-cell leukemia-lymphoma is treated with antiviral or skin-directed therapy. Medications that are used to treat skin lesions of cutaneous T-cell lymphomas are also used for the cutaneous-type adult T-cell leukemia-lymphoma. Etretinate, a synthetic retinoid, has been used for treating cutaneous T-cell lymphomas; however, its clinical effectiveness for the treatment of cutaneous-type adult T-cell leukemia-lymphoma has not been fully studied. We conducted a retrospective assessment of the efficacy and safety of etretinate in 9 patients with cutaneous-type adult T-cell leukemia-lymphoma. Complete and partial responses to etretinate were observed in 1 and 7 patients, respectively. Among the responders, remission was maintained for more than 6 years in 2 patients. These results suggest that etretinate is a promising treatment option for cutaneous-type adult T-cell leukemia-lymphoma.

Human T-lymphotropic virus type I proviral loads in patients with adult T-cell leukemia-lymphoma: Comparison between cutaneous type and other subtypes.

Adult T-cell leukemia-lymphoma (ATL), characterized by various clinicopathological features, is divided into four clinical subtypes, namely, acute, lymphoma, chronic and smoldering types, and the treatment strategy differs according to the clinical subtype. The designation cutaneous type ATL has been proposed to describe a peculiar subgroup of smoldering type ATL in which the skin is predominantly affected. However, diagnostic criteria and prognostic factors for cutaneous type ATL remain to be determined. Therefore, we performed a retrospective study to obtain a precise method for subtype classification and to clearly define cutaneous type ATL. A total of 87 ATL patients (acute, n = 31; lymphoma, n = 6; chronic, n = 24; smoldering, n = 26) were enrolled. The human T-lymphotropic virus type I (HTLV-1) proviral load in peripheral blood and the serum soluble interleukin-2 receptor (sIL-2R) level were evaluated with respect to the clinical features of the different types of ATL. The HTLV-1 proviral load was significantly increased in the acute and chronic type and the serum sIL-2R level was increased in the acute and lymphoma type. The HTLV-1 proviral load was significantly lower in cutaneous than other smoldering types of ATL without skin lesions. The clinical findings of cutaneous type ATL were also different from other subtypes. These results indicate that, in combination, determination of the HTLV-1 proviral load and the serum sIL-2R level is useful for distinguishing among the different types of ATL, and strongly suggest that cutaneous type ATL is a distinct clinical entity.

Trichothiodystrophy group A: a first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene.

Trichothiodystrophy group A (TTD-A) is one of the three types of photosensitive TTD and is a very rare genodermatosis with deficient post-ultraviolet (UV) DNA repair. We herein describe the first Japanese case with a novel mutation in the GTF2H5 gene responsible for TTD-A. A 5-year-old male, born as a collodion baby from healthy non-consanguineous parents, exhibited sun sensitivity, brittle hair, ichthyosis, cataracts and mental/physical retardation. He demonstrated neither neurological abnormalities nor pigmentary changes following sun exposure. The patient's primary fibroblasts were hypersensitive to killing by UV (D0  = 1.5 J/m(2) ), and the post-UV unscheduled DNA synthesis was 13% of normal. A host cell reactivation complementation analysis showed a decreased DNA capacity without recovery after transfecting any xeroderma pigmentosum genes. We identified a novel homozygous mutation (c.166G>T) in the coding region of the GTF2H5 gene that resulted in a predicted amino acid change: p.E55X. Thus far, only one Japanese case of TTD with a mutation of the XPD gene had been reported. The present case is the first of TTD-A and the second case of TTD in Japan, suggesting that it is necessary to differentiate TTD from other photosensitive disorders, although the incidence of TTD is very low in Japan compared to that observed in Western countries.

Effect of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia-lymphoma: cutaneous adverse reactions may predict the prognosis.

