Hereditary alpha-tryptasemia (HAT) is a genetic trait caused by an increased alpha-tryptase tryptase alpha/beta 1 gene copy number. Basal serum mast cell tryptase (MCT) level is typically greater ...than or equal to 8.0 ng/mL.
To study the clinical disease spectrum of HAT and determine its UK prevalence.
Droplet digital PCR was used to determine tryptase alpha/beta 1 copy number in 432 DNA samples from an unselected UK birth cohort and in 70 patients referred with a basal MCT level greater than 8 ng/mL. Baseline MCT concentrations and clinical presentation were also assessed in 4283 samples sent to a regional immunology laboratory.
Duplication in alpha copy number was present in 5% of the unselected British birth cohort, with all affected individuals having a basal MCT level of greater than or equal to 8.0 ng/mL. Basal MCT levels of greater than or equal to 8.0 ng/mL were also found in 5% of the 4283 individuals referred for MCT testing because of clinical symptoms. In 70 patients confirmed to have HAT (79% with a duplication; 21% with a higher alpha gene copy number), urticaria/angioedema (51%), skin flushing (41%), food intolerances (39%), and altered bowel habits (36%) were common presenting complaints. However, clinical manifestations were not more common in patients with gene triplications or quintuplications than in those with duplications. Some immediate family members with the same genetic trait and high basal MCT levels were asymptomatic.
Five percent of people in the United Kingdom may have HAT. The diagnosis should be considered when basal MCT level is greater than or equal to 8 ng/mL. HAT has variable clinical penetrance. It may modify the expression of multifactorial allergic diseases rather than directly cause specific phenotypes.
In recent years, knowledge about mechanisms underlying mast cell activation (MCA) and accumulation in various pathologic conditions increased substantially. In addition, criteria and a classification ...of MCA syndromes (MCASs) have been set forth. MCAS is defined by typical clinical symptoms, a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase, and a response of the symptoms to drugs targeting mast cells, mediator production, and/or mediator effects. Alternative diagnostic criteria of MCAS have also been suggested, but these alternative criteria often lack specificity and validation. In this report, we critically review the contemporary literature relating to MCAS and compare the specificity, sensitivity, and strength of MCAS-related parameters within proposals to diagnose and classify MCAS and its variants. Furthermore, we highlight the need to apply specific consensus criteria in the evaluation and classification of MCAS in individual patients. This is an urgent and important medical necessity because as an increasing number of patients are being given a misdiagnosis of MCAS based on nonspecific criteria, which contributes to confusion and frustration by patients and caregivers and sometimes may delay recognition and treatment of correct medical conditions that often turn out to be unrelated to MCA.
Anaphylaxis and Mast Cell Disorders Gülen, Theo; Akin, Cem
Immunology and allergy clinics of North America,
02/2022, Volume:
42, Issue:
1
Journal Article
Peer reviewed
Open access
There is strong evidence of an association between severe anaphylaxis, especially hymenoptera venom induced, and mast cell (MC) disorders. It has been thought that intrinsic abnormalities in MCs, ...including the presence of the activating KIT D816V mutation in mastocytosis or of genetic trait, hereditary alpha-tryptasemia, may influence susceptibility to severe anaphylaxis. This article evaluates the potential mechanisms leading to severe MC activation, as well as the differential diagnosis of and range of symptoms attributable to MC mediator release. Also, we offer a global classification for disorders related to MC activation.
Paediatric mastocytosis is a rare clonal disorder characterized by the overproduction and organ infiltration of mast cells. Symptoms are due to mast cell mediator release. Cutaneous mastocytosis is ...the most common presentation in children with systemic disease being rare. Our aim is to provide a practical guideline in differentiating subtypes of paediatric mastocytosis while providing actionable recommendations on diagnosis, clinical management, follow-up and prognosis.
Longitudinal cohort studies of paediatric cutaneous mastocytosis have shown spontaneous remission with favourable prognosis. Hereditary alpha-tryptasemia may coexist with mastocytosis; thus, screening for this disorder is recommended. There is an emerging role for serum tryptase in asthma endotyping and potential for using therapeutic tryptase inhibitors.
Morbidity in paediatric mastocytosis typically arises from symptoms secondary to mast cell mediator release. Prognosis for nonaggressive disease is typically favourable; however, risks for anaphylaxis and psychosocial morbidity may be underestimated. Symptomatic management and anticipatory guidance may help support patients and families throughout the disease course.
Purpose of Review
Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase in Western populations. It is a risk factor for severe ...anaphylaxis among individuals with venom allergy and an established modifier of anaphylaxis and mast cell mediator–associated symptoms among patients with systemic mastocytosis. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HαT is the first step in identifying optimal medical management and targets for novel therapeutics.
Recent Findings
HαT prevalence is increased in both clonal and non-clonal mast cell–associated disorders where it augments symptoms of immediate hypersensitivity, including anaphylaxis. The unique properties of naturally occurring α/β-tryptase heterotetramers may explain certain elements of phenotypes associated with HαT, though additional mechanisms are being evaluated.
Summary
This review provides an overview of the clinical and translational studies that have identified HαT as a modifier of mast cell–associated disorders and anaphylaxis and discusses mechanisms that may potentially explain some of these clinical findings.
The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to ...establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.
Mast cell activation syndrome (MCAS) and anaphylaxis are the result of a spontaneous or triggered pathological degranulation of mast cells (MCs) and might have as substrate normal or pathological MCs ...(increased burden, aberrant MCs or both).
This review summarizes the most recent evidence on immunoglobulin E (IgE)-mediated and non IgE-mediated mechanisms underlying MC activation and degranulation and highlights the importance of standardized diagnostic criteria for MCAS. Application of these criteria implies that in most cases the clinical presentation of MCAS meets the diagnostic criteria for anaphylaxis.
Integrating clinical parameters and diagnostic test recognition and underlying clonal MC disease are of utmost importance for a patient-tailored approach. Hereditary alpha-tryptasemia can be encountered in context of anaphylaxis, MCAS and primary MC disorders.
Hereditary alpha tryptasemia (HaT), an autosomal dominant condition first described in 2014, has previously been associated with multiple dermatologic, allergic, gastrointestinal, neuropsychiatric, ...autonomic, and connective tissue abnormalities. We describe a pediatric patient with predominantly mixed cutaneous inflammatory manifestations and atopic manifestations resistant to treatment who was found to have HaT. HaT should be considered in individuals with refractory inflammatory dermatologic disease and signs and/or symptoms concerning for mast cell activation.
Hereditary alpha-tryptasemia (HαT) is associated with elevated basal serum tryptase (bST) and is associated with a higher risk of severe anaphylactic reactions in patients with clonal mast cell ...disorders or IgE-mediated Hymenoptera venom-induced anaphylaxis. The consequence of this genetic trait remains to be determined in other allergic diseases and food allergy in particular.
Here, we describe three cases of peanut allergy among siblings from a single family of four: two of them were associated with HαT, and the third one was associated with the tryptase wild-type genotype.
genotypes were determined by digital PCR. After the case description, we provided a review of the literature regarding bST levels and tryptase genotypes in anaphylaxis, with a particular focus on food allergy.
Compared to the sibling with the conventional tryptase genotype, the two siblings with HαT presented a lower peanut threshold at the initial oral food challenge, higher peanut skin prick test reactivity, higher levels of specific IgE to peanut, Ara h 2, and Ara h 6, and a lower IgG4/IgE ratio after 10 years of oral immunotherapy.
The tryptase genotype and HαT status might modify the clinical presentation and biological features of food allergy.
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