Systemic mastocytosis revisited with an emphasis on skeletal manifestations.

Systemic mastocytosis (SM) is a rare form of mastocytosis that can affect various organ systems. Bone involvement is the most common and prominent imaging feature in patients with SM regardless of the subtype. Furthermore, bone involvement is a prognostic factor as it may entail an aggressive course of the disease. Diagnosis is established by bone marrow biopsy complemented by imaging modalities such as radiography, CT, and magnetic resonance (MR) imaging. The radiographic and CT appearances are that of sclerotic, lytic, or mixed patterns with focal or diffuse distribution, involving primarily the axial skeleton and the ends of the long bones. Bone marrow infiltration is best recognized on MR imaging. Osteoporosis is common in SM; thus, a bone mineral density measurement at lumbar spine and proximal femur by dual-energy X-ray absorptiometry should be obtained. Imaging plays a huge part in the diagnostic process; when skeletal imaging findings are carefully interpreted and correlated with clinical features, they can lead to the suspicion of SM. The primary aims of this review article were to focus on the role of imaging in detection and characterization of skeletal patterns of SM and to discuss relevant clinical features that could facilitate prompt and correct diagnosis.

Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis.

Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is KIT p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in TET2, SRSF2, ASXL1, RUNX1, CBL and JAK2, and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (IL13, IL6, IL6R, IL31, IL4R) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased TPSAB1 copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.

Higher prevalence of vertebral fractures in systemic mastocytosis, but not in cutaneous mastocytosis and idiopathic mast cell activation syndrome.

Little is known about osteoporosis in mast cell disorders (MCDs) not related to systemic mastocytosis. We described osteoporosis and fractures in MCDs and showed that systemic mastocytosis was the only studied MCDs associated with osteoporotic vertebral fractures. INTRODUCTION: To describe osteoporosis (OP) and fragility fractures in mast cell disorders (MCDs). METHODS: We retrospectively analyzed data concerning all successive patients with systemic mastocytosis (SM), cutaneous mastocytosis (CM), and mast cell activation syndromes (MCAS) diagnosed in our mastocytosis expert center between 2004 and 2015. We collected data concerning demographic profiles, clinical signs of MCD, osteoporosis, fractures, densitometry, and biological assessment of MCD. We compared CM and MCAS patients with SM patients with regard to the characteristics of OP and fragility fractures. RESULTS: We assessed 89 SM patients, 20 CM patients, and 20 MCAS patients. Osteoporosis was less frequent in CM (15.0%) and MCAS (10.0%) than in SM (44.9%). Similarly, fractures were less frequent in non-SM MCDs, respectively 5.0%, 5.0%, and 28.1%. SM patients displayed high prevalence of vertebral fractures (22.5%), mostly multiple. Conversely, in non-SM patients, vertebral fractures appeared to be uncommon (5%) and more frequently associated with risk factors for osteoporosis. CONCLUSIONS: SM is associated with multiple vertebral osteoporotic fractures, whereas CM and MCAS do not appear to be associated with this phenotype.

Everyday life and mastocytosis from a patient perspective-a qualitative study.

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.

Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview.

Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.

Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement.

BACKGROUND: Telangiectasia macularis eruptiva perstans (TMEP) has not been fully characterized. OBJECTIVE: We sought to estimate the frequency and clinical characteristics of TMEP in a cohort of adult patients with cutaneous mastocytosis, and to assess the presence of systemic involvement. METHODS: We included all consecutive patients evaluated for cutaneous mastocytosis in 2 centers: the Mastocytosis Competence Center of the Midi-Pyrénées from May 2006 to December 2013, and the French Reference Center for Mastocytosis from January 2008 to September 2013. Skin phenotype, histopathology, presence of KIT mutation in the skin, and assessment of systemic involvement according to World Health Organization (WHO) criteria were prospectively investigated. RESULTS: Of 243 patients with cutaneous mastocytosis, 34 (14%) were given a diagnosis of TMEP. The diagnosis of systemic mastocytosis was established in 16 patients (47%) with TMEP. Three patients (9%) had aggressive systemic mastocytosis (C-findings according to WHO). In all, 32 patients (94%) exhibited at least 1 mast cell activation-related symptom. LIMITATIONS: Patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis so that the clinical findings and incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. CONCLUSION: TMEP accounts for about 14% of patients with cutaneous mastocytosis. The disease manifests as mast cell activation symptoms in almost all patients and can be associated with systemic involvement in about 50% of cases.

Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis.

BACKGROUND: Fragility fractures (FFxs) and osteoporosis occur frequently in patients with indolent systemic mastocytosis (ISM), even before 50 years of age. OBJECTIVE: We sought to develop a prediction model to identify individual patients with ISM at risk of new FFxs. METHODS: Data on lifetime fractures and trauma circumstances were collected from vertebral morphometry, patients' records, and questionnaires. Clinical, lifestyle, and bone characteristics were measured. Patients receiving treatment for osteoporosis before ISM diagnosis or with missing bone data were excluded from FFx risk assessment. RESULTS: In total, 389 lifetime fractures occurred in 127 of the 221 patients with ISM (age, 19-77 years), including 90 patients with 264 FFxs. Median follow-up after diagnosis was 5.4 years (range, 0.4-15.3 years), with 5- and 10-year FFx risks of 23% ± 3% and 31% ± 4%, respectively. Male sex, high levels of bone resorption (serum type I collagen C-telopeptide), low hip bone mineral density, absence of urticaria pigmentosa, and alcohol intake at the time of ISM diagnosis were independent predictors of future FFxs. The MastFx score, a prediction model using these 5 characteristics, showed good accuracy (area under the curve, 0.80) to determine the risk of new FFxs. QFracture, a validated risk scoring tool for persons aged 30 to 99 years, was not useful in patients with ISM. CONCLUSION: The MastFx score distinguishes patients with ISM at high, intermediate, and low risk of new FFxs. The included characteristics sex, serum type I collagen C-telopeptide, hip bone mineral density, urticaria pigmentosa, and alcohol intake are easy to collect in clinical practice. The high occurrence of FFxs in patients with ISM underlines the importance of optimizing bone quality and early start of therapeutic prevention in patients at risk.

Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis.

UNLABELLED: Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations. INTRODUCTION: It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated. METHODS: We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation. RESULTS: We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis. CONCLUSION: Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement.

Systemic mastocytosis in the elderly.

"Later onset" of systemic mastocytosis (SM) has been associated with a poorer prognosis. We examined clinical and laboratory findings, associated disorders, and survival in an older mastocytosis population. After receiving Mayo Clinic Institutional Review Board approval, we identified 42 patients aged 70 years and older at the time of diagnosis of SM. Associated disorders, cytogenetic abnormalities, laboratory findings, and survival were recorded. Only 10 patients had no associated hematologic disorder. Single or multiple chromosomal abnormalities, exclusive of the KIT Asp816Val mutation, were detected in eight patients (19%). KIT Asp816Val mutation was present in 14 patients, negative in three, and not tested in 25. Slight to marked bone marrow hypercellularity was observed in 33 patients (79%). Concurrent hematologic abnormalities included chronic myelomonocytic leukemia (n = 7), acute myelocytic leukemia (n = 1), myelodysplastic syndrome (MDS; n = 7), eosinophilia (n = 7), myelofibrosis (n = 1), myeloproliferative disorder (n = 1), multiple myeloma (n = 1), B-cell lymphoma (n = 1), and thrombocytopenia (n = 4). Eight patients had a hematologic disorder that preceded the diagnosis of SM. Tryptase levels were elevated in 38 of 39 patients tested. Survival from the diagnosis of SM was poor for patients with associated thrombocytopenia, leukemias, and MDS. In conclusion, patients with SM diagnosed at age 70 or older have an increased risk of secondary hematologic disorders and abnormal laboratory findings. Cytogenetic abnormalities are common, and survival is short in many SM patients with associated leukemias, MDS, or eosinophilia.

