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American Journal of Medical Genetics Part C (Seminars in Medical Genetics)

R E S E A R C H R E V I E W

Mast Cell Disorders in EhlersDanlos Syndrome


SURANJITH L. SENEVIRATNE, ANNE MAITLAND ,* AND LAWRENCE AFRIN

Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and
surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical
mediators. After being recruited to connective tissues, resident MCs progenitors undergo further differentiation,
under the inuence of signals from surrounding microenvironment. It is the differential tissue homing and local
maturation factors which result in a diverse population of resident MC phenotypes. An abundance of MC reside
in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and
urogenital tracts). Situated near nerve bers, lymphatics, and blood vessels, as well as coupled with their ability to
secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell
populations, broblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed
hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs). This report reviews basic
biology of mast cells and mast cell activation as well as recent research efforts, which implicate a role of MC
dysregulation beyond atopic disorders and in a cluster of EhlersDanlos Syndromes, non-IGE mediated
hypersensitivity disorders, and dysautonomia. 2017 Wiley Periodicals, Inc.

How to cite this article: Seneviratne SL, Maitland A, Afrin L. 2017. Mast cell disorders in EhlersDanlos
syndrome. Am J Med Genet Part C Semin Med Genet 9999C:111.

INTRODUCTION: MAST survival, migration, and effector functions. peritoneal cavity contain tryptase (MCT) in
CELLS AND THEIR MCs acquire a tissue specific phenotype their granules and express interleukin-5
PROPERTIES depending on signals they receive from the (IL-5) and interleukin-6 (IL-6). MCs
local tissue environment. Several factors homing to the gut and respiratory mucosa
In the late 19th century, Paul Ehrlich such as interleukin-3 (IL-3), interleukin-4 contain tryptase and chymase (MCTC), and
named a granule-dense cell, mast- (IL-4), interleukin-9 (IL-9), and trans- express IL-4 [Sigal, 2011]. When fully
zellen, situated near blood vessels in forming growth factor b1 (TGFb1) have differentiated, MCs exhibit a wide range of
the mucosa and connective tissue. He been shown to influence the number and biological properties including phagocyto-
theorized these cells were providing mediator content of MCs [Galli et al., sis, antigen presentation, cytokine and
nourishment to the local tissue environ- 2011]. chemokine production, and the immediate
ment. Using commercial dyes such as Under non-pathological states, ma- release of vasoactive substances. They have
dahlia, toluidine blue, methylene blue, ture differentiated MCs are found exclu- a role in local tissue homeostasis (tissue
and neutral red, he noted metachromati- sively within tissues, compared to other repair, angiogenesis) and co-ordination of
cally staining mature mast cells (MCs) in innate immune cells, such as basophils, immune responses to a myriad of patho-
the connective tissue of several organs. neutrophils, and eosinophils. Within tis- gens, recognized through evolutionarily
MCs develop from multipotent he- sues, MCs congregate around nerves, conserved surface receptors like toll-like
mopoietic progenitors in the bone marrow blood vessels, and lymphatic vessels. Based receptors, complement receptors, and
[Moon et al., 2010]. Stem cell factor (KIT on their location (connective tissue or receptors for adenosine phosphate, oestro-
ligand) binds to homodimeric KIT (a mucosal) and content of their granules, two gen, and immunoglobulins), physical stim-
transmembrane tyrosine kinase receptor) types of MCs have been described. MCs uli (pressure, temperature), and toxins. As
and influences MC differentiation, growth, residing in connective tissue, skin, and the yet, no animal model or disease state has

Suranjith L. Seneviratne, Institute of Immunity and Transplantation, Royal Free Hospital and University College London, United Kingdom; Faculty of
Medicine, Department of Surgery, University of Colombo, Colombo, Sri Lanka.
Anne Maitland, Division of Clinical Immunology, Department of Medicine, Mount Sinai Hospital, New York, New York.
Lawrence Afrin, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Disclosure of potential conict of interest: Anne Maitland receives honoraria for participation in the speakers bureau for Genentech.
*Correspondence to: Anne Maitland, MD, PhD, Division of Clinical Immunology, Department of Medicine, Mount Sinai Hospital, Box 1089, 1
Gustave L. Levy Place, New York, NY 10028. E-mail: anne.maitland@mssm.edu
DOI 10.1002/ajmg.c.31555
Article rst published online in Wiley Online Library (wileyonlinelibrary.com).

