Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

Abstract

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital PCR in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (p<0.001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs. HαT- cases: 34.5 ng/mL, p=0.004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.

Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management

“…The correlation between MC mediator levels and presence of MC mediator‐release symptoms (MCMRS) or systemic MC burden remains incompletely understood; in one study of indolent mastocytosis patients, MC mediator levels were significantly correlated with BM MC burden, but not MCMRS 55 . In contrast, mastocytosis patients with HAT demonstrate significantly higher serum tryptase level and frequency of Hymenoptera venom reactions/anaphylaxis, independent of BM MC burden 65 …”

“…Normal MC display a spectrum of “activation levels” in vivo, and the mechanisms governing the secretory phenotype and mediator release patterns are not completely understood 64 . Further, the prevalence of hereditary α‐tryptasemia (HAT), a relatively common genetic trait associated with increased basal serum tryptase level and increased predilection for mast cell activation, has been shown to be significantly higher in mastocytosis patients (17.2%) as compared to normal controls (4.4%) 65 . In SM, a persistently elevated serum tryptase level (>20 ng/ml) counts as a minor diagnostic criterion per the WHO framework 1 ; while the levels vary widely, serum tryptase is elevated in the vast majority of SM patients across all WHO subgroups; a significantly greater proportion of ASM and SM‐AHN patients exhibit a markedly elevated serum tryptase level (>200 ng/ml) compared to those with ISM 10 .…”

Mediator-Related Symptoms and Anaphylaxis in Children with Mastocytosis

“…Recently, hereditary alpha-tryptasemia (HαT) has been described, a genetic trait with duplicated TPSAB1 germline copy numbers leading to elevated basal serum tryptase (60)(61)(62), but also to MC mediator-related symptoms. It can be found in about 5% of unselected healthy individuals (61)(62)(63)(64). The prevalence of certain symptoms related to MC activation has been described to be higher in HαT carriers than in the general population, with urticaria/angioedema in 51%, skin flushing/pruritus in 32-55% and irritable bowel syndrome or food intolerance in28-49% of patients (58,62).…”

“…The prevalence of HαT was similar in patients with hymenoptera venom allergy with and without mastocytosis, however their clinical reactions were more severe. In a study assessing TPSAB1 germline copy number variants in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort, α-tryptase encoding TPSAB1 copy number gains corresponding to HαT were identified in 17.2% of mastocytosis patients as compared to only 4.4% of the control population (p<0.001) (63). This pronounced difference indicates a possible pathogenic role of TPSAB1 copy number gains in the evolution of mastocytosis.…”

The Ingenious Mast Cell: Contemporary insights into mast cell behavior and function

“…Also reported are connective tissue abnormalities and dysautonomia. Individuals with multiple duplications show higher tryptase levels in serum, are more symptomatic, and have higher risk for severe anaphylaxis 92,93 . Recent mechanistic studies have demonstrated that unique enzymatic properties of alpha-tryptase containing heterotetrameric tryptases may contribute to this association 94 .…”