Scleromyxedema in a 21 year old female patient with acute lymphoblastic leukemia: a case report.

BACKGROUND: Scleromyxedema is a rare, para-neoplastic, chronic, progressive condition of the Lichen myxedematosus (LM) family. The clinical picture consists of generalized confluent papular eruptions with possible systemic manifestations, which may be fatal as it still constitutes a therapeutic dilemma. Histologically, it is characterized by dermal mucin deposition, fibroblast proliferation with fibrosis, with monoclonal gammopathy in the absence of thyroid disease. Some atypical forms of the disease were reported in the literature, but none were reported in acute leukemia. CASE PRESENTATION: Herein, we report a case of a 21 years old female patient, known case of acute lymphoblastic leukemia (ALL), who developed numerous hyper-pigmented erythematous papules and plaques, mainly over her thighs, lower abdomen, and sub-mammary flexures. Histopathology of skin lesions confirmed the diagnosis of atypical scleromyxedema. Her symptoms significantly improved with the use of high dose intravenous immunoglobulin (IVIG). CONCLUSIONS: Despite that scleromyxedema is associated with many hematologic disorders, it is very rarely associated with acute lymphoblastic leukemia, and a high index of suspicion is needed for diagnosis. IVIG remains a reasonable management of such a disabling disease.

Immunotherapy-refractory vacuolar myopathy with mucin deposition in scleromyxedema: A possible role of fibroblast growth factor 2.

Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.

Clinical and Molecular Phenotyping in Scleromyxedema Pretreatment and Posttreatment With Intravenous Immunoglobulin.

OBJECTIVE: Scleromyxedema (SMX) is a rare systemic sclerosis mimic that often responds to intravenous immunoglobulin (IVIG) therapy, yet the resulting clinical and biochemical changes have not been well characterized. To better understand the pathogenesis of the disease and the efficacy of IVIG, we sought to explore whether IVIG would introduce a measurable biologic effect corresponding with clinical improvement. METHODS: Fifteen patients with SMX were recruited for the study. Clinical information and peripheral blood mononuclear cells for flow cytometry were obtained immediately before and again 1-2 weeks after patients received IVIG therapy. Ten patients also underwent skin biopsies for gene expression analysis both before and after IVIG therapy. Clinical data included measures of skin involvement (modification of the modified Rodnan skin thickness score [MMRSS] and percentage of body surface area) and several patient-reported outcome measures assessing patients' skin. RESULTS: Posttreatment, the average MMRSS score decreased from mean ± SD 13.6 ± 2.6 to 10.3 ± 1.9; P = 0.003. There were also significant improvements in skin flexibility (mean ± SD 5.4 ± 0.8 to 3.2 ± 0.7; P = 0.003) and softening (mean ± SD 4.9 ± 0.9 to 2.6 ± 0.6; P = 0.022). Baseline levels of Tc17 cells (CD8+CCR6+CXCR3+CCR4-) correlated with the extent of skin involvement as measured by MMRSS pretreatment (r = 0.69, P = 0.012) and decreased after IVIG therapy (mean ± SD 3.4% ± 3.2% to 1.3% ± 1.7%; P = 0.008). Posttreatment analysis of RNA in skin tissue revealed a decrease in gene expression of transforming growth factor ß (TGFß) cytokines as well as several interferon-inducible proteins. CONCLUSION: This open-label study further supports the evidence that patients with SMX respond both objectively and subjectively to IVIG therapy. Biologic studies suggest a role for T lymphocytes in the pathogenesis of the disease and reveal the potential significance of TGFß and interferon pathways.

Histopathologic characteristics of scleromyxedema: A study of a series of 34 cases.

BACKGROUND: Few histologic studies describe the histopathologic aspects of scleromyxedema. OBJECTIVE: We sought to describe the histopathologic and immunohistochemical features of scleromyxedema in a large series of patients. METHODS: We studied all the cases with scleromyxedema diagnosed between 2000 and 2014 at participating centers. Sections with hematoxylin-eosin and special stains were examined. Immunohistochemistry for CD3, CD4, CD8, CD20, CD68, and factor XIIIa was performed in 10 cases. RESULTS: A total of 44 skin biopsy specimens from 34 patients were reviewed. Two different histopathologic patterns were observed: the classic microscopic triad (dermal mucin deposition, fibroblast proliferation, fibrosis) was identified in 34 specimens, whereas an interstitial granuloma annulare-like pattern was found in 10 specimens. A superficial perivascular infiltrate with T lymphocytes was found in all specimens whereas an interstitial proliferation of CD68(+) epithelioid cells was identified in the 10 specimens with an interstitial granuloma annulare-like pattern. Elastic fibers were largely lost, explaining the redundant folds of the disease. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Scleromyxedema shows 2 histopathologic patterns, including the classic type with the microscopic triad of mucin, fibroblast proliferation and fibrosis, and an interstitial granuloma annulare-like pattern. Recognition of these histologic presentations expands the spectrum of scleromyxedema and highlights the difficulty in diagnosing this disabling condition in the absence of a clinicopathological correlation.