2017 Wiley Periodicals, Inc.


2 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

been identified where there is a complete MCs are best known for their role (more often MCAS than SM). Several
lack of MCs [Metcalfe et al., 1997]. When in immediate IgE-mediated, allergic reports have described of co-morbid
activated, MCs produce a range of pre- responses in anaphylaxis, food allergy, clinical manifestations in patients with
formed and newly synthesised mediators venom allergy, and asthma. Recent CTDs, including EDS, functional gastro-
(Fig. 1) [Louisias et al., 2013]. Within reports have also implicated MCs in intestinal disorders [Fikree et al., 2015];
minutes of activation, preformed media- nonallergic disorders, including head- eosinophilic gastrointestinal disorders
tors (histamine and proteases) are released. ache syndromes, irritable bowel syn- [Abonia et al., 2013]; an increased preva-
This is followed by de novo synthesis of drome, non-celiac gluten enteropathy, lence of asthma [Morgan et al., 2007],
membrane-derived lipid mediators (pros- osteoporosis, autoimmune syndromes, neuropsychiatric conditions [Sinibaldi
taglandins and leukotrienes) and a range of neuropsychiatric disorders, and intersti- et al., 2015], and osteoporosis [Deodhar
pro- and anti-inflammatory cytokines and tial cystitis [Theoharides et al., 2015]. and Woolf, 1994]; and orthostatic intoler-
chemokines. ance [Garland et al., 2015]. Luzgina et al.
[2011] found an increased number of
MAST CELLS AND chymase-positive MCs in the eyelid skin of
CONNECTIVE TISSUE patients with CTDs (joint hypermobility,
MCs residing in connective skin hyper-elasticity, spinal deformities,
Different components of the extracellu-
thumb and wrist sign, vascular, fragility,
tissue, skin, and the lar matrix affect the migration and
varicose veins, and telangiectasias).
differentiation of MC progenitors, MC
peritoneal cavity contain activation, and pattern of mediator
tryptase (MCT) in their release. Human MCs express laminin
receptors and can adhere to fibronectin
granules and express and vitronectin. Several reports have described
interleukin-5 (IL-5) and The hypermobile type of Ehlers of co-morbid clinical
interleukin-6 (IL-6). Danlos Syndrome (hEDS) is the dominant
form of EDS. A subpopulation of hEDS
manifestations in patients
patients have been found to have MCAD with CTDs, including

Figure 1. MC activate and release bioactive substances, responding to a variety of mechanical, biological, or chemical stimuli. MCs
release preformed mediators in granules (histamine, heparin, serotonin, and enzymes) and newly synthesized (cytokines, growth factors,
and lipid metabolites). C-kit, transmembrane tyrosine kinase receptor; CR, complement receptor; CRF-R1, corticotropin releasing factor
receptor 1; CRH, corticotropin releasing hormone; FceRI, Fc epsilon receptor I; FcgRI, Fc gamma receptor I; LPS, lipopolysaccharide;
MC, mast cell; NGF, nerve growth factor; SCF, stem cell factor; TLR, Toll-like receptor; TNF, tumor necrosis factor-a; VIP, vasoactive
intestinal peptide; VIP-R1, vasoactive intestinal peptide receptor 1. Adapted from the following references: [Afrin, 2013; Cardet et al.,
2013; Theoharides et al., 2015] and arranged using images from shutterstock.com.
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EDS, functional Postural Orthostatic Tachycardia Syn- Consensus diagnostic criteria have
gastrointestinal disorders; drome (POTS), and EDS. Patients having been established for most of the forms of
a diagnosis of POTS and EDS were given a mastocytosis (e.g., the WHO 2008
eosinophilic gastrointestinal screening questionnaire to look for symp- criteria define the approach to systemic
disorders; an increased toms consistent with MCAS, and 66% of mastocytosis (SM) [Horny et al., 2008].
the respondents reported such symptoms. However, as MCAS is so recently
prevalence of asthma, Recently, Milner et al. identified families recognized, no consensus definition
neuropsychiatric conditions, with an elevated, baseline serum tryptase, has yet been established. There are two
which was associated with the triad of proposals for diagnostic criteria for
and osteoporosis; and dysautonomia, MCAD, and joint hyper- MCAS [Molderings et al., 2011; Valent
orthostatic intolerance. mobility [Lyons et al., 2016]. The elevated et al., 2012] (Table II). The presence of
tryptase level was not consistent with SM. EDS (of any form) in the patients
Instead, increased copy numbers of the history is not known to affect the
Several investigators have noted a TPSAB gene, that encodes alpha tryptase, approach to diagnostic evaluation for
possible link between EDS and MCAD, were detected. Moreover, these observa- MCAD.
primarily patients with the hypermobility tions highlight the role of MCA, impacting The most well-known form of
type of EDS. Immunohistochemisty anal- the structure and function of connective MCAD, MC disorders proven to be
ysis identified an increased content of tissue, as described in inflammatoryarthritis primary/clonal are rare, with an esti-
chymase positive MCs in undamaged skin [Nigrovic and Lee, 2005]. mated prevalence of one case per
of patients with signs suggestive of CTDs 10,000100,000 persons. Primary,
(hyperelasticity of the skin, joint hypermo- clonal MC disorders include mastocy-
bility, spine and thorax deformities, thumb MAST CELL ACTIVATION
tosis and MMCAS. Reported secondary
sign, wrist sign, vascular fragility, varicose DISORDERS
causes of MC disorders include co-
veins, and telangiectasias) [Luzgina et al., Mast cell activation disorder (MCAD) morbid immune disorders, including
2011]. Louisias et al. [2013] described refers to an increased number of MCs, classic atopic syndromes (allergies/
symptoms compatible with a non-IgE increased activity of MCs, or both. Akin IgE-Fce receptor-mediated MC activa-
mediated MC disorder in patients with et al. [2010] classified diseases associated tion); autoimmune disorders (autoim-
the joint hypermobility syndrome: most with MC activation as primary, second- mune chronic urticaria, multiple
reported naso-ocular symptoms, asthma, ary, and idiopathic groups (Table I). The sclerosis, rheumatoid arthritis) [Benoist
and history of anaphylaxis and describe a conditions may be associated with (1) and Mathis, 2002]; and chronic infec-
positive response to classical MC/MC an expansion of clonal MCs, and/or tions, of which some likely occur in the
mediator antagonists. Plasma histamine (2) by increased, aberrant MC mediator context of primary immune deficiency
and serum tryptase levels were normal release. Monoclonal MC activation disorders [Cardet et al., 2013].
and prostaglandin measurements were not syndrome (MMCAS) was included Allergic disorders are a well-recog-
undertaken. Cheung and Vadas [2015] within the primary group; non-clonal nized cause of MC activation (MCA).
suggested a possible new disease cluster: MC activation syndrome (MCAS) was Here, allergens cross link IgE molecules
Mast Cell Activation Syndrome (MCAS), included within the idiopathic group. on the surface of MCs, leading to MCA,

