Diagnosis of systemic mastocytosis (SM) and mast cell activation disorders (MCADs) is challenged by the heterogeneity of their clinical manifestations and their complex pathologies, especially for patients with relatively low disease burden, atypical clinical signs and symptoms, or pathogenic factors other than mast cells. Meanwhile, a tryptase genotype termed hereditary alpha-tryptasemia (HαT) has increasingly been associated with mast cell disorders because it causes elevated baseline serum tryptase (BST) levels, intensifies mast cell-mediated reactions and potentially contributes to the development of clonal mast cell disease. This article reviews the recent advances in biomarker application and optimization of diagnostic workups and algorithms for the diagnosis of SM and MCADs respectively, while summarizing and discussing the clinical impacts of HαT. For SM, emphasis is placed on correction of diagnostic threshold BST levels based on tryptase genotypes, standardization of KIT mutation analysis, characterization of complex mutational landscape, and strategies to tackle diagnostic challenges in non-advanced variants of SM. For MCADs, both patients fulfilling the criteria of mast cell activation syndrome and others with less severe, localized or even uncertain mast cell-dependent symptoms are concerned, followed by the comparison of serum tryptase and urinary mediator metabolites as mast cell activation biomarkers. Particular attention is given to the current evidences and controversies about the implications of HαT in the development and clinical outcomes of mast cell disorders, and how tryptase genotyping may be incorporated into the diagnostic algorithms.
Hong Lian (Fri,) studied this question.