Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

Telangiectasia macularis eruptiva perstans treated with narrow-band UVB phototherapy and heliotherapy during the COVID-19 pandemic

@#Telangiectasia macularis eruptiva perstans (TMEP) is a rare disease, previously classified as a variant of cutaneous mastocytosis. While no gold standard of treatment exists, several treatments have been studied. We report a case of a 63-year-old woman who presented with long-standing asymptomatic telangiectatic macules beginning on the upper chest, back, and bilateral arms, with occasional pruritus and no other systemic symptoms. Skin biopsy, along with Giemsa stain, revealed findings consistent with TMEP. The patient underwent testing for serum tryptase level, which was within normal limits. The patient was started on topical steroids for two weeks and antihistamine therapy, with a noted decrease in pruritus but no change in cutaneous lesions. She was then advised to start phototherapy, and subsequently underwent a total of five sessions of narrow-band ultraviolet B phototherapy, after which she noted lightening of the lesions. Due to the COVID pandemic, the patient was shifted to heliotherapy with continued lightening of lesions after two months of thrice weekly sessions. This rare case is supportive of narrow-band ultraviolet B phototherapy and heliotherapy as promising treatment options for cases of TMEP.

Hypnotherapy in Treatment of Mastocytosis: A Prospective Study.

Mastocytosis is an orphan disease associated with many systemic symptoms, chronic handicap, and potentially marked social consequences despite improved therapies. In this study, the authors aimed to measure the effect of 2 hypnosis sessions on mastocytosis symptoms in a clinical setting. Questionnaires (pain, flushes, energy, digestive symptoms, quality of life, perceived symptom severity, and global impression of change) were completed pre- and posthypnosis intervention. Data from 20 patients were analyzed (mean age: 53.3 years, 75% female). Compared to baseline assessment, patients exhibited a significant improvement immediately after the first and second hypnosis sessions with regard to the number of days with abdominal pain, abdominal pain intensity and fatigue (p = .03 and p = .005; p = .05 and p = .02; p = .034, and p = .039, respectively). Perceived severity of symptoms was significantly improved throughout the study (p = .0075). Long-term improvement in global impression of change was observed in half the responders (8/16). Patients with mastocytosis had an improvement in disabling symptoms with the impact of hypnotic intervention persisting at 1 month. Several patients experienced long-term improvement.

N-acetyl-L-cysteine reduces Leishmania amazonensis-induced inflammation in BALB/c mice.

BACKGROUND: Leishmaniasis is a emergent disease characterized by different clinical manifestations in both humans and dogs. Predominant clinical features of cutaneous leishmaniasis are ulcerative painless skin lesions. Several data reported that pain is associated with human and dog leishmaniasis, out with areas of painless ulcerative lesions per se. Actually, current medications used for leishmaniasis management are characterized by several side effects and, in addition, some cases of the disease are refractory to the treatment. On this background it is mandatory the identification of new and safe candidates for designing less toxic and low-cost remedies. Therefore, the search for new leishmanicidal compounds is indispensable. METHODS: In the present paper we investigated the effect of orally N-acetyl-L-cysteine (NAC) supplementation at dose of 200 mg/Kg for 10 weeks, in subcutaneous Leishmania (L). amazonensis infected BALB/c mice. And evaluating the effect of NAC on inflammatory response such as TNF-α, IL-6, IL-1ß levels, and on thermal and mechanical hyperalgesia. RESULTS: In the present paper we showed how NAC supplementation affected parameters of oxidative stress (GSH, MDA, SOD), inflammation such as cytokines levels (IL-1ß, IL-6, TNFα) and mast cell activation and consequently on induced pain, during leishmaniosis in BALB\c mice. CONCLUSIONS: The findings of our study provided the scientific data demonstrating that L. amazonensis infection induces inflammation and pain in BALB/c mice that are reversed by administration of NAC.

Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome.

Mast cell activation syndrome (MCAS) is a complex disorder hallmarked by chronic multisystem inflammatory, allergic and growth dystrophic phenomena caused by inappropriate mast cell activation. MCAS has been estimated to affect as many as 17% of the population with a severity ranging from mild to life-threatening. MCAS patients are more sensitive than the average person to chemicals in the environment, including the nondrug ("inactive") ingredients (excipients) in medications and supplements. Excipient reactivity may explain unusual side effects to medications health professionals often find puzzling, such as the patient who appears intolerant of prednisone, acetaminophen, levothyroxine, or a vitamin. We present a series of patients with MCAS to illustrate important points regarding excipient reactivity which may be useful in everyday practice.