TABLE I. Classification of Diseases Associated With Mast Cell Activation (Adapted From [Akin, 2014;
Theoharides et al., 2015])

Primary Mastocytosis
Monoclonal Mast Cell Activation Syndrome
Secondary Allergic/atopic (IgE mediated) disorders
Mast cell activation associated with chronic
inflammatory or neoplastic disorders
Physical urticarias
Chronic autoimmune urticaria
Idiopathic Anaphylaxis
Angioedema
Urticaria
Mast cell activation syndrome
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TABLE II. Diagnostic Criteria for Systemic Mastocytosis and Mast Cell Activation Syndrome (Adapted From Afrin, World
Journal of Haematology, 2014)
WHO 2008 diagnostic criteria for systemic mastocytosis
Major criterion
Multifocal dense aggregates of MCs (15 or more) in sections of bone marrow or other extra-cutaneous tissues and confirmed with tryptase
immunochemistry or other special stains
Minor criteria
Atypical or spindled appearance of at least 25% of the MCs in the diagnostic biopsy
Expression of CD2 and/or CD25 by MCs in marrow, blood, or extra-cutaneous organs
KIT codon 816 mutation in marrow, blood, or extra-cutaneous organs
Persistent elevation of serum total tryptase >20 ng/ml
Diagnosis of SM made by either (1) major criterion any one or more minor criteria or (2) any three minor criteria
Proposed diagnostic criterion for MCAS: Valent et al. [2012] criteria
Chronic/recurrent symptoms (flushing, pruritus, urticaria, angioedema, nasal congestion or pruritus, wheezing, throat swelling, headache,
hypotension, and/or diarrhea) consistent with aberrant MC mediator release
Absence of any other known disorder that can better account for these symptoms
Increase in serum total tryptase of 20% above baseline plus 2 ng/ml during or within 4 hr after a symptomatic period
Response of symptoms to histamine H1 and/or H2 receptor antagonists or other MC-targeting agents such as cromolyn
Proposed diagnostic criteria for MCAS: Molderings et al. [2011] criteria
Major criteria
Multifocal MC aggregates as per WHO major criterion for SM
Clinical history consistent with chronic/recurrent aberrant MC mediator release
Minor criteria
Abnormal MC morphology as per WHO SM minor criterion 1
CD2 and/or CD25 expression as per WHO SM minor criterion 2
Detection of known constitutively activating mutations in MCs in blood, marrow, or extracutaneous organs
Elevation in serum tryptase or chromogranin A, plasma heparin or histamine, urinary N-methylhistamine, and/or other MC-specific mediators such as
(but not limited to) relevant leukotrienes (B4, C4, D4, E4) or PGD2 or its metabolite 11-b-PGF2a

TABLE III. Diagnosis of MCAS Made by Either (1) Both Major Criteria, or (2) the Second Major Criterion Plus Any One of
the Minor Criteria, or (3) Any Three Minor Criteria
A: Clinical signs & symptoms of mastocytosis patients. Adapted from [Alvarez-Twose et al., 2010]
Sign/symptom %
Skin lesions 90
Pruritus 82
Flushing 56
Diarrhoea 35
Abdominal cramping 30
Neuropsychiatric symptoms 23
Anaphylactic 23
Peptic symptoms 20
Osteoporosis 18
Hepatomegaly 12
Splenomegaly 08

