ABSTRACT
Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10-15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10-12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10-9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10-14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10-11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (ß)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10-8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Mastocytosis/genetics , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-kit/genetics , Amino Acid Transport System y+/genetics , CCAAT-Enhancer-Binding Proteins/genetics , DNA, Intergenic , Female , Humans , Interleukin-13/genetics , Introns , Male , RNA, Long Noncoding/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Repressor Proteins/genetics , Telomerase/genetics , Tryptases/geneticsABSTRACT
INTRODUCTION: Venom immunotherapy (VIT) and adrenaline autoinjector (AAI) are important therapies in venom anaphylaxis. Adherence to VIT and AAI in patients with venom allergy has been evaluated in a few studies; however, solid data are lacking. This study aimed to evaluate VIT and AAI retrieval rates in patients with venom allergy with a special focus on adherence to treatment. Adherence was compared to subcutaneous immunotherapy (SCIT) with inhalant allergens. METHODS: This was a retrospective study among patients registered for allergen immunotherapy at the Allergy Center, Odense University Hospital, Denmark, from January 1, 2010, to December 31, 2014. Data on purchased immunotherapy and AAI were obtained from the Danish National Health Service Prescription Database. Multivariable logistic regression was used to analyze if allergen, age, sex, mastocytosis, and treatment site affected adherence. RESULTS: The 3-year adherence to VIT was 92.4% (244/264) compared to 87.4% (215/246) in SCIT with inhalant allergens, and the 5-year adherence to VIT was 84.1% (222/264) compared to 74.8% (184/246) in SCIT with inhalant allergens (p = 0.045). Females treated with VIT were more adherent than males (p = 0.45 [3-year], p = 0.008 [5-year]), whereas allergen, age, mastocytosis, or treatment site did not significantly affect adherence. Only 28.6% of patients (12/42) purchased an AAI after premature termination of VIT. CONCLUSION: In this register-based study, we found that the 3- and 5-year adherences to VIT and SCIT with inhalant allergens are at the upper end of the spectrum hitherto reported. Patients' 5-year adherence to VIT was higher than patients' 5-year adherence to SCIT with inhalant allergens. If VIT was prematurely terminated, less than 1/3 would have purchased an AAI.
Subject(s)
Anaphylaxis , Insect Bites and Stings , Mastocytosis , Venom Hypersensitivity , Male , Female , Humans , Epinephrine/therapeutic use , Retrospective Studies , State Medicine , Anaphylaxis/epidemiology , Anaphylaxis/etiology , Desensitization, Immunologic/adverse effects , Allergens , ImmunotherapyABSTRACT
Mast cell neoplasms are an emerging challenge in the fields of internal medicine, allergy, immunology, dermatology, laboratory medicine, and pathology. In this review, we discuss the current standards for the diagnosis and prognostication of mast cell neoplasms with special reference to clinically relevant germline and somatic gene variants. In patients with cutaneous mastocytosis or with indolent systemic mastocytosis (SM), various KIT-activating mutations act as key molecular drivers of the disease. In adults, KIT p.D816V is by far the most prevalent driver, whereas other KIT mutants are detected in nearly 40% of children. In advanced SM, including aggressive SM, SM with an associated hematological neoplasm, and mast cell leukemia, additional somatic mutations in other genes, such as SRSF2, JAK2, RUNX1, ASXL1, or RAS, may be detected. These drivers are more frequently detected in SM with an associated hematological neoplasm, particularly in male patients. Recently, hereditary alpha-tryptasemia has been identified as a genetic trait more prevalent in SM compared with healthy controls. Moreover, hereditary alpha-tryptasemia is more frequent in patients with SM with Hymenoptera venom allergy and severe mediator-related symptoms than in patients with SM without symptoms. On the basis of this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathologic criteria to establish the diagnosis and prognosis in SM.