Lower prevalence of vitamin D insufficiency in German patients with systemic mast cell activation syndrome compared with the general population.

Introduction The common mastocytosis variant systemic mast cell activation syndrome (MCAS) may underlie at least a subset of patients with irritable bowel syndrome (IBS). A critical role of vitamin D (VD) in the stabilization of mast cells (MCs) with deficiency of VD resulting in MC activation has been demonstrated. If so, supplementation of VD would be a potential therapeutic approach in the treatment of those IBS patients. Methods We investigated in the present study for the first time systematically whether the VD level in 100 MCAS patients differed from that in the German general population (Ggp) and made a first attempt to elucidate potential reasons for possible differences by simultaneously determining the blood levels of heparin and cholesterol. Results In contrast to the Ggp, the VD level was detected in a sufficient range (> 30 ng/mL) in 53 % of the MCAS patients (Ggp 8 %), and only 34 % had values in the range of deficiency (< 20 ng/mL; GgP 75 %). There was no correlation between VD blood level and heparin and cholesterol blood levels. Conclusions The demonstration that in the majority of MCAS patients the VD level is not in a deficient range argues against an essential contribution of VD deficiency to the high prevalence of MCAS in Germany. Our findings do not exclude the possibility of smaller effects of VD level on MC activation in vivo. However, if such effects are present, the effect sizes seem to be too small to become identifiable in the multifactorial process of disease development.

Natural history and treatment of cutaneous and systemic mastocytosis.

INTRODUCTION: Mastocytosis, a heterogeneous group of disorders, is characterized by an abnormal increase in the number of mast cells that is limited to the skin (cutaneous mastocytosis), involving extracutaneous tissues (systemic mastocytosis), or presenting as solid tumours (mastocytoma and mast cell sarcoma). Recent studies estimate that 1 in 10,000 people are diagnosed with mastocytosis. Although prompt diagnosis and appropriate management are crucial, little is known about the natural history and currently there are no established management guidelines. We have conducted a systematic review to assess the natural history and management of different mastocytosis subtypes. METHODS: A systematic review and meta-analysis were conducted using the PubMed and Ovid database of studies published in English and French over the last fifteen years, from January 2001 to December 2016. Keywords 'Cutaneous mastocytosis', 'Systemic mastocytosis', 'pathophysiology', 'clinical course', 'prognosis', 'drug therapy', and 'therapy' were searched. Rate of complete resolution was subjected to pooled analysis for different mastocytosis subtypes. Meta-analysis was conducted using Stata version 12.0. RESULTS: We reviewed 634 papers, of which 5 were included in the analysis of resolution, and 138 were included in the assessment of management. Pooled estimate for rate of complete resolution varied depending on the mastocytosis subtype. In cutaneous mastocytosis, the complete resolution rate for mastocytoma was 10% per year (95% CI: 4.8%, 15.1%) while the rate for urticaria pigmentosa was 1.9% per year (95% CI: -0.5%, 4.3%). Diffuse cutaneous mastocytosis and systemic mastocytosis subtypes did not show evidence of complete resolution in the studies reviewed. Treatment of cutaneous and systemic mastocytosis is purely symptomatic with topical corticosteroids, antihistamines, omalizumab and imatinib being common choices. CONCLUSION: Rate of resolution of mastocytosis is only shown in urticaria pigmentosa and mastocytoma. Better management guidelines are required to improve the health of these patients.