B: Clinical signs & symptoms of Non-clonal mast cell activation disorder. Adapted from [Hamilton et al., 2011]
Sign/symptom %
Abdominal pain 94
Dermatographism 89
Flushing 89
Headache 83
Neuropsychiatric symptoms 67
Diarrhoea 67
Rhinitis 39
Asthma 39
Anaphylaxis 17
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releasing a range of mediators and The following criteria have been tryptase is not always secreted fol-
producing the well-known range of proposed for diagnosing MCAD: lowing engagement of different
allergic manifestations. Physical MC MC activation pathways [Marshall,
triggers constitute common, non-IGE (1) Typical signs and symptoms of MC 2004].
MCADs, such as those affected by mediator release (affecting at least two (4) Response to therapy that directly or
physical urticarias, including cholinergic organ systems) indirectly blocks MC mediator activ-
and cold-induced urticaria [Simons, (2) [Akin, 2014; Theoharides et al., 2015] ity [Cardet et al., 2013; Akin,
2010]. Research efforts are now describ- 2014]
ing mechanisms of non-IGE mediated
MCA. Oxidative mechanical stress has Skin Flushing, pruritis,
been shown to induce MC mediator urticaria, angioedema
release [Briganti et al., 2001]. Boyden Cardiovascular Hypotension
Histamine H1 and H2 receptor blockade
et al. [2016] described a missense variant Respiratory Asthma: cough, wheezing;
Ketotifen
in ADGRE2 associated with vibratory throat swelling
Cromolyn sodium
urticaria. Recently, in subjects with an Gastrointestinal Diarrhea, bloating,
Aspirin
inherited, elevated baseline of serum cramping
Leukotriene receptor antagonists
tryptase, Milner et al. described a domi- Naso-ocular Rhinitis, pruritis
Omalizumab
nant inheritance of increased copy Anaphylaxis Stinging insect allergy,
number of TPSAB1 gene, which enc- peri-operative
odes alpha tryptase. Clinical manifesta- anaphylaxis A diagnostic algorithm for MCAD is
tions of hypertryptasemia include shown in Figure 2 [Picard et al.,
dysautonomia, joint hypermobility, and (3) Objective evidence of MC-derived 2013].
MC activation [Lyons et al., 2016]. mediator release or chronically acti-
Active research is also exploring the vated MCs [Afrin, 2013; Cardet et al.,
neurohormonal activation of MCs [The- 2013]
oharides et al., 2015]. If a clonal MC
LABORATORY
disorder is not detected nor a secondary Tryptase Baseline elevated level; ASSESSMENT OF MCAD
cause identified, as detailed above, then Elevated serum
children and adults with clinical symp- tryptase, following a Diagnostic pursuit of MCAS typically
tomology and with evidence of aberrant suspected MC focuses on probing blood and urine for
MC mediator release are deemed to have activation event: elevated levels of mediators relatively
idiopathic MCAD [Cardet et al., 2013; 20% 2 ng/ml above specific to the MC [Afrin and Molder-
Picard et al., 2013; Theoharides et al., baseline ings, 2014]. However, at present, of the
2015]. Histamine Elevated 24-hr urinary over 100 mediators produced by acti-
histamine metabolite vated MCs, only handful can be mea-
(N-methylhistamine) sured within commercial laboratories.
CLINICAL FEATURES OF
Prostaglandin Elevated 24-hr urinary Assays certified for clinical use are not
MCAD
prostaglandin D2; 11- available for most MC mediators, and
The clinical presentation of MCAD b-prostaglandin-F2a even for those MC mediators which can
tends to be very heterogeneous. Tissue Biopsy CD117 cells that are be tested in the clinical laboratory, most
Clinicians need to be aware of this clustered and/or, have an unfavorable level of specificity
so as to suspect the condition and spindle-shaped; co- for the MC, leaving relatively few
carry out appropriate testing. Muta- expression of CD25 mediators to be tested. Furthermore,
tional heterogeneity in the affected and CD2 on many of the diagnostic tests are not
MC subsets may contribute to the CD117 Cells (MCs) widely available to the clinician or are
heterogeneity of clinical expression. Heparin Increased blood level cost-prohibitive. Ideally, serum tryptase
Common presenting symptoms and Chromogranin Increased blood level and chromogranin A, plasma histamine,
signs of mastocytosis and MCAS are A (note confounders of prostaglandin (PG)D2, and heparin, as
given in Table III [Alvarez-Twose cardiac or renal failure, well as urinary (random and 24-hr)
et al., 2010; Hamilton et al., 2011]. proton pump inhibitor histamine, N-methylhistamine (NMH),
Conditions that need to be considered use, or neuroendocrine PGD2, 11-b-PGF2a, and leukotriene
in the differential diagnosis of MCAD cancer) (LT) E4 should be assessed. Whether to
include: cardiovascular, endocrine, pursue such tests in parallel or sequen-
gastrointestinal and neurological dis- tially depends on the balance between

orders, infections, and medication- Although all MCs contain tryp- diagnostic expediency versus contain-
induced side effects. tase, there is evidence indicating that ment of testing costs.
6 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Figure 2. Diagnostic algorithm for mast cell activation disorders. Permission to reprint from Dr. Mariana Castells, [Picard et al.,
2013]. KIT, a transmembrane type III tyrosine kinase receptor; AHNMD, associated hematologic non-mast cell lineage disease; MCA,
mast cell activation; MCAD, mast cell activation disorder; MCAS, mast cell activation syndrome; MMAS, monoclonal mast cell activation
syndrome; SM, systemic mastocytosis.