Subject(s)
Hematologic Neoplasms , Mastocytosis, Systemic , Adult , Child , Cytogenetic Analysis , Genetic Markers , Humans , Male , Mast Cells/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/pathology , Mutation , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Disease Management , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Systemic/drug therapy , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Diphosphonates/therapeutic use , Expert Testimony , Glucocorticoids/adverse effects , Histamine Antagonists/therapeutic use , Humans , Immunosuppressive Agents/adverse effects , Mast Cells/drug effects , Mast Cells/immunology , Mast Cells/pathology , Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/epidemiology , Mastocytosis, Cutaneous/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/epidemiology , Mastocytosis, Systemic/pathology , Myeloablative Agonists/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Precision Medicine/methods , Risk Factors , SARS-CoV-2 , Vitamin D/therapeutic useABSTRACT
In childhood, the most common type of eczema/dermatitis is atopic dermatitis, which occurs in up to 25% of children world-wide. However, the diagnosis may sometimes be challenging and atopic dermatitis may resemble other types of dermatitis as well as other skin diseases such as psoriasis, infections, infestations and malignancies as well as metabolic, genetic and autoimmune disorders. This review will focus on how to recognize the most common types of dermatitis in children and adolescents and how to separate them from the most common differential diagnoses clinically and histologically.
Subject(s)
Dermatitis, Atopic/diagnosis , Eczema/diagnosis , Psoriasis/diagnosis , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , MaleABSTRACT
BACKGROUND: While much is known on childhood atopic diseases, knowledge about persistence of atopic diseases from childhood to adulthood is limited. We therefore aimed to study the clinical course of atopic diseases and type I sensitization prospectively in an unselected cohort of adolescents followed into adulthood. METHODS: A cohort of unselected 8th-grade school children (mean age 14 years) established in 1995 and followed up in 2010 were evaluated with questionnaire, clinical examination, skin prick tests and measurements of specific IgE. RESULTS: The lifetime prevalence of atopic diseases was high and increased significantly from adolescence (31%) to adulthood (57%); particularly allergic rhinitis increased with an incidence rate of 17.5/1000 person-years. Childhood predictors for adult allergic rhinitis were atopic dermatitis, asthma and asymptomatic sensitization to pollen and house dust mite. Among those with asymptomatic sensitization in adolescence, 53%-78% developed allergic rhinitis in adulthood. Furthermore, type I sensitization increased significantly from adolescence to adulthood mostly due to increased sensitization to pollen. Type I sensitization was found mainly in those with allergic rhinitis. A high number of adults had oral allergy symptoms due to the high number of birch pollen allergic individuals. CONCLUSION: Persistence of atopic diseases in adulthood is common, and a high proportion of the adult population is sensitized giving a high prevalence of allergic rhinitis. Many with asymptomatic sensitization in adolescence will develop allergic rhinitis in adult life. The focus should be on prevention of atopic diseases and sensitization already in childhood.
Subject(s)
Allergens/immunology , Hypersensitivity, Immediate/epidemiology , Hypersensitivity, Immediate/immunology , Immunoglobulin E/immunology , Rhinitis, Allergic/epidemiology , Rhinitis, Allergic/immunology , Adolescent , Adult , Biomarkers , Dermatitis, Atopic/epidemiology , Female , Humans , Hypersensitivity, Immediate/diagnosis , Male , Prevalence , Prognosis , Rhinitis, Allergic/diagnosis , Skin Tests , Surveys and QuestionnairesABSTRACT
Mast cell activation syndrome (MCAS) is a condition characterized by recurrent episodes of clinically relevant, systemic, severe reactions to mast cell (MC)-derived mediators released in the context of anaphylaxis or another acute MC-related event. It is important to document MC involvement in these reactions in order to establish the diagnosis MCAS. The most specific and reliable marker of systemic MC activation is an acute and substantial event-related (transient) increase in the serum tryptase level over the individual's baseline value. However, the baseline level of tryptase varies depending on the underlying disease and the genetic background. For example, an estimated 3-5% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding for alpha-tryptase, and over 30% of all patients with myeloid neoplasms, including mastocytosis, have elevated basal tryptase levels. Therefore, it is of utmost importance to adjust the event-related diagnostic (MCAS-confirming) increase in tryptase over the individual baseline in a robust approach. To address this challenge, the 20% + 2 formula was proposed by the consensus group in 2012. Since then, this approach has been validated in clinical practice by independent groups and found to be sound. In the current article, we discuss the emerging importance and value of the 20% + 2 formula in clinical practice and its role as a criterion of severe systemic MC activation and MCAS.