Actualización en mastocitosis. Parte 2: categorías, pronóstico y tratamiento / Update on Mastocytosis (Part 2): Categories, Prognosis, and Treatment

Las mastocitosis constituyen un grupo heterogéneo de enfermedades caracterizadas por la proliferación clonal de mastocitos en distintos órganos, siendo la localización cutánea la más frecuente. La Organización Mundial de la Salud (OMS) clasifica las mastocitosis cutáneas en mastocitomas, mastocitosis máculo-papulosas y mastocitosis cutánea difusa, mientras que las formas sistémicas incluyen las mastocitosis indolentes, las agresivas, las asociadas a otra hematopatía monoclonal y la leucemia mastocitaria; el sarcoma mastocitario y el mastocitoma extracutáneo son variantes muy poco frecuentes. Aunque la evolución de la enfermedad en los niños es impredecible, con frecuencia las lesiones desaparecen durante la infancia; en los adultos la enfermedad tiende a persistir. El tratamiento se dirige a controlar las manifestaciones clínicas debidas a la acción de los mediadores mastocitarios, mientras que las formas agresivas requerirán de tratamientos dirigidos a reducir la masa mastocitaria

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in different organs. The organ most often affected is the skin. The World Health Organization classifies cutaneous mastocytosis into mastocytoma, maculopapular cutaneous mastocytosis, and diffuse mastocytosis. The systemic variants in this classification are as follows: indolent systemic mastocytosis (SM), aggressive SM, SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. The two latest systemic variants are rare. Although the course of disease is unpredictable in children, lesions generally resolve by early adulthood. In adults, however, the disease tends to persist. The goal of treatment should be to control clinical manifestations caused by the release of mast cell mediators and, in more aggressive forms of the disease, to reduce mast cell burd

Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy.

IgE antibodies and mast cells play critical roles in the establishment of allergic responses to food antigens. Curcumin, the active ingredient of the curry spice turmeric, has anti-inflammatory properties, and thus may have the capacity to regulate Th2 cells and mucosal mast cell function during allergic responses. We assessed whether curcumin ingestion during oral allergen exposure can modulate the development of food allergy using a murine model of ovalbumin (OVA)-induced intestinal anaphylaxis. Herein, we demonstrate that frequent ingestion of curcumin during oral OVA exposure inhibits the development of mastocytosis and intestinal anaphylaxis in OVA-challenged allergic mice. Intragastric (i.g.) exposure to OVA in sensitized BALB/c mice induced a robust IgE-mediated response accompanied by enhanced OVA-IgE levels, intestinal mastocytosis, elevated serum mMCP-1, and acute diarrhea. In contrast, mice exposed to oral curcumin throughout the experimental regimen appeared to be normal and did not exhibit intense allergic diarrhea or a significant enhancement of OVA-IgE and intestinal mast cell expansion and activation. Furthermore, allergic diarrhea, mast cell activation and expansion, and Th2 responses were also suppressed in mice exposed to curcumin during the OVA-challenge phase alone, despite the presence of elevated levels of OVA-IgE, suggesting that curcumin may have a direct suppressive effect on intestinal mast cell activation and reverse food allergy symptoms in allergen-sensitized individuals. This was confirmed by observations that curcumin attenuated the expansion of both adoptively transferred bone marrow-derived mast cells (BMMCs), and inhibited their survival and activation during cell culture. Finally, the suppression of intestinal anaphylaxis by curcumin was directly linked with the inhibition of NF-κB activation in curcumin-treated allergic mice, and curcumin inhibited the phosphorylation of the p65 subunit of NF-κB in BMMCs. In summary, our data demonstrates a protective role for curcumin during allergic responses to food antigens, suggesting that frequent ingestion of this spice may modulate the outcome of disease in susceptible individuals.

Molecular defects in mastocytosis: KIT and beyond KIT.

In all variants of mastocytosis, activating KIT mutations are frequently found. In adults, neoplastic mast cells (MCs) cells show the KIT mutation D816V, whereas in children, MCs invading the skin are frequently positive for non-KIT D816V mutations. The clinical course and prognosis of the disease vary among patients with systemic mastocytosis (SM). Additional KIT-independent molecular defects might cause progression. Additional oncogenic lesions have recently been identified in advanced SM. In advanced SM the presence of additional genetic lesions or altered signaling worsening the prognosis might lead to the use of alternative therapies such as combined antisignaling targeted treatments or stem cell transplantation.

Taurine drinking attenuates the burden of intestinal adult worms and muscle larvae in mice with Trichinella spiralis infection.