Some metabolites have longer half- be acknowledged. If mediator testing is heparin. The isoforms are continuously
lives (e.g., tryptase, histamine) and are negative in a patient whose clinical released from MCs into the bloodstream
thermostabile than others (e.g., heparin, history strongly suggests MC activation, and basal levels are a reflection of total
the prostaglandins). It is prudent to repeat testing should be done at a MC numbers [Schwartz, 2006]. The
continuously chill all specimens timepoint when the patient is particu- ImmunoCAP1 Tryptase assay measures
throughout collection and handling larly symptomatic. Upper and/or lower total tryptase levels (that is all inactive
(including centrifugation). The authors gastrointestinal tract mucosal biopsies proforms of alpha-tryptase and beta-
recommend identifying at least two stained for MCs (CD117 at a minimum) tryptase, as well as the enzymatically
elevated MC mediator levels (either looking for increased numbers of or active mature beta-tryptase). The con-
the same mediator, or different media- constitutively active MCs also can be ditions/disorders that cause an elevated
tors), and preferably across two different helpful. basal serum tryptase level are given in
time points (in keeping with the chronic Serum Tryptase Levels. Tryptase is Table IV.
clinical nature of the disease), before the most abundant protein in MCs and is Basal serum tryptase levels of
diagnosing MCAS in a patient with a heat stable. The amount found in 20 ng/ml are considered as a decision
history consistent with chronic/recur- basophils is about 300 times lower than point in several MC diagnostic criteria.
rent aberrant MC mediator release and in MCs. The human tryptase gene is For example, a basal serum tryptase
absence of any other evident disease located on chromosome 16, and codes level greater than 20 ng/ml is a minor
better accounting for the full range and for five isoenzymes: alpha, beta, gamma, diagnostic criterion for SM. Valent
chronicity of all the symptoms and delta, and epsilon. Beta tryptase is the et al. [2012] suggested a rise in serum
findings in the past. predominant form stored in the MC total tryptase of 20% above baseline,
The technical and logistical chal- granule. It is found as a tetramer and is plus 2 ng/ml, within 4 hr of the onset
lenges in MC mediator testing need to stabilized by proteoglycans such as of an acute flare of symptoms as a
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 7

TABLE IV. Conditions/Disorders That Could Cause Elevated Basal Serum Tryptase Levels Adapted From the Following
References [Cardet et al., 2013; Picard et al., 2013]

Condition/disease Source of tryptase


SM Neoplastic MCs
MCAS Activated MCs (monoclonal or polyclonal)
Allergic/atopic disorders Activated MCs and/or activated basophils
End stage kidney disease Normal MCs
Helminth infection Reactive MCs
Myelodysplastic syndromes Neoplastic MCs or/and basophils or/and blast cells
Acute myeloid leukaemia Myeloblasts
Chronic myeloid leukaemia Immature leukaemic basophils (rarely MCs)
Chronic eosinophilic leukaemia Neoplastic MCs
Idiopathic Unknown

Some haemodialysis patients may present with elevated tryptase levels, due to reduced excretion.
MC, mast cell; MCAS, mast cell activation syndrome; SM,systemic mastocytosis.

significant rise. However, as yet there 11-b-prostaglandin-F2a, or leukotriene co-expression of CD117 together with
has not been clinical validation of this (LTE4) are measured in plasma or a CD25 and/or CD2, CD30, and muta-
formula as a discriminating tool for 24-hr urine sample [Schafer et al., tional assessment for mutations in KIT
diagnosing MCAS. 2014]. The patient needs to take care (in particular, the KIT D816V mutation
It needs to be stressed that a normal in keeping the sample chilled when at a minimum) should be done. CD25
serum tryptase level does not exclude collecting a 24 hr urine sample. PG expression in MCs is a minor diagnostic
MCAS. Furthermore, levels above interpretation is confounded by recent criterion in SM. When MCAS seems
20 ng/ml do not exclude MCAS, and use of non-steroidal anti-inflammatory more likely than SM, marrow examina-
levels below 20 ng/ml do not exclude drugs (NSAIDs). When NSAIDs have tion is usually unhelpful. Even if
SM. Persistence of the serum tryptase not been recently used, the finding of MMCAS is found on flow cytometric
level above 20 ng/ml makes SM more PG levels below the lower limit of or mutational testing, at present there
likely, necessitating marrow examina- normal may point toward the loss of the are no known differences in prognosis
tion to exclude mastocytosis. Even if the samples thermal integrity while en of, or the therapeutic approach toward,
serum tryptase level is persistently below route to the reference laboratory. MMCAS versus MCAS.
20 ng/ml, consideration of SM may
need to made if the patients history of
Histopathological Examination of Histopathological Examination of
illness is more consistent with SM (i.e.,
Bone Marrow Other Tissues
sudden onset of symptoms in middle or
older age in contrast to MCASs usual A bone marrow biopsy needs to be If mediator testing is unrevealing, the
history of symptoms dating back to considered when the baseline tryptase Molderings diagnostic criteria (REF)
adolescence or childhood). level is >20 ng/ml or those who have provide an alternative path to diagnosis
syncopal or pre-syncopal events as part of MCAS, namely, finding increased
of their symptoms (irrespective of the MCs in extracutaneous tissue, most
Urinary or Plasma Histamine and
tryptase levels) [Akin, 2014]. Such an commonly gastrointestinal (GI) or gen-
Histamine Metabolites
examination may need to be bilateral to itourinary (GU) tract mucosal biopsies.
Levels are measured in a 24 hr urine increase the chances of finding the Biopsy specimens obtained from the
collection, a spot urine sample and typically patchily distributed aggregates gastrointestinal tract, urinary bladder,
plasma sample. Sample chilling is im- of abnormal MCs [Butterfield and Li, and skin should be stained for mast cells.
portant and special care needs to be 2004]. A cut-off of >20 MCs per high power
taken with sample collection and stor- In addition to evaluating the num- field has been considered by several
age. The levels are best measured during ber of MCs, changes in morphology or groups when interpreting the tissue
an attack or soon thereafter and should distribution and evidence of degranula- biopsy findings. Traditionally, staining
be undertaken within a laboratory with tion should be looked for. Antibodies of tissue biopsies for MC disease has
experience in their measurement. against KIT (i.e., CD117), CD25, employed stains targeting MC granules
Prostaglandins and leukotrienes in tryptase, and chymase should be or their contents, for example, tryptase,
urine or plasma: Prostaglandin (PGD2), used. Flow cytometric assessment for Giemsa, toluidine blue, Alcian blue, etc.
8 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

