A concise, practical guide to diagnostic assessment for mast cell activation disease

Table 1 Symptoms and findings in mast cell activation disease

System	Potential manifestations of MCAD (most are chronic, low-grade; some are persistent, but many are either episodic or fluctuant)
Constitutional	Fatigue, malaise, asthenia, “chronic fatigue syndrome”, subjective and/or objective hyperthermia and/or hypothermia, “sense of feeling cold much of the time”, sweats/diaphoresis (not always nocturnal), flushing, plethora or pallor, increased or decreased appetite, early satiety, weight gain or loss, pruritus, chemical and/or physical environmental sensitivities (often odd)
Dermatologic/ integument	Rashes and lesions of many sorts (classic urticaria pigmentosa, “freckles”, telangiectatic/angiomatous lesions, xerosis, warts, tags, folliculitis, ulcers, dyshidrotic eczema, diffusely migratory but sometimes focally persistent patchy macular erythema), pruritus (often diffusely migratory, sometimes aquagenic), flushing, angioedema, striae, dermatographism, hair thinning and alopecia, onychodystrophy (brittle nails, longitudinal ridges), poor healing
Ophthalmologic	Irritated eyes, increased or decreased lacrimation, suffusion, conjunctivitis, episodic difficulty focusing, lid tremor/tic (blepharospasm), solar sensitivity, infectious or sterile inflammation
Otologic/osmic	Infectious or sterile otitis externa and/or media, hearing loss or hyperacusis, tinnitus, otosclerosis, dysosmia, coryza, congestion
Oral/oropharyngeal	Pain or irritation (sometimes “burning”), leukoplakia, fibrosis, lichen planus, ulcers, sores, angioedema, dental decay, dysgeusia, throat tickle/discomfort/irritation/pain, post-nasal drip
Lymphatic	Adenopathy, usually sub-pathologic and often waxing/waning in size, sometimes asymptomatic but not uncommonly tender, sometimes focal, sometimes migratory, pathology usually shows reactive lymphocytosis or sometimes an atypical non-specific lymphoproliferative disorder; left upper quadrant discomfort (likely from release of mediators from splenic mast cells with or without detectable splenomegaly)
Pulmonary	Rhinitis, sinusitis, pharyngitis, laryngitis, bronchitis, pneumonitis (often confused with infectious pneumonia), cough, dyspnea (often low-grade, inconstant, “I just can’t catch a deep breath” despite normal pulmonary function tests), wheezing, obstructive sleep apnea, pulmonary hypertension
Cardiovascular	Presyncope (lightheadedness, weakness, dizziness, vertigo) and/or syncope (patients may have been diagnosed with postural orthostatic tachycardia syndrome or neurocardiogenic syncope), hypertension and/or hypotension, palpitations, dysrhythmias, chest discomfort or pain (usually non-anginal in character), coronary and peripheral arterial atherosclerosis/spasm/infarction, idiopathic acute or chronic heart failure (e.g., takotsubo), aneurysms, hemorrhoids, varicosities, aberrant angiogenesis (hemangiomas, arteriovenous malformations, telangiectasias), migratory edema (often non-dependent and with normal cardiac and renal function)
Gastrointestinal	Aerophagia, angioedema in any segment of the luminal tract, dysphagia (often proximal, possibly due to pharyngeal angioedema), bloating/gas, pain/inflammation (often migratory) in one or more segments of the luminal tract (from esophagitis to proctitis) and/or one or more solid organs (e.g., hepatitis, pancreatitis), queasiness, nausea, vomiting (sometimes “cyclical”), diarrhea and/or constipation (often alternating), malabsorption (more often selective micronutrient malabsorption than general protein-calorie malabsorption), ascites either from portal hypertension and/or peritoneal serositis; gastroesophageal reflux disease (often “treatment-refractory”) and inflammatory/irritable bowel syndrome are common pre-existing diagnoses
Genitourinary	Inflammation (often migratory) in one or more segments of the luminal tracts (ureteritis, cystitis, urethritis, vaginitis, vestibulitis) and/or one or more solid organs (e.g., nephritis, prostatitis), chronic kidney disease, endometriosis, chronic low back pain or flank pain or abdominal pain, hydronephrosis (likely from ureteral angioedema), infertility, erectile dysfunction, decreased libido; in the appropriate setting of multisystem morbidity, miscarriages should prompt consideration of antiphospholipid antibody syndrome potentially due to MCAD
Musculoskeletal	Clinical myositis, often diffusely migratory (fibromyalgia is a common pre-existing diagnosis), subclinical myositis (i.e., asymptomatic elevated creatine kinase not otherwise explained), arthritis (typically migratory), joint laxity/hypermobility (patients may have been diagnosed with Ehlers-Danlos Syndrome Type III), osteoporosis/osteopenia, osteosclerosis, sometimes mixed osteoporosis/osteopenia/osteosclerosis; MCAD-driven musculoskeletal pain not uncommonly is poorly responsive to non-steroidal anti-inflammatory drugs and narcotics
Neurologic	Headache (esp. migraine), presyncope and/or syncope, peripheral (usually distal) sensory and/or motor neuropathies including paresthesias, tics, tremors (typically resting), chronic inflammatory demyelinating polyneuropathy, seizure disorders (can be “treatment-refractory”), pseudoseizures, dysautonomia
Psychiatric	Mood disturbances (e.g., anger, depression), bipolar affective disorder, attention deficit-hyperactivity disorder, post-traumatic stress disorder, anxiety and panic, psychoses, memory difficulties, word-finding difficulties, other cognitive dysfunction, wide variety of sleep disruptions
Endocrinologic/meta-bolic	Abnormal electrolytes (including magnesium) and liver function tests, delayed puberty, dysmenorrhea, endometriosis, osteosclerosis and/or osteoporosis, hypothyroidism, hyperthyroidism, dyslipidemia, hyperferritinemia, selective vitamin and/or other micronutrient deficiencies, weight change, possibly diabetes mellitus
Hematologic/coagu-lopathic	Polycythemia or anemia (may be macrocytic, normocytic, or microcytic), leukocytosis or leukopenia, chronic (usually mild) monocytosis or eosinophilia or basophilia, thrombocytosis or thrombocytopenia, arterial and/or venous thromboembolic disease, “easy” bruising/bleeding; in mast cell activation syndrome the marrow usually does not show increased (or even flow-cytometrically aberrant) mast cells; marrow histology often read as normal or as unspecified myelodysplastic/myeloproliferative syndrome; standard cytogenetic studies are almost always normal or show culture failure
Immunologic	Type I, II, III and IV hypersensitivity reactions, increased risk for malignancy, autoimmunity, impaired healing, increased susceptibility to infection, elevated or decreased levels of one or more isotypes of immunoglobulin; modest monoclonal gammopathy of undetermined significance not uncommon

MCAD: Mast cell activation disease.