Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis

Benedetta Sordi; Fiorenza Vanderwert; Francesca Crupi; Francesca Gesullo; Roberta Zanotti; Patrizia Bonadonna; Lara Crosera; Chiara Elena; Nicolas Fiorelli; Jacqueline Ferrari; Federica Grifoni; Mariarita Sciumè; Roberta Parente; Massimo Triggiani; Boaz Palterer; Valentina Mecheri; Fabio Almerigogna; Raffaella Santi; Lisa Di Medio; Maria Luisa Brandi; Maria Loredana Iorno; Isabella Ciardetti; Sara Bencini; Francesco Annunziato; Carmela Mannarelli; Lisa Pieri; Paola Guglielmelli; Francesco Mannelli; Alessandro M Vannucchi

doi:10.1016/j.jaci.2022.09.038

Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis

J Allergy Clin Immunol. 2023 Feb;151(2):485-493.e11. doi: 10.1016/j.jaci.2022.09.038. Epub 2022 Oct 27.

Authors

Benedetta Sordi¹, Fiorenza Vanderwert¹, Francesca Crupi¹, Francesca Gesullo¹, Roberta Zanotti², Patrizia Bonadonna³, Lara Crosera², Chiara Elena⁴, Nicolas Fiorelli⁵, Jacqueline Ferrari⁵, Federica Grifoni⁶, Mariarita Sciumè⁶, Roberta Parente⁷, Massimo Triggiani⁷, Boaz Palterer⁸, Valentina Mecheri⁹, Fabio Almerigogna⁹, Raffaella Santi¹⁰, Lisa Di Medio¹¹, Maria Luisa Brandi¹², Maria Loredana Iorno¹³, Isabella Ciardetti¹⁴, Sara Bencini⁸, Francesco Annunziato⁸, Carmela Mannarelli¹, Lisa Pieri¹, Paola Guglielmelli¹, Francesco Mannelli¹, Alessandro M Vannucchi¹⁵

Affiliations

¹ CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi, Florence, Italy.
² UO Ematologia, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
³ UO Allergologia, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁴ Divisione di Ematologia, IRCCS S. Matteo Hospital Foundation, Pavia, Italy.
⁵ Dipartimento di Medicina Molecolare, Università di Pavia, Pavia, Italy.
⁶ UOC Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
⁷ Dipartimento di Medicina, Divisione di Allergologia e Immunologia Clinica, Università di Salerno, Salerno, Italy.
⁸ Centro di Diagnostica Citofluorimetrica e Immunoterapia, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Florence, Italy.
⁹ SOD Immunoallergologia, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Florence, Italy.
¹⁰ Sezione di Patologia, Dipartimento di Scienze della Salute, Università di Florence, Florence, Italy.
¹¹ SOD Malattie del Metabolismo Minerale e Osseo, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
¹² SOD Malattie del Metabolismo Minerale e Osseo, Azienda Ospedaliera Universitaria Careggi, Florence, Italy; FirmoLab, Fondazione FIRMO, Florence, Italy.
¹³ Allergologia e Immunologia Clinica Azienda Toscana Centro Ospedale S. Giovanni di Dio, Florence, Italy.
¹⁴ Dipartimento di Scienze della Salute, sezione Dermatologia, Università degli Studi di Florence, Florence, Italy.
¹⁵ CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Denothe Excellence Center, Università degli Studi, Florence, Italy. Electronic address: amvannucchi@unifi.it.

PMID: 36309122
DOI: 10.1016/j.jaci.2022.09.038

Abstract

Background: Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms.

Objective: In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains.

Methods: Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed.

Results: We confirmed a higher incidence of HαT⁺ cases (n = 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT⁺ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT⁺ (10.2%) compared to HαT^- (3.4%, P = .029) patients. We also confirmed that HαT⁺ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations.

Conclusion: These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

Keywords: Mastocytosis; anaphylaxis; clonal mast cell activation syndrome; hereditary tryptasemia.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Clinical Relevance
Humans
Mast Cells / pathology
Mastocytosis* / diagnosis
Mastocytosis, Systemic* / diagnosis
Mastocytosis, Systemic* / genetics
Tryptases / genetics

Substances

Tryptases

Supplementary concepts

Hereditary alpha-tryptasemia syndrome