aUniversity of Maryland School of Medicine, Baltimore, MD bDepartment of Dermatology, George Washington Medical Faculty Associates, Washington, DC cGeorge Washington School of Medicine and Health Sciences, Washington, DC
gest that MCAD may comprise a spectrum of similar disease including both iMCAS and SM, a lack of sufficient sampling andadequate comparison groups leave the validity of these findings in question.9The clinical presentation of iMCAS is characterized by symptomatic heterogeneity.13 Most commonly, symptoms of iMCASinclude fatigue, fibromyalgia-like pain, presyncope or syncope,headache, pruritus, urticaria, paresthesias, nausea, vomiting, chills, migratory edema, eye irritation, dyspnea, and gastroesophageal reflux.14 Abdominal pain and flushing are also prominent symptoms.14 Current validated MC activation markers include serum tryptase along with urine histamine metabolites, prostaglandin (PG) D2, PG metabolites, or leukotriene E4.15–17 Interestingly, tryptase has been shown to be a non-specific and unreliable marker of iMCAS, as levels are often normal or only mildly elevated.6,18,19 The utility of serum tryptase in iMCAS differs from its utility in SM, as tryptase levels have been shown to be associated with quantified burden of MCs in the body as opposed to the level of overall MC activation.20–24Understanding of iMCAS is pivotal for dermatologists due to its occasionally equivocal laboratory findings, seemingly non-specific multi-systemic symptoms, and association with comorbidities. In terms of laboratory work, the iMCAS clinical picture may include normal or only mild elevations of serum tryptase.6,8,10,19 The presentation is further confounded by heterogeneity of symptoms, underlying co-morbidities, and possible MC-mediated connective tissue (CT) effects resulting in an EDS-like phenotype.25–28 This article delivers a concise review of the dermatologic symptoms of iMCAS while exploring the association between iMCAS and CT disorders (CTDs) with the objective of providing dermatologists with a higher acuity of recognition of this multifaceted disorder.
Review of PubMed® and SCOPUS® databases was performed using search terms including “mast cell activation syndrome”and “mast cell activation disorder.” Articles published in English from January 1, 1990 through February 8, 2018 were included.Furthermore, included studies featured at least 1 patient meeting diagnostic criteria presented in Table 1, which combines elements from iterations of proposed diagnostic criteria of iMCAS.5,6,29 Criterion of response to medications targeting MC activation was not included due to several studies including iMCAS patients without explicitly commenting on therapy or response to therapy. Dermatologic descriptions of only the individual patients meeting the aforementioned criteria shown in Table 1 were included. Only 16 primary articles meeting inclusion criteria mentioned dermatologic manifestations of iMCAS.A separate literature review regarding iMCAS association with CTDs was also performed. Due to the paucity of literature available, aforementioned diagnostic criteria implemented for the previous search were relaxed to include studies with patient(s) who may not have had a diagnostic workup to rule out otherforms of MCAD.
Early Descriptions of iMCAS
Studies including dermatologic descriptions of patients with iMCAS are summarized in Table 2. In total, 562 patients withdermatologic manifestations of iMCAS, as defined in the present review, were identified in 16 published reports (Table 2).The first descriptions of iMCAS, prior to proposed diagnostic criteria in 2010, emerged in 2007.6,7 Molderings et al studied a17-patient cohort, which included 7 patients with SM and 4 patients not meeting criteria for SM, who also lacked evidence ofbone marrow involvement after assessment.7 In the 4 patients with an iMCAS-like picture, dermatologic symptoms were prevalent,including flushing and anal pruritus in 3 of the 4 patients, clotting dysfunction in all 4 of the patients, and unspecified“skin signs” in half of the patients. In the following year, Butterfield and Weiler published a case series of 4 patients presentingwith various symptoms of MC activation from selective release of PGD2.30 Authors noted pruritus, flushing, urticaria, and angioedema were symptoms noted in at least half the patients examined.30 One patient experienced periorbital swelling.30Since the initial evidence of non-proliferative MC disease,multiple case reports and series focusing on iMCAS disease associations and treatments have emerged and mentioned dermatologic manifestations. Afrin presented a case series describing iMCAS associated with sclerosing mediastinitis in 2 patients, both of whom noted migratory pruritus.31 One patient experienced a diffuse migratory rash following a waxing and waning course.31 Multiple case reports surfaced in the same year detailing iMCAS patients diagnosed per criteria proposed by Akin et al and suffering from symptoms including flushing, urticaria, and dermatographism.6,32,33 In a case report, Afrin et al described iMCAS involving symptoms of flushing, migratory pruritic rash, edema, hives, dermatographism, dys-
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