[Monoclonal immunoglobulin (M-Ig) and skin diseases from the group of mucinoses--scleredema adultorum Buschke and scleromyxedema. Description of four cases and an overview of therapies]. / Monoklonální imunoglobulin a kozní nemoci ze skupiny mucinóz--scleredema adultorum Buschke a scleromyxedema: popis 4 prípadu a prehled lécebných mozností.

INTRODUCTION: The mucinoses of the type of scleredema and scleromyxedema are diseases marked by excessive production of mucin deposits in the skin and subcutaneous tissue, which causes skin hardening. The skin and subcutaneous deposits hamper the movement of limbs, the thorax as well as mouth. The same mechanism also damages other organs (the heart, lungs, oesophagus). It is probably caused by the stimulation of mucin production in fibroblasts by immunoglobulins, frequently monoclonal immunoglobulin. Therefore these diseases are typically associated with monoclonal gammopathy. CASE REPORTS: We describe a cohort of 4 patients, skin manifestations were twice identified as scleredema and twice as scleromyxedema. All the four patients had type IgG monoclonal immunoglobulin and had clonal plasma cells in the bone marrow proven by histologic examination and flow cytometry. Therefore we commenced chemotherapy in all of them. In one case this chemotherapy was ended by a high-dose chemotherapy with transplanting of autologous red blood cells. This therapy attained the complete disappearance of monoclonal immunoglobulin as well as cutaneous and extracutaneous manifestations of scleredema (obstipation). In one case chemotherapy led to partial hematologic remission and partial improvement of skin manifestations. The other two patients did not respond to standard chemotherapy. The condition of one of them resulted in dermato-neuro syndrome (confusion, somnolence passing into coma and grand mal seizure) and improved following an intensive treatment including also intravenous application of immunoglobulins in a dose of 2 g/per 1 kg weight. This patient has now been under long-term treatment with these immunoglobulins, during which the skin symptoms have significantly diminished, but the concentration of monoclonal immunoglobulin has not changed. The fourth patient not responding to standard chemotherapy was treated with intravenous immunoglobulins also in a dose of 2 g/per 1 kg of weight 1× in a month. After 4 applications the thickening of skin and subcutaneous tissue moderately diminished, so the range of possible movement of the upper limbs and neck became larger and the itchy skin morphs which accompanied the disease disappeared completely. CONCLUSION: It is possible to use chemotherapy and high-dose chemotherapy in the treatment of mucinosis associated with monoclonal gammopathy, as in the treatment of multiple myeloma. If such treatment is not possible or it has not attained disappearance of monoclonal immunoglobulin, improvement can be achieved through repeated application of intravenous immunoglobulins. The treatment with intravenous immunoglobulins in an immunomodulation dose of 2 g/per 1 kg of weight effects the moderation of skin manifestations, but it does not lead to the decrease in monoclonal immunoglobulin.

Allogeneic stem cell transplantation for the treatment of refractory scleromyxedema.

Scleromyxedema is a rare disorder of connective tissue with unknown etiology. Its manifestation includes a generalized mucin deposition, which is frequently associated with paraproteinemia. The course of scleromyxedema is progressive and often lethal. As a result of its poorly understood pathogenesis, there is no causative treatment option. The efficacy of cytoreductive agents and autologous stem cell transplantation has been reported, but so far allografting as a treatment option has not yet been documented. Herein, we report on a patient with severe neurologic involvement and refractory course attaining durable remission after receiving an allogeneic hematopoietic cell transplant from an human leukocyte antigen-matched sibling. This case not only illustrates a potential new treatment option for selected patients, but also provides insights into the pathogenesis of this rare disease.

[Efficacy of intravenous immunoglobulin in Arndt-Gottron scleromyxedema]. / Efficacité des veinoglobulines dans le scléromyxoedème d'Arndt-Gottron.

BACKGROUND: Arndt-Gottron scleromyxedema is characterized by cutaneous mucinosis occasionally associated with systemic disorders, and it has a chronic and unpredictable course. The lesions are due to abnormal fibroblastic activity leading to acid mucopolysaccharide deposits in tissue. We report the case of a 50-year-old woman treated with intravenous immunoglobulin (IVIG), with excellent results in terms of her cutaneous lesions. CASE REPORT: A 50-year-old woman presented with multifocal micropapular lesions and cutaneous sclerosis that progressively limited joint movement and mouth opening and which were associated with a circulating monoclonal IgG Kappa. Previous treatments, including steroids, PUVA therapy, interferon, acitretin, methotrexate, melphalan and D-penicillamin were either ineffective or were stopped because of adverse effects. IVIG resulted in a remarkable and durable response at decreased dosage (0.5 g/kg per day for 3 days) with a 2-month treatment interval. DISCUSSION: IVIG at a dose of 2g/kg for 5 days constitutes a valuable alternative treatment because of its immunomodulatory effect. In scleromyxedema without systemic lesions, we propose a maintenance regimen at lower dosage, i.e. 0.5 g/kg per day for 3 days. CONCLUSION: Since Arndt-Gottron scleromyxedema is a rare disease, no standardized treatment has been yet established. The combination of minimal adverse effects and real efficacy makes IVIG an interesting alternative treatment for this disease.