Adult T-cell leukemia-lymphoma (ATL) is one of the most malignant lymphomas with poor prognosis. ATL cells express CC chemokine receptor 4 (CCR4) and mogamulizumab, a monoclonal antibody against CCR4 that exhibits very strong cytotoxicity for ATL cells via antibody-dependent cellular cytotoxicity. Although its effect is dramatic in ATL, serious adverse reactions such as Stevens-Johnson syndrome have been reported. However, these eruptions can appear as therapeutic signs of mogamulizumab. We evaluated the effectiveness of mogamulizumab in five acute-type ATL patients. Peripheral blood (PB) and lymph nodes (LN) were affected in three and four patients, respectively. In PB, complete response (CR) was obtained in all three patients and partial response (PR) was recorded in LN of one patient. In skin lesions, four of five patients manifested CR; in two, the lesions worsened after the start of mogamulizumab treatment and subsequently improved. In these lesions, CD4(+) 8(-) 25(+) ATL cells were replaced by CD3(+) 8(+) cytotoxic T cells. Cutaneous adverse reactions (CAR) developed in two patients with CR; they did not show a relapse of ATL over the course of 9 months. Our findings suggest that mogamulizumab should be continued and surface marker evaluation should be performed even in patients whose skin lesions show aggravation, and that CAR may be a marker for a favorable prognosis.

Indication for random skin biopsy for the diagnosis of intravascular large B cell lymphoma.

BACKGROUND: The use of random skin biopsy (RSB) to diagnose intravascular large B cell lymphoma (IVLBCL) has increased. OBJECTIVE: To explore the indication for RSB to diagnose IVLBCL. METHODS: We retrospectively evaluated the medical records of 18 Japanese adults who underwent RSB between January 2008 and December 2009. RESULTS: A final diagnosis of IVLBCL was returned in 2 patients based on RSB findings and in 1 based on brain biopsy findings. All 3 patients manifested neurological symptoms, hematocytopenia, elevated levels of LDH and soluble interleukin-2 receptor (sIL-2R), and the absence of lymphadenopathy. Malignant lymphoma other than IVLBCL was diagnosed in 6 patients, and in 5 of 6 patients who underwent nodal or parenchymal biopsy diagnostic findings were made. CONCLUSION: Although RSB is useful for the early diagnosis of IVLBCL, careful selection of patients is necessary. In patients with neurological symptoms, hematocytopenia, elevated LDH and sIL-2R and no nodal involvement, RSB may be useful.

Retinoic acids exhibit anti-fibrotic activity through the inhibition of 5-lipoxygenase expression in scleroderma fibroblasts.

The pathogenesis of systemic sclerosis (SSc) is not fully understood and there is no effective treatment for this disease. Retinoic acid (RA) can modulate connective tissue metabolism, exhibit anti-fibrotic activity, and improve the clinical symptoms of SSc. However, the mechanisms by which RA elicits its anti-fibrotic actions remain to be determined. The aim of this study was to elucidate the underlying mechanisms by which RA exerts beneficial effects on scleroderma. Cultured skin fibroblasts from patients with scleroderma were treated with RA and their effect on the expression of 5-lipoxygenase (LOX), transforming growth factor (TGF)-ß1, connective tissue growth factor (CTGF), type I and type III collagen was tested by reverse transcription polymerase chain reaction (RT-PCR) and western immunoblotting. The effect of MK886, a 5-LOX-specific inhibitor, on the expression of TGF-ß1, CTGF, type I and type III collagen was also examined by RT-PCR. In cultured scleroderma fibroblasts, the expression of 5-LOX was elevated compared with normal human dermal fibroblasts. RA significantly inhibited the expression of 5-LOX and of TGF-ß1, CTGF, type I and type III collagen. We further found that the expression of TGF-ß1, CTGF and type I and type III collagen mRNA was inhibited by MK886 in scleroderma fibroblasts. In vitro, RA reduced 5-LOX expression in scleroderma fibroblasts and downregulated TGF-ß1 and CTGF expression, leading to the inhibition of type I and type III collagen synthesis. Our results indicate that the clinical effects of RA on scleroderma are, at least in part, attributable to the reduction of 5-LOX expression and the subsequent suppression of TGF-ß1 and CTGF expression that results in the blockade of collagenogenesis.

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells.

Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36 x 10(-9) M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyl-tetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridine-monophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells.

Uptake of a recombinant human alpha-L-iduronidase (laronidase) by cultured fibroblasts and osteoblasts.

