Clinical spectrum of patients diagnosed with childhood mastocytosis: a retrospective single center experience.

Summary: Background. Pediatric cutaneous mastocytosis patients diagnosed and followed up by our specialist were enrolled in this study, and clinical and laboratory evaluations were retrospectively analyzed from patients' archived files. Methods. Patients, who applied to the Division of Pediatric Allergy And Immunology Unit of a University Training and Research Hospital between 01.01.2010 and 28.04.2021, were enrolled in this study. Results. Of the 33 patients included in the study, 11 (33.3%) were female and 22 (67.7%) were male. The median age of onset of the patient's complaints was 7 (0-60) months. The median age at diagnosis was 11 (2-64) months. Their complaints' median regression age was 54 (6-192) months. Resistant clinical findings were followed in 13 (39.4%) patients. Itching, redness, gastrointestinal symptoms, and maculopapular eruption were the most common complaints. The rashes were mostly polymorphic and larger than 1 cm. Heat was the most common trigger. Darier's sign was positive in 97% of the patients. Antihistamines were the most commonly used drug for prophylaxis and treatment. The autoinjector prescription rate was 24.2%. Conclusions. Quality of life was mildly affected in 48,5% of the patients based on the CDLQI scores. Thus, patients should be followed up through adolescence for the development of systemic signs and symptoms.

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.

COVID-19 Vaccines Are Safely Tolerated in Adolescents with Cutaneous Mastocytosis.

INTRODUCTION: The management of the COVID-19 vaccine in children with mastocytosis is unclear due to a lack of data. In the current study, we aimed to evaluate the adverse reactions following COVID-19 vaccination in adolescents with cutaneous mastocytosis (CM). METHODS: This study included 27 paediatric patients who were diagnosed with CM and were followed up in the paediatric allergy department of a tertiary care children's hospital. RESULTS: The median (IQR) age of the patients at the time of COVID-19 vaccination was 180 (156-203) months. Forty-four per cent of patients were vaccinated with the COVID-19 vaccine. Among all participants, the vaccination rate was found to be higher in older children, those who had been diagnosed with MPCM, and those who had not been infected with COVID-19 (p = 0.019, p = 0.009, p = 0.002, respectively). A total of 23 doses of the COVID-19 vaccine, including two doses of Sinovac/CoronaVac and 21 doses of Pfizer/BioNTech, were administered to 12 paediatric patients with CM. One of the patients had a history of intense itch, erythematous urticarial plaques, and had an exacerbation of existing skin lesions within 24-48 h after both doses of Pfizer/BioNTech vaccination. CONCLUSION: The COVID-19 vaccination of patients with CM in this series seems to be safe, and the rate of adverse events was comparable to that in the general population. These results found in adolescents with CM are in line with the existing evidence that CM does not preclude vaccination in children.

The Role of Mast Cells in the Induction and Maintenance of Inflammation in Selected Skin Diseases.

Under physiological conditions, skin mast cells play an important role as guardians that quickly react to stimuli that disturb homeostasis. These cells efficiently support, fight infection, and heal the injured tissue. The substances secreted by mast cells allow for communication inside the body, including the immune, nervous, and blood systems. Pathologically non-cancerous mast cells participate in allergic processes but also may promote the development of autoinflammatory or neoplastic disease. In this article, we review the current literature regarding the role of mast cells in autoinflammatory, allergic, neoplastic skin disease, as well as the importance of these cells in systemic diseases with a pronounced course with skin symptoms.

Perioperative management of mastocytosis.