However, more recently, it has become Chromogranin A (CgA) which either are aggressive malignancies
clear that CD117 (the dominant MC themselves (e.g., aggressive SM or MC
CgA is a heat-stable, 439-amino acid
regulatory element brightly present on leukemia) or are associated with signifi-
protein, and a member of the granin
virtually all MCs) more reliably reveals cant malignancies (e.g., SM with associ-
family of proteins. Granins are wide-
MCs [Feyerabend et al., 2005; Leclere ated clonal hematologic non-MC-lineage
spread in endocrine, neuroendocrine,
et al., 2006]. Given that the essence of disease, or SM-AHNMD in the WHO
peripheral, and central nervous tissues,
MCAD is inappropriate MCA and thus 2008 classification) are cytotoxic/chemo-
where they are found in secretory
inappropriate MC degranulation, rely- therapeutic and cellular therapies consid-
granules. CgA is also secreted by MCs.
ing on granule-targeting stains may ered. Such therapies have been extensively
It is known to be elevated in heart and
increase the false negative rate. MCs in discussed elsewhere in the literature and
renal failure, neuroendocrine cancer,
SM are found in abnormal aggregates are beyond the scope of this paper.
and when proton pump inhibitors
but remain normally dispersed in In general, co-morbidity of EDS
(PPIs) are being used. PPI therapy
MCAS. Furthermore, the MCs in SM (any form) is not known to affect the
should be omitted for at least 5 days
typically are of aberrant morphology approach to treatment of MCAD,
prior to measurement of baseline levels.
(most commonly spindled) while in except to note that chronic glucocorti-
MCAS they retain their normal round coid therapy (a poor choice anyway in
to ovoid shape. Again, CD117 co- Plasma Heparin MCAD given the treatments chronic
expression with CD25 and/or CD2 is Heparin may be the single best perform- toxicities, including in connective tis-
uncommonly found on flow cytometry ing diagnostic marker for MC activation sues) may be an even poorer choice in
in MCAS (whether in marrow or other [Vysniauskaite et al., 2015]. However, MCAD patients also featuring EDS.
tissue), and KIT codon 816 mutations, the level of endogenous plasma heparin Desensitization therapy can be consid-
too, are rarely found in MCAS. found normally and even in most cases of ered. It is important that patients
MCAS is below the lower limits of identify potential triggers for their
detection of most clinical assays for this symptoms (dietary, chemicals, medica-
Gene Mutation Analysis
metabolite (typically 0.100.30 anti- tions, allergens), and environmental
Although KIT D816V mutation testing Factor Xa units/ml). Standard clinical modifications, to reduce exposures.
by routine PCR analysis in the blood of assays are engineered to assist with Common MC triggers are given in
SM patients is often positive (but far monitoring of heparin therapy, which Table V. MCAD patients have many
from perfect), this testing is virtually produces far higher levels of heparin than physical sensitivities (e.g., heat, cold,
always negative in the far more prevalent found normally or in MCAS. Thus, ultraviolet radiation, exertion, etc.) and
setting of MCAS. Real-time quantita- although an occasional MCAS patient antigenic sensitivities (e.g.,pollen, mold,
tive PCR testing for KIT D816V is far may present a level detectable by one of etc.). There is a core group of foods
more sensitive and has been shown in at the commonly used assays, typically a (tending to be patient-specific) that
least one study to be positive in 100% of more sensitive assay is needed. As the many patients find difficult to consume
SM patients [Kristensen et al., 2011]. half-life of heparin is approximately without developing adverse symptoms.
There have been no reports that 1 min (similar to PGD2), sample chilling
investigated this technique in the is important.
MCAS population. In general, co-morbidity of
Molderings [2015] have published
TREATMENT OF MCAD EDS (any form) is not known
two studies showing that on full
sequencing of MC KIT, although one MCAD is presently incurable (except to affect the approach to
or more mutations are found in almost for the rare instance of a solid mastocy-
every MCAS patient, codon 816 muta- toma) and therapy, is therefore, symp- treatment of MCAD, except
tions (whether D816V or any other) are tomatic except when cytoreduction is to note that chronic
virtually never found in MCAS. Clearly, additionally required in advanced mas-
glucocorticoid therapy (a poor
codon 816 mutations have consequen- tocytosis. MCAD therapy should always
ces that strongly influence the include maneuvers aimed at controlling choice anyway in MCAD
development of MCAD toward the MC mediator production, release, and given the treatments chronic
mastocytosis phenotype. Without co- end-organ effects.
don 816 mutations, it is far more likely Many cases of childhood cutaneous toxicities, including in
MCAD will develop toward the MCAS mastocytosis (CM) seem to spontaneously connective tissues) may be an
phenotype. Although testing for this regress in adolescence. However, it seems
mutation on a bone marrow sample is that MCAS emerges in at least some such
even poorer choice in MCAD
more appropriate in SM, some patients patients within several years after regres- patients also featuring EDS.
do not wish to undergo the more sion of CM (personal observation, LBA).
invasive procedure. Only in the relatively rare forms of SM
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 9