To examine the uptake of a recombinant human alpha-L-iduronidase (laronidase) by cultured fibroblasts from a patient with mucopolysaccharidosis I (MPS I) and its effect on the cleavage of accumulated substrates, we performed enzymological, Western blotting, immunocytochemical and morphological studies. Laronidase was incorporated into the MPS I cells dose-dependently mainly via mannose 6-phosphate (M6P) receptors. Then the incorporated enzyme was transported to lysosomes and processed to the mature form, the pathological changes of the cells being improved. Furthermore, we compared the uptake of laronidase by cultured mouse osteoblasts with that by cultured mouse fibroblasts. The enzyme was incorporated into the cultured mouse osteoblasts mainly via M6P receptors, although mannose (Man) receptors were partially involved in the uptake of the enzyme, as in the cultured fibroblasts. But the uptake by the former was apparently lower than that by the latter. The administration of a high dose of the enzyme or development of a recombinant alpha-L-iduronidase containing many M6P residues is required for further improvement of enzyme replacement therapy for skeletal disorders caused by MPS I.

Case of adult T-cell leukemia with pulmonary involvement presenting as nodular shadows.

A 60-year-old man with a diagnosis of smoldering adult T-cell leukemia (ATL) had been treated successfully for 4 years with psoralen and ultraviolet A therapy, gamma-interferon, oral etoposide and sobuzoxane. He subsequently developed rapidly-growing skin nodules over his entire body. Chest X-ray and thoracic computed tomography showed nodular shadows in the right lower lung field and nodules in both lower lung lobes. Despite combined chemotherapy, he died. Upon autopsy, numerous nodules were found in the bilateral lower lobes; microscopically, the nodules were diffusely infiltrated by ATL cells. Our review of the published work found only two previously reported cases of ATL with pulmonary involvement manifested as nodular shadows. Herein, we present details on the third case.

The 3G5 antigen is expressed in dermal mast cells but not pericytes.

BACKGROUND: It has been shown that the 3G5 antigen recognized by monoclonal antibody 3G5 (mAb 3G5) is a useful marker of pericytes in normal human skin. However, most 3G5 antigen-expressing cells in capillary vessels were stained negatively for alpha-smooth muscle actin (alpha-SMA), a prominent pericyte marker. This study was designed to determine whether the expression of the 3G5 antigen is restricted to specific stages of pericyte development, or if it is expressed in other cells rather than pericytes in capillary vessels. METHODS: 3G5 antigen-expressing cells were detected in normal human skin, granulating tissues from decubitus ulcers and inflammatory psoriatic skin with extensive angiogenesis using double immunofluorescent staining with mAb 3G5 and monoclonal antibodies (mAbs) to various pericyte markers, tryptase and chymase. Furthermore, using immunoelectron microscopy, 3G5 antigen-expressing cells were observed in the granulating tissues. RESULTS: The immunoelectron microscopic findings and double immunofluorescent staining (using mAb 3G5 and either anti-tryptase or anti-chymase mAbs) showed that 3G5 antigen-expressing cells were mast cells in normal skin, granulating tissues and psoriatic skin. CONCLUSIONS: The results indicated that 3G5 antigen is a marker of mast cells, but not of pericytes in normal and diseased skin.

Immunohistochemical comparison of beta-catenin expression by human normal epidermis and epidermal tumors.

beta-Catenin, a cytoplasmic protein that binds directly to the intracellular domain of cadherin, controls various functions such as cell adhesion. In many human carcinomas, E-cadherin-mediated cell-cell adhesion is lost or disturbed and related to metastasis. The purpose of this study was to compare the expression of beta-catenin in the normal epidermal keratinocytes and samples from cutaneous benign and malignant epidermal tumors in 140 patients. Our study population consisted of 140 patients with benign or malignant epidermal tumors. Using immunohistochemical methods, we compared the expression of beta-catenin in their normal epidermal keratinocytes, and in samples from 61 benign (seborrheic keratosis, n = 33; verruca vulgaris, n = 14; keratoacanthoma, n = 14), and 79 malignant (Bowen's disease, n = 18; basal cell carcinoma, n = 33; squamous cell carcinoma, n = 28) epidermal tumors. beta-Catenin was found to be expressed in the cell membrane of normal keratinocytes. Compared to other cell components of the normal epidermis, basal cells showed the strongest beta-catenin expression in all 140 patients. While absent in three of 61 benign tumors, compared to normal basal cells, the expression of beta-catenin in the other 58 tumors was not significantly different; it was reduced in 71 of 79 malignant tumors (P < 0.0001). In Bowen's disease, the expression of beta-catenin on the tumor cell membrane was reduced, however, strong expression was seen in the nuclei and cytoplasm. Our results suggest that beta-catenin expression on the membrane of keratinocytes is associated with the differentiation of normal keratinocytes but not with their stage of differentiation, nor with the proliferation ability of epidermal tumor cells.

