A high prevalence of hereditary alpha‐tryptasemia in pediatric mastocytoma

Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in one or more organs. The condition can occur in childhood or adulthood. Most cases of pediatric mastocytosis are limited to the skin and spontaneously decrease.1 The World Health Organization classification distinguishes between three subtypes of cutaneous mastocytosis (CM): maculopapular cutaneous mastocytosis (MPCM), mastocytoma, and diffuse cutaneous mastocytosis (DCM).2-4 Recently, a new genetic trait called hereditary alpha-tryptasemia (HαT), which corresponds to a duplication/amplification of the alpha-1 allele of the tryptase alpha/beta 1 gene, has been described. HαT is significantly associated with (i) all subtypes of mastocytosis in adulthood (prevalence around 13%) and (ii) a greater risk of severe anaphylaxis.5-8 The objective of the present study was to estimate the prevalence of HαT in a large cohort of patients with pediatric mastocytosis. Ninety patients were included in the present study (Table 1). The median (range) age at onset of mastocytosis was 4 months (0–144) (Table 1). Eighty-six patients (95.6%) had CM, including 48 (53.3%) with MPCM, 31 (34.4%) with mastocytoma and 7 (7.8%) with DCM. Seven of the 90 (7.8%) patients presented with HαT, a prevalence similar to that of the general population in France (5.9%, p = .62) (Table 2). The distribution of tryptase genotypes is represented in Figure S1. There were no differences between the HαT+ and HαT− patients with regard to their clinical, laboratory, and molecular characteristics (Table 1). The prevalence of HαT was 2.1% in patients with MPCM and 0% in patients with DCM (Table 2); it was significantly higher in patients with mastocytoma (19.4%) than in patients with other subtypes of CM (1.8%, 1 out of 55, p = .004) or the general population in France (5.9%, p = .017). The prevalence of cutaneous and digestive symptoms of MC activation (MCA) were similar in HαT+ and HαT− mastocytomas (66.7% vs. 64%, p = .95 and 33.3% vs. 20%, p = .59, respectively) (Table S1). None of the patients with mastocytoma had a history of severe anaphylaxis. The mean basal serum level was significantly higher in HαT+ mastocytoma than in HαT− mastocytoma (13 μg/L vs. 4.7 μg/L, respectively; p < .001). We next compared the prevalence of HαT according to the age of mastocytosis onset by including data from our previous study of adult cohorts.6 The prevalence of HαT was lower (albeit not significantly) in pediatric-onset mastocytosis than in adult-onset mastocytosis (7.8% vs. 12.6%, p = .22; data not shown). We then compared the MPCM pediatric subgroup and adult patients with MPCM in a context of CM, mastocytosis in the skin, or indolent systemic mastocytosis (n = 233). The prevalence of HαT was significantly lower in the pediatric-onset MPCM group compared to the adult-onset group (2.1% vs. 12.4%, p = .03) (Figure S2). Here, we showed that in pediatric mastocytosis, HαT is associated with mastocytoma only. HαT+ patients with mastocytoma did not exhibit more MCA symptoms than HαT− patients with mastocytoma—suggesting that the high prevalence of HαT in mastocytoma was not due by the greater diagnosis of mastocytoma, as revealed by the presence of HαT. Our results further suggest that HαT might predispose the patient to local mast cell accumulation (in association with KIT mutation). The presence of HαT in our pediatric cohort was not associated with a higher risk of anaphylaxis; however, further studies of larger cohorts are needed to confirm this result. We showed that the prevalence of HαT was significantly lower in patients with pediatric onset MPCM than in adult-onset MPCM highlighting the pathophysiological difference between pediatric- and adult-onset types of mastocytosis.1 In conclusion, the prevalence of HαT is specifically high in patients with pediatric mastocytoma. Pathophysiological studies are now needed to understand the link between these two entities. L.P: designed the study. M.M, C.D, and J.A performed in vitro experiments. C.Bu provided DNA from healthy controls. C.B, L.B, N.B, A.W, J.B, P.B, C.M, and L.P enrolled the patients. M.M and L.P wrote the manuscript. J.R, P.D, C.B, and O.H corrected the manuscript. The authors thank the participating patients and their families. This research did not receive any specific funding from agencies or organizations in the public, commercial, or not-for-profit sectors. L.P. was funded by the Bettencourt Schueller Foundation. The CoV-CONTACT study was funded by the INSERM's REACTing program, the French Ministry of Health's PHRC-N COVID-19 program (grant reference: PHRC-20-0242), and the European Commission's RECoVer program (grant reference: 101003589). The authors declare no conflicts of interest with regard to the present study. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1. Figure S2. Data S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.