Subject(s)
Biomarkers , Mast Cells/enzymology , Mastocytosis/blood , Mastocytosis/diagnosis , Tryptases/blood , Anaphylaxis/blood , Anaphylaxis/diagnosis , Humans , Mast Cells/immunology , Mastocytosis/immunology , Reference Values , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
AIM: To investigate and gain knowledge about patients' perspectives on everyday life with mastocytosis and how they experience, understand and manage symptoms and challenges. BACKGROUND: Indolent systemic mastocytosis (ISM) is a disease characterised by the accumulation and activation of mast cells. Symptoms are diverse and range from mild to severely debilitating or even fatal. It is considered rare but is underdiagnosed due to lack of awareness. Quantitative studies have shown that ISM can negatively impact quality of life. No qualitative studies have described everyday life with the disease. DESIGN: A qualitative interview study taking a phenomenological approach. METHODS: Seven qualitative, semi-structured interviews with adult patients with ISM. The analysis was inspired by Giorgi's phenomenological method. COREQ reporting guidelines were used. RESULTS: Three themes and five subthemes emerged from the analysis. (a) The everyday life with a rare disease, unknown to most people. Being perceived as a hypochondriac in the encounter with the health system. The diagnosis makes a difference. Expert knowledge is important. (b) Living with and handling the invisible and visible symptoms. The visible body. (c) Fearing an attack. Feeling safe and vulnerable at the same time. CONCLUSION: Patients with ISM are severely affected in their everyday lives, especially in terms of their relationship with family and social network. Symptoms restrict and complicate activities and participation in social contexts, and the fear of an anaphylactic attack is always present. The disease affects patients' self-perception and sexuality. The rarity of the disease and general low awareness seems to be of great importance in the encounter with the healthcare system, both before and after diagnosis, and there is a need for expert knowledge, support and care. RELEVANCE FOR CLINICAL PRACTICE: The focus of counselling should not only be on the disease itself, but also on living life with the disease.
Subject(s)
Mastocytosis, Systemic/psychology , Quality of Life , Adult , Attitude of Health Personnel , Counseling , Female , Humans , Male , Mastocytosis, Systemic/nursing , Mastocytosis, Systemic/physiopathology , Middle Aged , Qualitative ResearchABSTRACT
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.
Subject(s)
Mastocytosis, Cutaneous/classification , Allergy and Immunology , Consensus , Humans , Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/immunology , Societies, MedicalABSTRACT
Next-generation sequencing (NGS) is becoming increasingly used for diagnostic mutation analysis in myeloid neoplasms and may also represent a feasible technique in mastocytosis. However, detection of the KIT D816V mutation requires a highly sensitive method in most patients due to the typically low mutation levels. In this study, we established an NGS-based KIT mutation analysis and analyzed the sensitivity of D816V detection using the Ion Torrent platform. Eighty-two individual NGS analyses were included in the study. All samples were also analyzed using highly sensitive KIT D816V mutation-specific qPCR. Measurements of the background level in D816V-negative samples supported a cutoff for positivity of 0.2% in three different NGS panels. Clinical samples from patients with SM that tested positive using qPCR with a D816V allele burden >0.2% also tested positive using NGS. Samples that tested positive using qPCR with an allele burden <0.2% tested negative using NGS. We thereby demonstrate that caution should be taken when using the potentially very sensitive NGS technique for KIT D816V mutation analysis in mastocytosis, as many patients with SM have D816V mutation levels below the detection limit of NGS. A dedicated and highly sensitive KIT D816V mutation analysis therefore remains important in mastocytosis diagnostics.
