Clinical Information

Primary mast cell activation syndromes (MCAS) have clonal markers, such as the KIT Asp816Val variant or aberrant expression of CD25 or CD2 on MC. The 2 primary groups of MCAS are mastocytosis (cutaneous and systemic) and monoclonal MCAS. Systemic mastocytosis (SM) is a disease in which clonally derived mast cells accumulate in peripheral tissues. Degranulation of these mast cells releases large amounts of histamines, prostaglandins, leukotrienes, and tryptase.

Patients with SM should fulfill the World Health Organization diagnostic criteria for this disorder. Diagnosis requires either the major plus one minor criterion or 3 minor criteria.(1-3)

The consensus diagnostic criteria for SM include:

Major criterion:

Imaging of the multifocal infiltrates

Minor criteria:

1. Identifying morphological features of above 25% of MC from bone marrow biopsy

2. Detection of the point alteration at codon 816 in the KIT gene

3. CD2, CD25, and/or CD30 expression in MC

4. Persistently elevated serum tryptase (>20 ng/mL)

The 2 main nonclonal MCAS categories include secondary MCAS, for which there is a known trigger for MC activation (IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes), and idiopathic, in which the etiology for MC activation is undefined.(1,3-7) Based on consensus criteria, the diagnosis of MCAS can be established when typical clinical symptoms arising from recurrent (episodic) acute systemic MC activation (typically in the form of recurrent anaphylaxis in at least 2 organ systems) have been documented; MC-derived mediators increase substantially in serum or urine over the individual's baseline; and the symptoms respond to drugs blocking MC activation, MC mediators, mediator production, or mediator effects.(6)

A recently proposed diagnostic algorithm for the evaluation of patients with suspected MCAS considers 2 main diagnoses that may underlie severe forms of MC activation (anaphylaxis), namely, IgE-dependent allergies and clonal MC disorders.(1,3-7) A serum tryptase level, which has long been used in diagnosing these disorders, has several drawbacks, including the need to obtain acute and baseline specimens to fulfill diagnostic criteria. Furthermore, an increased baseline tryptase level has been reported in hereditary alpha tryptasemia, complicating the diagnostic possibilities.(1,5) In addition to the limitations of serum tryptase, there are reports of symptomatic patients with features of MC activation who do not meet all the criteria for MCAS but have elevated baseline mediator metabolites.(3,5,7) In these patients, there is evidence that their symptoms respond to drugs that target MC activation, the mediators released by MC, and/or the effects of these mediators. Based on these observations, validated biomarkers suggestive of MC activation, such as an increase in the histamine metabolite (N-methylhistamine) or the prostaglandin D2 metabolite (2,3-dinor 11 beta-prostaglandin F2 alpha), have been recommended for testing when tryptase is not available, or the result is inconclusive.(7) Elevated concentrations of leukotriene E4 are associated with both clonal (primary) and nonclonal (secondary and idiopathic) MCAS.(1,4,5)