TABLE V. Triggers of Mast Cell Activation Adapted From the Following References [Cardet et al., 2013; Picard
et al., 2013]

Alcohol
Heat
Drugs: antibiotics, NSAIDs (nonsteroidal anti-inflammatory drugs), Narcotics, Neuromuscular blocking agents
Radiocontrast media
Invasive procedures (e.g., general anaesthesia, biopsy, endoscopy)
Hymenoptera stings
Fever or infection
Exercise
Physical stimuli (e.g., pressure, friction)
Emotions/stress

Patients and clinicians should be Since both physical and psychological receive tends to vary. Commonly used
alert to the propensity of MCAD stress have long been known to activate medications include H1 and H2 antihist-
patients to react to medication exci- MCs, interventions aimed at stress amines, sodium cromoglicate, ketotifen,
pients. The emergence of adverse reac- reduction (e.g., psychotherapy) can be omlaizumab, and the leukotriene recep-
tion within the first few doses of an helpful. tor blockers. Medications should usually
ordinarily well tolerated medication be added one at a time, with an adequate
should prompt (1) a review of the time interval between the additions of
formulations ingredient list to try to successive drugs. Some patients need to
identify a particular offending excipient; In spite of the substantial begin medications at a lower dose and
and (2) identification of alternative then gradually escalate to a standard
formulations to be tried, containing as fatigue and malaise that many dose. Patients need to be told that the
few of the excipients in the offending MCAD patients experience, time for noticing an initial symptomatic
formulation as possible. Sometimes response may be a few weeks [Cardet
MCAD patients benefit from custom-
they should be strongly et al., 2013; Akin, 2014; Zhang et al.,
compounded formulations of their encouraged to exercise 2016].
medications. regularly. This should only be Many agents have been shown to
Some MCAS patients are highly significantly help various MCAD pa-
reactive to a range of foodstuffs. Elimi- to the usual individual limit tients, but at present therapeutic re-
nation diets such as described for the of tolerance that each patient sponse profiles appear highly
eosinophilic esophagitis population are individualized. There are no biomarkers
helpful in some patients but not others. has likely learned from predictive of response in general or of
As with medication trials, diet trials experience. which symptoms will respond to any
typically need to last only 12 months to given agent in a given patient.
determine if they are going to be
significantly beneficial. The implemen- An effective primary physician
H1 and H2 Antihistamines
tation of more than one change around whether a primary care physician or
the same time (e.g., a dietary change specialistis critically important for These medications block the H1 and H2
around the same time as a medication successful management of most complex receptors present on many end organs
change) can be greatly confounding and diseases, including MCAD. The absence and on MCs themselves, too. They have
should be avoided. of a local physician/partner who can been in use for many years and most
In spite of the substantial fatigue reliably help the patient access local doctors are aware of their beneficial
and malaise that many MCAD patients health care resources as needed and effects and potential adverse effects.
experience, they should be strongly remote resources could lead to the Longer acting, generally non-sedating
encouraged to exercise regularly. This MCAD patient facing difficulty in second generation H1 antihistamines
should only be to the usual individual gaining and then maintaining control (e.g., cetirizine, fexofenadine, lorata-
limit of tolerance that each patient has over their disease. dine) have been used in preference to
likely learned from experience. This is Drug treatment needs to be tailored the older, sedating H1 antihistamines.
because overexertion could trigger a to the individual patient as their toler- Most patients need a higher dose
flare of MC activation in some patients. ance and the symptomatic benefit they (between two to four times) the dose
10 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