The parasitic nematode Trichinella spiralis can cause trichinellosis, which leads to pathological processes in the intestine and muscle. The intestinal invasion determines the development, subsequent course, and consequences of the disease. Gastrointestinal nematode infection, including with T. spiralis, is accompanied by a rapid and reversible expansion of mucosal mast cell and goblet cell in the intestinal epithelium, which play important roles in the host immune response to parasite and worm expulsion from the intestine. Taurine and its derivatives have anti-infection and anti-inflammatory properties. We investigated whether taurine supplementation in mice could influence the development and pathological processes of infection with T. spiralis. Supplementing 1% taurine in drinking water in mice infected with T. spiralis could alleviate the burden of intestinal adult worms on days 7 and 10 postinfection (all p < 0.01) and the formation of infective muscle larvae in striated muscle during T. spiralis infection (p < 0.01). As compared with T. spiralis infection alone, taurine treatment increased the number of goblet cells on days 7, 10, and 15 (p < 0.01 and p < 0.05) and alleviated intestinal mucosal mast cell hyperplasia on days 10 and 15 (all p < 0.01). So taurine supplementation in drinking water increased infection-induced intestinal goblet cell hyperplasia and ameliorated mucosal mastocytosis. Thus, taurine can ameliorate the pathological processes of trichinellosis and may be of great value for the treatment and prevention of infection with T. spiralis and other gastrointestinal nematodes.

The RCPCH care pathway for children with urticaria, angio-oedema or mastocytosis: an evidence and consensus based national approach.

AIMS: The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies; the urticaria, angio-oedema or mastocytosis pathway is the fifth pathway. The pathways focus on defining the competences required to improve the equity of care received by children with allergic conditions. METHOD: The urticaria, angio-oedema or mastocytosis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. RESULTS: Three pathways are described: urticaria with or without angio-oedema, angio-oedema without weals, and mastocytosis. The results are presented in four parts: evidence review, mapping, external review and core knowledge documents. Acute urticaria has many causes and is often not allergic in origin. It is frequently of relatively short duration and easily managed with antihistamines alone. However, at the other extreme, causes of chronic urticaria and angio-oedema are difficult to diagnose and treatment can be complex. Thus defining the competence required for each extreme is critical to ensure optimal care. The evidence review identified that allergy testing and thyroid function testing were helpful in the investigation of chronic urticaria, that increasing the dose of antihistamine was effective in treating urticaria and that ciclosporin A and prednisolone were effective second line treatments. CONCLUSIONS: From the common presentation of acute (intermittent) urticaria to the uncommon presentations of chronic urticaria, angio-oedema and cutaneous mastocytosis, this pathway is a tool to assist health professionals to differentiate and manage these conditions.

[Systemic mastocytosis--definition of an internal disease]. / Die systemische Mastozytose--Standortbestimmung einer internistischen Erkrankung.

Systemic mastocytosis comprises disorders characterized by an accumulation of genetically altered mast cells in all organs and tissues due to an increased proliferation rate and reduced apoptosis of those pathologic mast cells. Release of their mediators can effectively influence organ function and can lead to systemic effects without inducing traces in routinely used laboratory parameters or imaging methods. In most cases, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy consisting of a basic medication with antihistamine and mast cell membrane-stabilizing compounds that should be supplemented, if required, by a medication adapted to individual symptoms, can be initiated. Because of the probably high prevalence of the disorder, systemic mastocytosis should be considered as a differential diagnosis in particular in the case of chronic gastrointestinal complaints such as abdominal pain/discomfort possibly associated with diarrhea, at an early stage.

Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours.

The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67.7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.

Diffuse Cutaneous Mastocytosis with Generalized Bullae

We report on a 9-month-old female infant with multiple tense bullae and erosions covering the entire body, including the face, scalp, and trunk. The histopathological examination revealed sub-epidermal bullae with a dense dermal cellular infiltrate. The infiltrate was identified as a collection of mast cells using toluidine blue and Giemsa stains. The direct immunofluorscence was negative. A diagnosis of cutaneous diffuse mastocytosis with generalized bullae was made based on these clinical and histopathological findings. In cases with diffuse cutaneous mastocytosis with generalized bullae, systemic involvement is more frequent and more severe compared to other types of cutaneous mastocytosis. Some lethal outcomes have been reported. This is the first reported case of diffuse cutaneous mastocytosis in the Korean literature.

Mastocitosis en un lactante / Mastocytosis in an infant

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