Hereditary alpha-tryptasemia in 101 patients with mast cell activation–related symptomatology including anaphylaxis

doi:10.1016/j.anai.2021.01.016

Annals of Allergy, Asthma & Immunology

Volume 126, Issue 6, June 2021, Pages 655-660

https://doi.org/10.1016/j.anai.2021.01.016 Get rights and content

Abstract

Background

Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes.

Objective

To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation–related symptoms and genotype-confirmed HαT.

Methods

We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation–related symptoms and underwent genotyping to confirm diagnosis of HαT.

Results

Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3β was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H₁- or H₂-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients.

Conclusion

HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

Introduction

Hereditary alpha-tryptasemia (HαT) is a genetic trait characterized by multiple copies of the TPSAB1 gene, which encodes alpha-tryptase.¹ The prevalence of this condition has been estimated as 4% to 6% of the White population.²^,³ Previous literature has identified complex symptomatology involving multiple organ involvement and anaphylaxis.⁴^,⁵ We report here a retrospective analysis of the genotypic, clinical, laboratory, and genetic characteristics of a large cohort of patients with confirmed HαT referred to a tertiary care clinic.

Tryptase is a serine peptidase produced predominantly by mast cells.⁶ Human tryptases are encoded by several genes within the tryptase locus on chromosome 16 including TPSAB1 and TPSB2, which encode α-tryptase/β-tryptase and β-tryptase, respectively.⁷^,⁸ Tryptase loci have considerable variability across different human populations.⁹ Most humans have 4 genes capable of producing α-tryptase and/or β-tryptase (TPSAB1 and TPSB2 on each chromosome). The presence of additional copies of TPSAB1-producing α-tryptase is a characteristic of and constitutes the genetic basis for HαT.¹⁰

Mast cell activation disorders are a group of disorders characterized by aberrant mast cell activation resulting in symptoms across multiple organ systems.¹¹^,¹² These disorders are currently classified as primary, secondary, and idiopathic.¹³ Primary mast cell disorders involve clonal proliferation of mast cells, characterized by activating mutations within the KIT gene, most often D816V.¹⁴ Secondary mast cell disorders are driven by other allergic and chronic inflammatory diseases. Idiopathic mast cell disorders have no discernable etiology.¹⁵ HαT is associated with an increased risk of anaphylaxis and as a biomarker for severe symptoms in mastocytosis.⁴^,⁵ Therefore, individuals with this trait may be predisposed to mast cell–related abnormalities and may present with clinical symptoms of mast cell activation.

The clinical phenotype of HαT has been described in previous literature and associated with multisystemic organ involvement. Symptoms include flushing; fatigue; gastrointestinal symptoms including abdominal bloating, cramping, and loose stools; and musculoskeletal pain, dizziness, heart racing, brain fog, sleep disturbances, and anaphylaxis.¹^,³^,¹⁰ Owing to the reported high prevalence of HαT in the general population, not all patients with the genetic trait present with symptoms of mast cell activation.² Better characterization of patients with symptoms of mast cell activation may lead to improved clinical management and help guide further research by improving the understanding of the underlying endotypes and genotypes. We report genetic, laboratory, and clinical characterization of a large cohort of patients with confirmed HαT who present with symptoms of mast cell activation.

Section snippets

Patient Population

We conducted a retrospective evaluation of 101 patients who were referred to the Brigham and Women’s Hospital (BWH) Mastocytosis Center for evaluation of mast cell activation–related symptoms. Patients of any age with a confirmed genetic diagnosis of HαT were eligible for inclusion. Patients underwent a complete history, physical examination, laboratory testing, and genetic testing for HαT. The study was approved by the Partners Healthcare Institutional Review Board under protocols 2012P002481

Patient Demographics

A total of 101 patients were included in this study. The age ranged between 4 years and 85 years. Patients were disproportionally of female sex (82/101, 81%). Approximately half of the patients had documented total immunoglobulin E values (53/101, 52%). The average total immunoglobulin E was 335.5 IU/mL (range 2.0-4000.0 IU/mL). The KIT D816V mutation was negative in all patients tested (90/90, 100%). A total of 11 patients did not have KIT D816V data collected. Full patient demographic

Discussion

Our data confirm the previously reported clinical phenotype of HαT, highlighting the wide range of baseline serum tryptase and reinforcing the use of omalizumab in those with severe symptoms of mast cell activation including anaphylaxis.

We reported a wide range of baseline serum tryptase values in this study. Our cohort includes 9 patients (8.9%) with “normal” tryptase values (<11.5 ng/mL). The lowest reported tryptase value is 6.2 ng/mL. Only 2% of the patients had a tryptase value less than 8

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: Dr Giannetti and Dr Weller contributed equally to this work as co-first authors.

: Gene by Gene, Ltd, provided testing for hereditary alpha-tryptasemia but did not have any role in the scientific direction of the study.

: Disclosures: Dr Giannetti and Dr Castells report receiving salary support from Blueprint Medicines. Dr Novak is an advisor and independent contractor for Dysimmune Diseases Foundation; reports receiving speaker’s honoraria from KabaFusion, LLC, and H. Lundbeck A/S; is a member of the scientific advisory board of Endonovo Therapeutics; and reports receiving royalties from Oxford University Press. The remaining authors have no conflicts of interest to report.

: Funding: The authors have no funding sources to report.

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Original ArticleHereditary alpha-tryptasemia in 101 patients with mast cell activation–related symptomatology including anaphylaxis

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patient Population

Patient Demographics

Discussion

J Allergy Clin Immunol Pract

Allergol Immunopathol (Madr)

J Allergy Clin Immunol

J Biol Chem

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol Pract

Blood

Ann Allergy Asthma Immunol

Original Article
Hereditary alpha-tryptasemia in 101 patients with mast cell activation–related symptomatology including anaphylaxis