PURPOSE: Patients with mastocytosis have an increased risk of anaphylaxis during surgical procedures with general anesthesia. Therefore, we reviewed the anesthesia course of a large cohort of patients with mastocytosis. METHODS: We retrospectively reviewed adult and pediatric patients with mastocytosis who underwent surgical procedures with general anesthesia at Mayo Clinic from January 1, 2000, through June 30, 2021. We also included any procedures with general anesthesia that occurred during the 3-year period preceding mastocytosis diagnosis and designated the patients who underwent these procedures as having an unknown diagnosis at the time of their surgical procedure. We analyzed whether patients received chronic antimediator treatment for mastocytosis and/or prophylactic medications before the procedures. We also determined whether medications indicative of mastocytosis-related adverse events were intraoperatively administered. RESULTS: We identified 113 patients who underwent 219 procedures during the study period; 25 procedures were performed before mastocytosis diagnosis. Of 194 procedures in patients with known mastocytosis, patients received chronic antimediator therapy and/or perioperative prophylactic medications for 178 (91.8%) procedures. Among these procedures, 10 were potentially complicated by mast cell activation, which was inferred from administration of inhaled albuterol (n = 3) or intravenous diphenhydramine (n = 8). In addition, there was only one case of intraoperative anaphylaxis which occurred in a patient who underwent anesthesia before mastocytosis diagnosis and therefore did not receive prophylaxis. CONCLUSION: Intraoperative anaphylaxis can be the first presenting sign of mastocytosis. Patients with mastocytosis who received chronic antimediator therapy and/or preoperative prophylactic medications had an uneventful surgical course.

Increased group 2 innate lymphoid cells in peripheral blood of adults with mastocytosis.

BACKGROUND: Systemic mastocytosis is a hematological disease in which aberrant mast cells accumulate because of gain-of-function mutations in the KIT receptor. Group 2 innate lymphoid cells (ILC2s) are effector cells of type 2 immune responses that also express KIT and colocalize with mast cells at barrier tissue sites. In mouse models, mast cell-ILC2 crosstalk can drive local inflammation. However, a possible role for ILC2s in the pathophysiology of mastocytosis remains unexplored. OBJECTIVE: We sought to characterize circulating ILC2s in a clinically diverse cohort of patients with mastocytosis. METHODS: We included 21 adults with systemic mastocytosis and 18 healthy controls. Peripheral blood ILC2 abundance and phenotype were analyzed by flow cytometry and correlated to clinical characteristics, including the presence of the D816V KIT mutation. RESULTS: ILC2 levels were significantly higher in D816V+ patients with mastocytosis compared with D816V- patients or healthy controls. We observed increased proportions of KIT+ ILC2s among patients with mastocytosis, regardless of D816V status. Patients with skin involvement and itch showed the highest levels of ILC2s, which was independent from atopy or serum tryptase levels. Allele-specific quantitative PCR showed that the vast majority of ILC2s did not carry the D816V mutation. CONCLUSIONS: Our findings suggest a role for ILC2s and pathogenic ILC2-mast cell crosstalk in mastocytosis. We hypothesize that a high cutaneous D816V+ mast cell burden alters the skin microenvironment to induce chronic local ILC2 activation and their dissemination into the circulation. Activated ILC2s could contribute to skin symptoms by producing inflammatory mediators and by further augmenting mast cell mediator release.

Developing a standardized approach for assessing mast cells and eosinophils on tissue biopsies: A Work Group Report of the AAAAI Allergic Skin Diseases Committee.

Mast cells and eosinophils are commonly found, expectedly or unexpectedly, in human tissue biopsies. Although the clinical significance of their presence, absence, quantity, and quality continues to be investigated in homeostasis and disease, there are currently gaps in knowledge related to what constitutes quantitatively relevant increases in mast cell and eosinophil number in tissue specimens for several clinical conditions. Diagnostically relevant thresholds of mast cell and eosinophil numbers have been proposed and generally accepted by the medical community for a few conditions, such as systemic mastocytosis and eosinophilic esophagitis. However, for other mast cell- and eosinophil-associated disorders, broad discrepancies remain regarding diagnostic thresholds and how samples are processed, routinely and/or specially stained, and interpreted and/or reported by pathologists. These discrepancies can obfuscate or delay a patient's correct diagnosis. Therefore, a work group was assembled to review the literature and develop a standardized consensus for assessing the presence of mast cells and eosinophils for a spectrum of clinical conditions, including systemic mastocytosis and cutaneous mastocytosis, mast cell activation syndrome, eosinophilic esophagitis, eosinophilic gastritis/enteritis, and hypereosinophilia/hypereosinophilic syndrome. The intent of this work group is to build a consensus among pathology, allergy, dermatology, hematology/oncology, and gastroenterology stakeholders for qualitatively and quantitatively assessing mast cells and eosinophils in skin, gastrointestinal, and bone marrow pathologic specimens for the benefit of clinical practice and patients.