Subject(s)
High-Throughput Nucleotide Sequencing/methods , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , Mutation , Proto-Oncogene Proteins c-kit/genetics , Adult , Alleles , Case-Control Studies , DNA Mutational Analysis , Female , Gene Expression , Humans , Male , Mastocytosis, Systemic/pathology , Real-Time Polymerase Chain ReactionABSTRACT
In patients with systemic mastocytosis (SM), several aspects of morbidity remain poorly understood. We assessed the risk of solid cancers, cardiovascular disease, anaphylaxis, osteoporosis, and fractures in SM patients. Using Danish medical registries, we conducted a nationwide population-based cohort study including 687 adult (≥15 years) SM patients diagnosed during 1997-2012. A comparison cohort of 68,700 subjects from the general Danish population who were alive and without SM at the given SM subject's diagnosis were age- and gender-matched. Outcomes were a new diagnosis of solid cancer, venous thromboembolism (VTE), myocardial infarction (MI), stroke, anaphylaxis, osteoporosis, or fracture. For solid cancers the hazard ratio (HR) was 2.4 (95% confidence interval [CI] 1.9-2.8) with a 10-year absolute risk (AR) in the SM-cohort of 12.6% (95% CI 9.4-16.3). Specifically, we found a HR of 7.5 (95% CI 4.4-13.0) for melanoma and a HR of 2.5 (95% CI 1.7-3.5) for non-melanoma skin cancers (NMSCs). For VTE we found a HR of 1.9 (95% CI 1.2-3.0), with a 10-year AR of 3.9% (95% CI 2.3-6.1); for MI a nonsignificant increased HR of 1.4 (95% CI 0.9-2.3), with a 10-year AR of 1.8% (95% CI 0.9-3.2); and for stroke a HR of 1.6 (95% CI 1.1-2.3) with a 10-year AR of 4.6% (95% CI 2.8-6.9). The HR for anaphylaxis was 7.2 (95% CI 5.3-9.9), and the 10-year AR was 3.1% (95% CI 1.9-4.9). For osteoporosis the HR was 3.6 (95% CI 2.7-4.6) with a 10-year AR of 7.2% (95% CI 5.2-9.8). For fractures the HR was 1.2 (95% CI 0.9-1.6) and the 10-year AR was 5.9% (95% CI 3.9-8.4). SM patients are at increased risk of solid cancers - especially melanoma and NMSC-and cardiovascular disease. The risk of anaphylaxis and osteoporosis is clearly increased in SM, though absolute risk was low in this population-based study. The fracture-risk was only slightly increased. Am. J. Hematol. 91:1069-1075, 2016. © 2016 Wiley Periodicals, Inc.
Subject(s)
Mastocytosis, Systemic/complications , Mastocytosis, Systemic/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Anaphylaxis/etiology , Cardiovascular Diseases/etiology , Cohort Studies , Fractures, Bone/etiology , Humans , Middle Aged , Neoplasms/etiology , Netherlands/epidemiology , Osteoporosis/etiology , Proportional Hazards Models , Registries , Risk Assessment , Young AdultABSTRACT
Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.
