Laboratory Assessment of Patients with Systemic Mastocytosis

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Abstract

In FY 2025, we investigated the prevalence of myeloid gene alterations in pediatric mastocytosis and compared prevalence of myeloid gene alterations between cutaneous and systemic subtypes. Pediatric mastocytosis is a heterogeneous disorder with two main different clinical subtypes, cutaneous mastocytosis and systemic mastocytosis. The molecular landscape of genetic mutations, beyond KIT D816V, remains largely unknown in pediatric mastocytosis. We thus investigated the prevalence of myeloid genetic mutations in peripheral blood samples of 69 pediatric patients with cutaneous mastocytosis (CM) and systemic mastocytosis (SM) using next-generation sequencing. KIT D816V was exclusively found in patients with SM, while other KIT mutations (D419del, A502_Y503dup, Y503_A507dup, G565V and N822H) were only detected in patients with cutaneous disease. We discovered that patients with systemic mastocytosis have increased prevalence of KIT M541L germline variant (20% of investigated patients). The results also showed that pediatric mastocytosis patients can carry multiple KIT variants. 21% of systemic mastocytosis and 11% of cutaneous mastocytosis patients carried two or more KIT variants. Most KIT M541L positive mastocytosis patients (82%) carried additional KIT alterations. Significantly, 75% of ISM patients positive for KIT M541L also carried somatic KIT D816V mutation. Although no other common non-KIT myeloid mutations were shared among patients, we identified 64 non-synonymous coding genetic mutations across 30 genes, including 15 classified as pathogenic/likely pathogenic, with none occurring in SRSF2 and ASXL1. Significantly, most of these pathogenic/likely pathogenic non-KIT mutations (86.7%) were found in pediatric patients with SM. In summary, we discovered a number of non-KIT myeloid alterations in pediatric mastocytosis, predominantly in children with systemic mastocytosis. Variant allele frequency of many of these gene alterations was about 50% or 100%, suggesting germline in nature. The long-term impact of these additional genetic alterations on disease course is uncertain at present and supports the need for assessment in long-term follow-up studies. In a separate study, we investigated fire ant-venom anaphylaxis prevalence in the general population and in patients with systemic mastocytosis. Stinging Hymenoptera can induce fatal anaphylaxis, especially in patients with systemic mastocytosis. Fire ants, Solenopsis invicta and Solenopsis richteri, originally from South America, have recently colonized three continents. Prevalence of fire ant-venom anaphylaxis is unknown. We performed a study to determine its prevalence among general population and patients with systemic mastocytosis. Our results showed that fire ant and flying Hymenoptera-venom anaphylaxis prevalence in the general population was 0.048% and 0.083%, respectively. Among patients with systemic mastocytosis, more patients with systemic mastocytosis had anaphylaxis triggered by fire ant than all flying Hymenoptera combined. Fire ant immunotherapy was the most frequently ordered individual immunotherapy prescription (45.9%). Fire ant prescriptions surpassed all flying Hymenoptera immunotherapy prescriptions combined. We concluded that fire ant-venom anaphylaxis prevalence in the general population and patients with systemic mastocytosis was higher than all flying Hymenoptera-venom anaphylaxis combined. However, fire ant-venom anaphylaxis in systemic mastocytosis was frequently misdiagnosed and not treated with epinephrine.