Pleomorphic mastocytoma associated with loss of chromosome 5, PDGFRA, and HRAS mutations: A case of cutaneous mastocytosis with severe atypia and indolent behavior.

A 21-year-old female presented with a 5-year history of an erythematous papule on her right breast. The biopsy showed a dense, dermal nodular infiltrate, extending focally into the subcutaneous tissue. The infiltrate was composed predominantly of pleomorphic cells with bi-lobed, multi-lobed, horseshoe, or ring-shaped nuclei. There was a smaller subset of monomorphous cells characterized by a round, reniform, or elongated single-lobed nucleus. Accompanying cells included few foamy histiocytes, lymphocytes, and numerous scattered eosinophils. No necrosis, vascular invasion, or ulceration was present. The pleomorphic and monomorphic granular cells were positive for Giemsa stain as well as for tryptase, CD117, CD68, CD2, and CD30 immunohistochemistry and negative for S100, CD1a, myeloperoxidase, lysozyme, and CD56. Clinical examination was negative for any additional similar lesions and serum tryptase was within normal limits. The bone marrow was not biopsied. In addition, fluorescent in situ hybridization revealed multiple clones with loss of number 5 chromosome and PDGFRA and HRAS mutations. The lesion did not recur or progress after a 6-year clinical follow-up. To our full knowledge, we report the first case of pleomorphic mastocytoma with loss of chromosome 5 and PDGFRA and HRAS mutations.

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Pediatric maculopapular cutaneous mastocytosis: Retrospective review of signs, symptoms, and associated conditions.

BACKGROUND/OBJECTIVES: Though maculopapular cutaneous mastocytosis is the most common form of pediatric mastocytosis, it remains unclear which patients will experience severe symptoms. We sought to better define the presentation and the cutaneous and systemic signs and symptoms in patients with maculopapular cutaneous mastocytosis. METHODS: We analyzed retrospective data on 227 patients diagnosed with maculopapular cutaneous mastocytosis prior to age 15 years from five US clinical sites. We collected data on signs, symptoms, age of onset, and laboratory testing. RESULTS: Median age of onset of maculopapular cutaneous mastocytosis was 3 months, with 94% of patients presenting prior to age 2 (range 0-15 years). Patients presenting before age 2 had significantly lower serum tryptase level (P = .019). Greater number of skin lesions (P = .006), number of reported skin signs and symptoms (P < .001), and higher tryptase levels (P < .001) were associated with more systemic symptoms. CONCLUSION: Children with maculopapular cutaneous mastocytosis, who have greater skin involvement, higher serum tryptase level, and more skin signs and symptoms, are more likely to have systemic symptoms.

Anaphylaxis and epinephrine autoinjector use in pediatric patients with cutaneous mastocytosis.

BACKGROUND/OBJECTIVES: Mastocytosis is a complex disorder presenting with a broad clinical spectrum. In this study, we aimed to evaluate the frequency of systemic symptoms, necessity of the usage of epinephrine autoinjectors (EAI), and factors affecting the use of EAI among pediatric patients with cutaneous mastocytosis (CM). METHODS: The study population was composed of 53 patients with CM. The clinical data were collected from the medical files. A questionnaire about the patient's anaphylaxis experiences and treatment attitudes toward EAI was performed. RESULTS: Thirty-three of 53 patients were male (62.3%), and the median age of the study participants was 80 months. Anaphylaxis was reported in two patients (3.7%). One of the patients had drug-induced anaphylaxis, and the other had venom-induced anaphylaxis. Three patients (5.6%) reported a personal history of EAI use due to systemic symptoms. Patients with higher serum tryptase level and cases of familial mastocytosis had more systemic symptoms (P = .012 and P = .010, respectively). The patient rate of compliance with EAI for prescription filling and carrying the EAI was 88.7% and 79.2% respectively. 41.5% of parents were hesitant to use EAI when necessary, although they were trained for the use of it by medical staff. CONCLUSIONS: The rate of anaphylaxis in patients with CM in the current study wassignificant and justifies prescribing EAI. Detailed education and counseling on EAI usage are needed to reduce parental hesitancy.