used for treatment of mild hay fever not be helpful in patients with a disorder classes of MC-targeted agents typically
symptoms. Many patients find a 23 of connective tissue such as EDS. without analgesic effect nevertheless
times daily dosing to be more helpful However, the use of a short course of prove analgesic (e.g., antihistamines
than a once daily dosing regimen. The steroids may be needed if there is acute may relieve chronic migraine headaches
H2 antihistamines (e.g., ranitidine, onset of skin or airway reactivity. Low in some MCAS patients).
famotidine) are helpful for abdominal dose inhaled steroids may be needed if Given the rarity of SM, together
symptoms and sometimes benefit airway hyper-reactivity is present. with how recently MCAS has come to
extra-gastrointestinal symptoms, too. be recognized, there are no large
Antihistamines need to be taken for an controlled studies of any intervention
Self-Injectable Epinephrine
adequate length of time. Patients should for MCAD. Few clinical trials in SM
Devices
be discouraged in making frequent have been performed, and there have
changes to the doses they take. All patients with systemic MC activation been no clinical trials yet in MCAS.
or susceptible to anaphylaxis should be Patient and treating clinician alike must
prescribed two self-injectable epinephrine take a methodical approach in stepping
Sodium Cromoglicate
devices and taught how and when this through trials of the many therapies
Many patients add the MC-stabilising should be used. A glucagon autoinjector shown helpful in various MCAD pa-
drug sodium cromoglicate to their H1/H2 may be needed instead if the patient tients, limiting to one change at a time in
antihistamines, with a view to getting requires beta adrenergic receptor blockade. the regimen whenever possible. Most
additional symptomatic benefit. It is such treatment trials need last only 12
important that mediator measurements months, typically starting at low doses
Other Medications
are done prior to this medication been and escalating step-wise as tolerated to
added. Some patients experience a flare of From the few reports available, non- identify maximal effective dosing.
symptoms during the initial few days of steroidal immunosuppressants such as Clearly significantly effective treatments
taking this drug. Oral, liquid, inhaled, and cyclophosphamide, cyclosporine, azathi- are retained, while others not meeting
ophthalmic formulations are available. oprine, and monoclonal antibodies such that high bar are stopped lest unman-
Although the drug is poorly absorbed as omalizumab [Zhang et al., 2016] and ageable polypharmacy develop. In the
and undergoes little systemic circulation, alemtuzumab are only occasionally help- absence of a more scientifically in-
there is a systemic (IV) formulation in ful [Afrin, 2013]. Several patients find a formed strategy at present, proceeding
development. range of other preparations (such as in order of treatment cost often is the
vitamin C, aspirin, flavone analogues, most reasonable approach.
cannabinoids, etc.) to help their symp- The most inexpensive and sustain-
Ketotifen
toms. Low-dose hydroxyurea helps some able therapy for MCAD includes the
This has both MC-stabilising and anti- MCAD patients and is safely used for histamine H1 and H2 receptor blockers.
histamine effects. A few patients are not years to decadesindeed, life-longin Benzodiazepines, NSAIDs including as-
able to tolerate this because of drowsi- certain other diseases. A wide range of pirin (in patients that can tolerate them),
ness. Tablet, liquid, and eye drop supportive medications are used by the flavonoids (such as quercetin and luteo-
formulations are available. Oral ketotifen MCAD population including decon- lin), alpha lipoic acid, N-acetylcysteine,
is an inexpensive drug, but its availability gestants, bronchodilators, antiemetics, and Vitamin C are also inexpensive
in the United States only in compounded proton pump inhibitors, anti-depressants interventions. Leukotriene receptor
form increases its expense there. of various classes (e.g. tricyclic agents), blockers and synthesis inhibitors are
bowel motility agents, micronutrient somewhat more expensive, as are sodium
supplements, pancreatic enzyme supple- cromoglicate, pentosan, and cannabi-
Leukotriene Receptor Blockers
ments, bone-strengthening agents such noids. Emergency and perioperative
(e.g., Montelukast)
as bisphosphonates, tumor necrosis factor management of severe flares of mast cell
This is a widely used medication in (TNF) alpha antagonists, etc. disease has been amply discussed in the
asthma and spontaneous chronic urticaria Next to fatigue, pain is one of the literature and is available publicly [Akin,
patients. It is generally well tolerated. most common symptoms of MCAD. 2014]. In general, histamine H1 and H2
Administration twice daily may benefit NSAIDs help some patients but are receptor antagonists, glucocorticoids,
MCAD patients more than once daily. triggers (potentially to anaphylactic and benzodiazepines form the core of
extent) in others and must be initiated the therapeutic attack at such a problem.
cautiously when no history of NSAID The clinical (and suspected underly-
Steroids
tolerance is known. Narcotics, too, ing mutational) heterogeneity of MCAD
The long-term use of oral steroids at any commonly are triggers; fentanyl, trama- ensure each therapy found helpful in
dose is discouraged due to well-known dol, and hydromorphone tend to be certain patients will fail in others. Thus,
toxicities. In addition to its many adverse better tolerated than other narcotics in failure of any given therapy (even antihist-
effects, its effect on bone density would MCAD patients. Sometimes other amines) should not be taken as a sign of
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 11

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