Subject(s)
Mastocytosis/diagnosis , Mastocytosis/therapy , Congresses as Topic , Consensus , Diagnosis, Differential , Humans , Mastocytosis/classification , Mastocytosis/epidemiology , Practice Guidelines as Topic , Prevalence , Scandinavian and Nordic Countries/epidemiology , World Health OrganizationABSTRACT
Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of mast cells. Systemic mastocytosis (SM), in which abnormal mast cells are present in tissues beyond the skin, is divided into seven subcategories with varying degrees of severity and prognosis. Very little is known about the epidemiology of SM and its subcategories. This retrospective cohort study of 548 adults with SM diagnosed 1997-2010 was constructed using linked Danish national health registries. The most common subtype of mastocytosis was indolent SM (including urticaria pigmentosa) (n = 450; 82%), followed by SM with subtype unknown (n = 61; 11%), SM with associated clonal haematological non-mast cell lineage disease (n = 24; 4%), aggressive SM (n = 8; 2%), and mast cell leukaemia (n = 5; 1%). The incidence rate for SM (all subtypes including urticaria pigmentosa) was 0·89 per 100 000 per year. Cumulative incidence was 12·46 per 100 000, and the 14-year limited-duration prevalence as of 1 January, 2011 was 9·59 per 100 000. This nationwide cohort from Denmark is the first population-based epidemiological study of mastocytosis. In this cohort of patients aged 15 years and older, SM was found to be overall relatively rare with notable variation by subtype for patient characteristics, survival and epidemiological measures.
Subject(s)
Mastocytosis, Systemic/epidemiology , Adolescent , Adult , Aged , Denmark/epidemiology , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
The recent progress in sensitive KIT D816V mutation analysis suggests that mutation analysis of peripheral blood (PB) represents a promising diagnostic test in mastocytosis. However, there is a need for systematic assessment of the analytical sensitivity and specificity of the approach in order to establish its value in clinical use. We therefore evaluated sensitive KIT D816V mutation analysis of PB as a diagnostic test in an entire case-series of adults with mastocytosis. We demonstrate for the first time that by using a sufficiently sensitive KIT D816V mutation analysis, it is possible to detect the mutation in PB in nearly all adult mastocytosis patients. The mutation was detected in PB in 78 of 83 systemic mastocytosis (94%) and 3 of 4 cutaneous mastocytosis patients (75%). The test was 100% specific as determined by analysis of clinically relevant control patients who all tested negative. Mutation analysis of PB was significantly more sensitive than serum tryptase >20 ng/mL. Of 27 patients with low tryptase, 26 tested mutation positive (96%). The test is furthermore readily available and we consider the results to serve as a foundation of experimental evidence to support the inclusion of the test in diagnostic algorithms and clinical practice in mastocytosis.
Subject(s)
Mastocytosis/blood , Mastocytosis/genetics , Proto-Oncogene Proteins c-kit/genetics , Adult , Bone Marrow Cells/pathology , Case-Control Studies , DNA Mutational Analysis , Diagnostic Tests, Routine , Humans , Mastocytosis/enzymology , Mastocytosis/pathology , Mutation , Proto-Oncogene Proteins c-kit/blood , Tryptases/blood , Tryptases/geneticsABSTRACT
BACKGROUND: Clinical manifestations of indolent systemic mastocytosis (ISM) comprise mediator-related symptoms, anaphylaxis, and osteoporosis. A new sensitive method for KIT D816V mutation detection allows quantification of the level of mutation-positive cells. OBJECTIVE: To investigate whether the fraction of KIT D816V positive cells in peripheral blood (PB) or bone marrow (BM) aspirate in adult patients with ISM correlates with clinical manifestations of the disease. METHODS: We included 48 adult patients with ISM (28 females/20 males) from our center in whom the KIT D816V mutation level in both BM aspirate and PB was analyzed. For each patient, the severity of mediator-related symptoms (skin, gastrointestinal, musculoskeletal, and neuropsychiatric) and episodes of anaphylaxis were evaluated by interview and medical record files. Bone mineral density was determined by using dual-energy x-ray absorptiometry. RESULTS: Median fraction (range) of KIT D816V positive cells was 0.6 (0.01%-90%) in BM and 0.3 (0.003%-49%) in PB. Mutation level did not differ between patients with none/mild symptoms and patients with moderate/severe symptoms, patients with and without anaphylaxis, or patients with osteoporosis/osteopenia and normal bone mineral density. No significant differences in clinical profile were detected in patients with different levels of mutation except for an indication of longer disease duration and age in patients with highest mutation levels. CONCLUSION: To our knowledge, this is the first report on the clinical impact of the fraction of KIT D816V mutation positive cells in ISM, which in the present study does not seem to correlate with clinical manifestations of the disease.
