Mast Cell Activation Syndrome (MCAS)

Overview

Mast cell activation syndrome (MCAS) refers to a group of disorders characterised by recurrent symptoms affecting multiple organ systems resulting from inappropriate mast cell activation and mediator release.^1,2 Diagnosis requires the exclusion of other causes and the fulfilment of relevant consensus diagnostic criteria. MCAS is predominantly documented in adults, with consensus diagnostic criteria rarely fulfilled in paediatric cases. When mast cell activation is identified in children, it is most commonly associated with IgE-mediated allergic mechanisms or other hypersensitivity disorders.³⁹ Other paediatric cases have been reported, although the complexity and overlap of symptoms and the difficulty of obtaining objective evidence of systemic mast cell activation can make diagnosis challenging.³

Broadly, MCAS is an unusual condition, and many patients suspected of having MCAS are ultimately diagnosed with other conditions, such as autoimmune, inflammatory, neoplastic, or infectious conditions unrelated to mast cell activation (MCA), or they experience MCA-related disorders (e.g. allergic conditions) and/or comorbidities without meeting the criteria for overt MCAS.⁴

MCAS may co-occur with conditions such as Ehlers-Danlos syndromes (EDS) and dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS). However, these conditions are not diagnostic of MCAS and do not alone warrant investigation or presumptive treatment for MCAS. Current evidence does not show that EDS or dysautonomia directly causes mast cell dysregulation or chronic mediator release. Genetic traits such as hereditary alpha tryptasemia (HαT), present in about seven per cent of the population, may affect basal serum tryptase levels and influence mast cell activation in some individuals.^5,6 HαT is not synonymous with MCAS, and many people with this trait do not experience mast cell activation symptoms.

Because multiple conditions with different clinical implications can coexist, accurate diagnosis of a person’s specific form of MCAS and identification of relevant underlying, accompanying or complicating conditions and comorbidities are important for appropriate monitoring and management.⁷

MCAS subtypes

There are three currently recognised subtypes of MCAS. Establishing a patient’s subtype is essential for accurate interpretation of pathology and for guiding optimal treatment and best-practice monitoring strategies:^1,5,6

Primary/Monoclonal MCAS

Primary or monoclonal MCAS (MMAS) is a rare clonal mast cell activation disorder (MCAD) diagnosed in individuals without urticaria pigmentosa lesions or full World Health Organization criteria for systemic mastocytosis (SM), but who have abnormal mast cells, elevated serum tryptase, KIT D816V, or other markers of mast cell clonality such as aberrant CD25 expression. If the diagnostic criteria for SM are later met, the diagnosis should be reassessed^1,5,6

Secondary MCAS

Secondary MCAS is caused by mast cells becoming overactive in response to an identifiable underlying condition, most commonly an allergy or another hypersensitivity disorder.^1,5,6

Effective management requires appropriately identifying and addressing the underlying condition, while also managing mast cell activation and mediator-related symptoms.^5,6

Idiopathic MCAS

Idiopathic MCAS is diagnosed when the clinical and laboratory criteria for MCAS are fulfilled but no clonal MCAD, allergy, another hypersensitivity condition or other identifiable cause of the MCA can be found.^1,5,6 Management focuses on controlling MCA and mediator-related symptoms, together with appropriate ongoing clinical review. A person’s classification may change if subsequent investigation identifies an underlying cause for their MCA, or if further testing reveals mast cell clonality.^1,5,6

Further categorisation of MCAS

Additional terms may be used to describe factors that coexist with or modify an established MCAD. These classifications do not replace a person’s primary diagnosis.

Combined MCAD

Combined MCAD describes the coexistence of a clonal MCAD, such as SM or MMAS, with a secondary condition contributing to MCA, such as an allergy or another hypersensitivity disorder.

In the past, patients may have heard certain cases described as “mastocytosis with MCAS”. The term combined MCAD evolves this terminology to improve patient clarity by recognising the coexistence of a secondary contributor to MCA in both SM and MMAS.

In these cases, MCA can be influenced by intrinsic mast cell abnormalities and by external or secondary mechanisms. Effective management includes treatment of clonal MCAD and management of secondary contributors to MCA.^1,5,6,8

Hereditary alpha tryptasemia (HαT)-associated MCAD
Individuals with an established MCAD who also have HαT may be described as having HαT-associated MCAD. HαT is an inherited genetic trait involving additional alpha-tryptase-encoding copies of the TPSAB1 gene and is often associated with elevated basal serum tryptase levels. Many people with HαT are described as asymptomatic, meaning they do not experience symptoms.

In some cases of MCAD, HαT may affect the interpretation of tryptase results and influence the severity or clinical presentation of mast cell mediator-related reactions. As such, HαT-associated MCAD is a proposed classification that does not replace the underlying diagnosis, such as SM, MMAS, or idiopathic MCAS; however, it may inform monitoring and treatment decisions, including the interpretation of basal serum tryptase and the assessment of risk of reaction severity, particularly anaphylaxis.^5,6

Note: In Australia and Aotearoa New Zealand, clinical guidelines currently recognise primary MCAS, secondary MCAS and idiopathic MCAS as primary diagnoses. Please note these further categorisations do not replace your primary diagnosis (e.g. idiopathic MCAS). Rather, they may be used at the discretion of specialists as clarifying terms that may help inform monitoring or management strategies.