Assessing vaccination reactions in pediatric patients with maculopapular cutaneous mastocytosis.

Immunization compliance in the United States is declining, in part due to misinformation and fear surrounding adverse vaccination reactions. Recently, there have been data published in the allergy and immunology literature to show that there may be a relationship between routine vaccinations and induction of symptoms in cutaneous mastocytosis patients; however, this has not yet been explored in the dermatology literature. We sought to uncover the prevalence of vaccine reactions due to mast cell activation within our cohort of maculopapular cutaneous mastocytosis (MPCM) patients in order to contribute to ensuring administration safety, managing familial expectations, and encouraging continued adherence. Our results indicate that while incidence of reaction rates may be higher than the national average, they are mild and families should be counseled to follow recommended immunization schedule guidelines.

Cutaneous mastocytosis: A dermatological perspective.

Mastocytosis is a rare disease characterised by expansion and collection of clonal mast cells in various organs including the skin, bone marrow, spleen, lymph nodes and gastrointestinal tract. The prevalence of mastocytosis has been estimated to be one in 10 000, while the estimated incidence is one per 100 000 people per year. Cutaneous mastocytosis is classified into (i) maculopapular cutaneous mastocytosis, also known as urticaria pigmentosa; (ii) diffuse cutaneous mastocytosis; and (iii) mastocytoma of the skin. In adults, cutaneous lesions are usually associated with indolent systemic mastocytosis and have a chronic evolution. Paediatric patients, on the contrary, have often cutaneous manifestations without systemic involvement and usually experience a spontaneous regression. Diagnosis of cutaneous mastocytosis may be challenging due to the rarity of the disease and the overlap of cutaneous manifestations. This short review describes pathogenesis and clinical aspects of cutaneous mastocytosis with a focus on diagnosis and currently available therapies.

-2518A/G polymorphism of monocyte chemotactic protein 1 (MCP-1/CCL2) is associated with cutaneous mastocytosis.

INTRODUCTION: Mastocytosis is a rare heterogeneous disease associated with pathological accumulation of mast cells (MCs) in one or more organs. The disease may be limited to the skin (cutaneous mastocytosis - CM), or present an internal organ involvement (systemic mastocytosis - SM). Pathophysiology of the disease is not well established. However altered proliferation, differentiation and chemotaxis of MC may play an essential role in the development of the disease. The monocyte chemotactic protein 1 (MCP-1/CCL2) may be one of the factors responsible for MCs migration to the skin and other organs. AIM: To analyse the frequency of biallelic A/G polymorphisms at position -2518 in the promoter of the MCP-1 gene and compare the serum level of MCP-1 in patients with both forms of mastocytosis and the healthy control group. MATERIAL AND METHODS: Using ARMS-PCR methods we analysed -2518A/G polymorphisms in the promoter region of the MCP-1 gene in 127 mastocytosis patients (95 CM and 32 SM), and 160 healthy controls. Additionally, the MCP-1 serum level was detected with ELISA technique in 70 patients and 40 controls. RESULTS: We have found that CM patients have more frequently the GG genotype of the MCP-1 gene (p = 0.01) in comparison to SM patients and controls. The GG genotype was more frequent in children than in adults (p = 0.02). The MCP-1 serum level was higher in SM patients than in CM patients and controls. CONCLUSIONS: Results of this study indicate that cutaneous mastocytosis could be associated with the -2518 A/G MPC-1 gene polymorphism.

Omalizumab in the treatment of adult patients with mastocytosis: A systematic review.