Subject(s)
Mastocytosis, Systemic/genetics , Proto-Oncogene Proteins c-kit/genetics , Adult , Aged , Anaphylaxis/complications , Anaphylaxis/genetics , Bone Marrow Cells/metabolism , Female , Humans , Male , Mastocytosis, Systemic/complications , Middle Aged , Mutation , Osteoporosis/complications , Osteoporosis/genetics , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: Mastocytosis is characterized by an accumulation of clonal mast cells (MCs) in tissues such as the skin. Skin lesions in mastocytosis may be clinically subtle or heterogeneous, and giving the correct diagnosis can be difficult. METHODS: This study compiles personal experiences together with relevant literature, discussing possible obstacles encountered in diagnosing skin involvement in mastocytosis and cutaneous mastocytosis (CM). RESULTS: The nomenclature of the term "CM" is ambiguous. The WHO classification defines CM as mastocytosis solely present in the skin. However, the term is also used as a morphological description, e.g., in maculopapular cutaneous mastocytosis (MPCM). This is often seen in systemic, as well as cutaneous, mastocytosis. Typical CM manifestations (MPCM), including mastocytoma or diffuse cutaneous mastocytosis (DCM), all share a positive Darier's sign, and can thus be clinically recognized. Nevertheless, distinguishing monomorphic versus polymorphic MPCM may be challenging, even for experienced dermatologists. Less typical clinical presentations, such as MPCM with telangiectatic erythemas (formerly called telangiectasia macularis eruptiva perstans), confluent, nodular or xanthelasmoid variants may require a skin biopsy for histopathological confirmation. Because MC numbers in CM have a large overlap to those in healthy and inflamed skin, detailed histopathological criteria to diagnose mastocytosis in MPCM are needed and have been proposed. D816V KIT mutational analysis in tissue is helpful for confirming the diagnosis. Biomarkers allow the prediction of the course of CM into regression or evolution of the disease. Further diagnostic measures should screen for concomitant diseases, such as malignant melanoma, and for systemic involvement. CONCLUSIONS: Whereas in typical cases the diagnosis of CM may be uncomplicated, less typical manifestations may require specific investigations for making the diagnosis and predicting its course.
ABSTRACT
Systemic mastocytosis (SM) is characterized by the growth of neoplastic mast cells (MCs). Most adults with indolent SM carry the KIT D816V mutation. We recently introduced the D816V+ allele fraction as a disease marker in SM using a sensitive and quantitative KIT D816V mutation analysis that consistently allows mutation detection in peripheral blood (PB) and bone marrow (BM). The D816V+ allele fraction represents a quantitative measure which allows KIT D816V-positivity to be analyzed as a continuous variable instead of a categorical variable (negative/positive) as previously described. Serum tryptase represents an established disease marker in SM, and it remains to be tested whether tryptase and the D816V+ allele fraction are associated or represent independent disease markers. In this study, correlation analysis between serum tryptase, the D816V+ allele fraction in PB and BM, and the MC fraction was performed in 57 indolent systemic mastocytosis (ISM) patients. We detected significant correlations between the D816V+ allele fraction, the mature neoplastic MC fraction, and serum tryptase which represent three different biological measures of disease burden. Mutation analysis was performed in two or more PB samples in 39 patients, and the results demonstrated high stability with no overall tendency to increasing D816V+ allele fractions over time. Considerable variation was nevertheless observed in the correlation analyses. Serum tryptase reflects the mature MC load, whereas the D816V+ allele fraction includes cells other than mature MCs to a variable extent. We conclude that tryptase and the D816V+ allele fraction represent different, although correlated, measures of disease status in SM.