Spontaneous regression of recurrent and metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumor with a high rate of recurrence and metastasis. Despite its high degree of malignancy, spontaneous regression has been documented. We report an 87-year-old woman who presented with recurrent MCC on her left cheek and regional lymph node metastasis. Although she received no treatment due to her poor condition, the recurrent metastatic lesion regressed spontaneously within 2 months.

Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant alpha-galactosidase.

Peripheral neuropathy is one of the important manifestations of Fabry disease. Enzyme replacement therapy with presently available recombinant alpha-galactosidases does not always improve the Fabry neuropathy. But the reason has not been determined yet. We established a Schwann cell line from Fabry mice, characterized it, and then examined the uptake of alpha-galactosidase by cells and its effect on the degradation of accumulated substrate. The cells exhibited a distinct Schwann cell morphology and biochemical phenotype (alpha-Galactosidase activity was deficient, and numerous cytoplasmic inclusion bodies were present in the cells). A recombinant alpha-galactosidase added to the culture medium was incorporated into the cultured Fabry Schwann cells dose dependently. But the increase in cell-associated enzyme activity was less than that in the cases of human and mouse Fabry fibroblasts. The administration of a high dose of the enzyme improved the pathological changes in cells, although a low dose of it did not. Cellular uptake of the enzyme was strongly inhibited in the presence of mannose 6-phosphate. This suggests that the enzyme is incorporated via cation-independent mannose 6-phosphate receptors in Schwann cells. The low expression of cation-independent mannose 6-phosphate receptors in Schwann cells must be one of the reasons their uptake of the present enzymes was low. The administration of a high dose of the enzyme or the development of an enzyme containing many mannose 6-phosphate residues is required to improve Fabry neuropathy.

Multicentric Castleman disease with cutaneous manifestations: report of 2 cases and comparison with systemic plasmacytosis.

We report 2 patients with multicentric Castleman disease. Both presented with multiple, indurated, hyperpigmented plaques, generalized lymphadenopathy and polyclonal hypergammaglobulinemia. Biopsy specimens showed infiltration of mature plasma cells and lymphocytes in the dermis and lymph nodes. Skin specimens were negative for human herpesvirus 8, latent nuclear antigen 1 and Epstein-Barr virus by in situ hybridization. PCR disclosed clonal T-cell receptor gene rearrangement in the bone marrow cells of 1 patient. We discuss the possible relationship between multicentric Castleman disease and systemic plasmacytosis as well as plasma cell proliferation.

Cytochemical analysis of storage materials in cultured skin fibroblasts from patients with I-cell disease.

BACKGROUND: In cultured fibroblasts from I-cell disease patients the transport of many lysosomal enzymes is defective, and affected cells contain inclusion bodies filled with undegraded substrates. However, the contents of these inclusion bodies have not been well characterized yet. We attempted to identify accumulated substances in cultured I-cell disease fibroblasts cytochemically. METHODS: Cultured fibroblasts from I-cell disease patients were double-stained with a monoclonal antibody to lysosome-associated membrane protein-1 (LAMP-1) and that to GM2 ganglioside, or a series of lectins that specifically bind to sugar moieties. RESULTS: The patients' cells were granularly stained with the antibody to GM2 ganglioside and the lectins including Maakia amurensis, Datura stramonium, and concanavalin A. Their localization was coincident with that of LAMP-1. CONCLUSIONS: GM2 ganglioside and various kinds of glycoconjugates having sialic acidalpha2-3galactose, galactosebeta1-4N-acetylglucosamine and mannose residues accumulate in enlarged lysosomes in I-cell disease fibroblasts.