A Review of the Dermatologic Symptoms of Idiopathic Mast Cell Activation Syndrome

February 2019 | Volume 18 | Issue 2 | Original Article | 162 | Copyright © 2019

Azam A. Qureshi BAa and Adam J. Friedman MDb,c

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

Abstract

Since the first reported cases in 2007, idiopathic mast cell activation syndrome has been increasingly recognized. Understanding of the cutaneous manifestations of this condition is imperative for dermatologists given the substantial clinical heterogeneity in its presentation and high estimated prevalence. A review of PubMed® and SCOPUS® databases was performed in order to investigate the most common dermatologic manifestations of idiopathic mast cell activation syndrome. Evidence to date suggests that flushing, pruritus, and clotting dysfunction or bleeding disorder are the most frequently observed dermatologic symptoms in idiopathic mast cell activation syndrome, while dermatographism has been identified as a common finding in patients as well. Mast cell activation syndromes have also been linked to connective tissue disorders, including an Ehlers-Danlos Syndrome-like phenotype possibly mediated by matrix metalloproteinases and tryptase released by mast cells. Current literature regarding dermatologic manifestations of idiopathic mast cell activation syndrome is limited by the heterogeneity of studies including clinical descriptions, inconsistency of diagnostic criteria implemented, and a paucity of literature available. This work provides a guide for dermatologists to strengthen diagnostic acuity for idiopathic mast cell activation syndrome, therefore contributing toward a goal of helping patients to receive timely, effective, and targeted therapy. J Drugs Dermatol. 2019;18(2):162-168.

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INTRODUCTION

Mast cells (MCs) are derived from a hematopoietic origin and are found in all human tissues. Upon activation by either immunologic or non-immunologic mechanisms, the former of which involves an immunoglobulin E-mediated process, MCs undergo degranulation to release a variety of mediator molecules.1 When active, MCs serve as guardians of homeostasis by releasing bioactive substances including histamine, heparin, serotonin, enzymes, cytokines, growth factors, and lipid metabolites which serve to influence local and distant tissue in response to environmental change or bodily insults.2–4Disorders of mast cell activation (MCAD) may arise from primary, secondary, or idiopathic origin.5 Primary entities include cutaneous mastocytosis, systemic mastocytosis, and monoclonal MC activation syndrome (MMAS).6 Secondary causes include allergic, inflammatory, or neoplastic origins, along with physical or autoimmune urticaria.6 Idiopathic entities include idiopathic anaphylaxis, angioedema, or urticaria.6 Since the first suggestion of MC disorders existing in the absence of MC proliferation was published in 2007, the entity of idiopathic MC activation syndrome (iMCAS) has also been differentiated as an additional subset of idiopathic, non-proliferative MCAD.6,7 Diagnostic criteria have evolved since its initial description, partly due to an increased appreciation of the inter-relatedness of MC diseases.5,6,8,9 Diagnostic criteria, initially proposed by Akin et al and subsequently modified, include: 1) Episodic symptoms of MC activation, 2) Increased markers of MC activity, and 3) Exclusion of primary or secondary causes of MC activation.5,6,8,10Sparse epidemiologic data suggest an iMCAS prevalence in the general population as high as 17% and a predilection for females.9,11 It is thought that iMCAS is more common than its proliferative MCAD counterparts including systemic mastocytosis (SM), which has been estimated to occur at a prevalence of 1 in 364,000, and MC leukemia, which occurs at a rate two orders of magnitude lower.11,12Given considerable overlap in MC-mediator induced symptomatology and biomarkers of MC-activation among all MCAD, previous work has investigated the genetics and epigenetics of MCAD seeking to elucidate a common genetic underpinning of disease.9 Molderings et al found variable alterations in KIT, a tyrosine kinase with well-characterized somatic mutations (including KITD816V) shown to contribute to SM, within all three families studied with co-occurrence of iMCAS or SM.9,11 Furthermore, authors noted increased prevalence of a specific KIT isoform in individuals with severe MCAD.9 This finding builds upon findings from Haenisch et al, who suggested that a predominance of this particular isoform may contribute to tumorigenicity, increased MCs, and/or increased MC activation.9,11 In a subsequent study, Haenisch et al found epigenetic differences between 21 MCAD (predominantly iMCAS) patients and a group of healthy controls. Although these studies sug-

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