BACKGROUND: Mastocytosis is associated with mast cell (MC) mediator-related symptoms for which limited therapies are available. OBJECTIVE: Our aim was to assess the efficacy and safety of omalizumab in the treatment of MC mediator-related symptoms in adult patients with mastocytosis. RESULTS: We identified one multi-centre retrospective cohort study (39 patients), one retrospective cohort study (13 patients), 4 case series and 10 case reports. No published controlled randomized study was identified. We included 69 patients (13 patients with cutaneous mastocytosis and 56 with systemic mastocytosis). The mean age was 48 years. Omalizumab maintenance dose was 300 mg for the majority of patients. The mean duration of treatment was 17 months. Treatment led to a tolerability of venom immunotherapy and to a complete resolution of severe reactions in all patients with post-honeybee sting anaphylaxis. Complete resolution of idiopathic anaphylaxis episodes was noted in 84% of the patients. Complete resolution of palpitations, gastrointestinal, cutaneous, neuropsychiatric, respiratory and musculoskeletal symptoms was observed at a rate of 43%, 29%, 27%, 11%, 9% and 0%, respectively. Efficacy was maintained for the entire duration of the treatment in all but four responders. Adverse events were reported for 13 patients. CONCLUSIONS AND CLINICAL RELEVANCE: Omalizumab appears to prevent some life-threatening reactions associated with mastocytosis and may be a good option to treat the associated symptoms. However, the evidence relied upon is observational, uncontrolled and from a small number of patients. A randomized controlled trial is needed to better understand the place of omalizumab in mastocytosis treatment.

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

BACKGROUND: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM. METHODS: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM. RESULTS: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly. CONCLUSION: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.

[Pediatric cutaneous mastocytosis]. / Cas clinique : La mastocytose cutanée pédiatrique.

Mastocytosis are orphan diseases characterized by the accumulation of mast cells in one or more organs. A distinction is made between systemic forms (10 %) and pure cutaneous forms (90 %), the latter being mainly pediatric and generally having a spontaneously favourable prognosis. In the absence of a systemic sign, the diagnostic criteria for cutaneous mastocytosis are Darier's sign, in principle, pathognomonic, as well as skin histology confirming mast cell infiltration. The treatment is essentially preventive (avoidance of factors triggering degranulation) and symptomatic (antihistamine agents).

Les mastocytoses sont des maladies orphelines caractérisées par l'accumulation de mastocytes dans un ou plusieurs organes. On distingue les formes systémiques (10 %) des formes cutanées pures (90 %). Ces dernières sont principalement pédiatriques et ont, généralement, un pronostic spontanément favorable. En cas d'absence de signe d'appel systémique, les critères de diagnostic de mastocytose cutanée sont le signe de Darier, en principe, pathognomonique ainsi que l'histologie cutanée affirmant l'infiltration mastocytaire. Le traitement est essentiellement préventif (éviction des facteurs déclenchant la dégranulation) et symptomatique (médicaments antihistaminiques).

The efficacy of omalizumab in Cutaneous Mastocytosis: A case series.

BACKGROUND: Mastocytosis describes a heterogeneous group of disorders arising from a clonal proliferation of mast cells. Given the lack of curative treatments for the cutaneous form, there is a significant need for superior therapies. Omalizumab is a recombinant DNA-derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It represents a potential treatment for the management of cutaneous mastocytosis, which currently has no standard treatment. METHODS: Two patients were treated with subcutaneous omalizumab 300 mg every 4 weeks. DISCUSSION: Patient 1 experienced 50% reduction in cutaneous infiltration and moderate improvement in pruritus. Patient 2 underwent 90% complete clearance of cutaneous lesions and reported full resolution of pruritus. The median duration of treatment was 24 weeks and time to response was 8 weeks. No significant changes in tryptase levels were observed. Both patients experienced injection site reactions. CONCLUSION: We provide evidence from two cases supporting the efficacy of IgE-mediated therapy in the treatment of cutaneous mastocytosis. Even at a higher-than-standard dose (300 mg vs. 150 mg), the drug was well-tolerated. As we await the results of pivotal clinical trials, omalizumab appears to be a promising treatment option in patients with cutaneous mastocytosis unresponsive to traditional therapies.

Management of a neonate with diffuse cutaneous mastocytosis: Case report and literature review.

Mastocytosis is an accumulation of clonal mast cells within tissues, commonly caused by mutations in the KIT proto-oncogene. This report describes the management of a neonate with diffuse cutaneous mastocytosis (DCM) caused by a rare activating KIT mutation, specifically internal tandem duplication of the Ala502Tyr503 pair on exon 9, and reviews current data regarding work-up of DCM in pediatric patients.