High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a rare disease characterized by accumulation of abnormal mast cells in various tissues, including bone marrow. Symptoms are usually related to release of mast cell mediators. The aims are to establish the prevalence of osteoporotic fractures in ISM and to investigate the association with serum tryptase and the urinary histamine metabolites, methylhistamine (MH), and methylimidazole acetic acid. METHODS: The fracture prevalence in 157 patients (65 men; 92 women), mean age 54 ± 12 years, was assessed by vertebral morphometry and data from patient records, supplemented by a questionnaire. Bone mineral density (BMD) of lumbar spine and femoral neck was measured, and tryptase and histamine metabolites were analysed. RESULTS: We registered 235 lifetime fractures in 154 patients, including 140 osteoporotic (low-energy trauma) fractures, of which 62% were vertebral, 1% hip and 36% other nonvertebral fractures. Osteoporotic fractures and osteoporosis were found in 37% and 28% of the patients, respectively. In men, the prevalence of these osteoporotic manifestations (46% <50 years; 73% ≥50 years) was much higher compared with women (18% <50 years; 58% ≥50 years). Older age, male gender, and higher urinary MH were independently related to the osteoporotic manifestations. CONCLUSIONS: This first publication about prevalence of fractures and osteoporosis in patients with ISM shows that the risk of osteoporotic fractures is high, especially in men. Higher urinary MH levels are associated with a higher risk of osteoporotic manifestations. Routine measurements of BMD and vertebral morphometry are warranted in these patients for early detection of osteoporosis.

Severe life-threatening or disabling anaphylaxis in patients with systemic mastocytosis: a single-center experience.

BACKGROUND: Mediator-related symptoms in patients with systemic mastocytosis (SM) range from mild episodic to severe life-threatening events. METHODS: We examined a series of 137 consecutive patients with mastocytosis (63 females and 74 males) referred to our center between 1988 and 2010. Almost all patients received prophylactic histamine receptor (HR1 and HR2) antagonists. RESULTS: Forty-two patients suffered from one or more mediator-related symptoms (hypotension, headache, flush, abdominal cramping, diarrhea) requiring therapy (SM(SY)). Severe life-threatening events (grade IV) occurred in 17 patients (12%). In 4 of these 17 patients, a deteriorating clinical course was recorded. One patient died of an apallic syndrome 1.5 years after an hymenoptera sting and cerebral hypoxia. One patient was disabled for months after an insect sting and cerebral hypoxia. Two patients with smoldering SM (SSM) suffered from severe recurrent hypotension requiring hospitalization and repeated resuscitation. Symptoms in these SSM patients did not respond to any of the antimediator-type drugs applied. However, after therapy with cladribine (2CdA), a major durable response was obtained in both cases. In patients with aggressive SM and mast cell leukemia (n = 6), life-threatening mediator-related events (grade IV) were not recorded. CONCLUSIONS: SM may be accompanied by life-threatening mediator-related symptoms. Most of these patients have indolent SM or SSM. In patients with SSM(SY) with uncontrolled symptoms (grade IV), therapy with 2CdA should be considered.

Clinical impact of pregnancy in mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) in 45 cases.

BACKGROUND: The impact of pregnancy on mast cell (MC)-related symptoms and newborn outcome in women with mastocytosis is not well described. We report a series of 30 women who had 45 pregnancies. METHODS: Patients completed a specific questionnaire concerning MC mediator release symptoms graded according to their frequency to detect clinical changes occurring during pregestation and pregnancy as well as postpartum. Information about the medications received during pregnancy and labor and about newborn medical complications was also recorded. RESULTS: Worsening of MC-related symptoms during pregnancy was observed in 10 cases (22%); additionally, 1 woman developed skin lesions as a manifestation of indolent systemic mastocytosis (ISM) within the third trimester of pregnancy. Conversely, 15 cases (33%) experienced clinical improvement during pregnancy, with a complete resolution of pregestational symptoms in 7 cases. MC mediator release symptoms intrapartum were observed in 5 cases (11%) without any fatal outcome. Newborn medical complications (e.g. prematurity, low birth weight, and respiratory distress) were detected in 7 infants (16%) who were all successfully managed with conservative measures. One infant developed cutaneous mastocytosis several years after birth. CONCLUSIONS: Mastocytosis has a heterogeneous clinical behavior during pregnancy: the profile of MC-related symptoms remained unchanged in half of the cases, while in the other half pregnant women experienced either an improvement or an exacerbation of the symptoms, with the manifestation of ISM during pregnancy in 1 case. To prevent potential life-threatening MC-related symptoms, adequate prophylactic antimediator therapy intrapartum should be systematically administered. The absence of both maternal and infant severe complications suggests that patients with nonaggressive categories of mastocytosis should not be advised against pregnancy.

Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.

BACKGROUND: Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators-related symptoms frequently associated with increased serum baseline tryptase (sBt). OBJECTIVE: To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. METHODS: Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs(-); n = 48) and other c-MCADs (n = 3)-both with CD25(++) BM MCs and either positive mast/stem cell growth factor receptor gene (KIT) mutation or clonal human androgen receptor assay (HUMARA) tests-and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. RESULTS: Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs(-), whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs(-) and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex (P = .01), presyncopal and/or syncopal episodes (P = .009) in the absence of urticaria and angioedema (P = .003), and sBt >25 microg/L (P = .006) as independent predictive factors. CONCLUSIONS: Patients with c-MCAD and ISMs(-) display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs(-) diagnosed at early phases of the disease.

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

Systemic mastocytosis and bone involvement in a cohort of 75 patients.

OBJECTIVES: To investigate bone involvement in a large cohort of systemic mastocytosis (SM) patients, and evaluate the efficacy of bisphosphonate therapy. PATIENTS AND METHODS: From 2000 to 2004, 75 patients with SM according to WHO criteria underwent skeletal x-rays and bone mineral density (BMD) assessment. Sequential BMD assessments were performed in nine patients treated with bisphosphonate (mean follow-up 65 months). RESULTS: 37 patients (49%) had bone involvement according to both x-rays and BMD evaluations: osteoporosis (23 patients, 31%, mean lumbar spine T score: -3 SD), with vertebral fracture (13 patients, 17%), axial skeleton osteosclerosis (six patients, 8%), mixed patterns (three patients), osteopenia with pre-existing fractures (four patients) and focal osteolytic lesion (one patient). Blood count abnormalities were associated with osteosclerosis (p=0.005). In nine patients with osteoporosis and bisphosphonate therapy, mean lumbar spine BMD increased from 0.83 to 0.92 g/cm(2) (+11.1%; ie, +2.05% per year) without recurrence of vertebral fracture. CONCLUSION: Half of adult patients with SM have bone involvement. Osteoporosis is the most prevalent bone manifestation in SM (31%). Bisphosphonate therapy seems efficient to improve lumbar spine BMD during SM-related osteoporosis. Spine x-ray and BMD should be performed in all SM patients to detect those who may benefit from anti-osteoporotic therapy.

Seventy-four-year-old woman with myelodysplastic syndrome and splenomegaly.

We present a 74-year-old woman with a recent diagnosis of myelodysplastic syndrome who presented with left upper quadrant abdominal pain and fatigue with significant splenomegaly, anemia, and thrombocytopenia. She underwent splenectomy and bone marrow biopsy. Pathology of both spleen and bone marrow revealed an unusual diagnosis. A review of the differential diagnosis, laboratory tests, nature of the underlying disease, and treatment are provided.

Mast cells and mastocytosis.

Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e.g. histamine and tryptase) and newly synthesised mediators (e.g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase- receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of non-erosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.