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Hereditary alpha-tryptasemia

Hereditary alpha-tryptasemia
Author:
Jonathan J Lyons, MD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: May 2024.
This topic last updated: Nov 16, 2022.

INTRODUCTION AND DEFINITION — Hereditary alpha-tryptasemia (HaT) is a common autosomal dominant genetic trait, first identified in 2016, which is defined by increased TPSAB1 gene copy number encoding alpha (a)-tryptase and characterized by elevated serum levels of total tryptase at baseline. The majority of individuals with HaT are asymptomatic, although, in a minority, the presence of HaT appears to increase the frequency and severity of immediate hypersensitivity reactions. The epidemiology, pathophysiology, possible clinical manifestations, diagnosis, and treatment of symptomatic HaT are discussed in this topic review.

EPIDEMIOLOGY — HaT affects approximately 5.7 percent of the general population in the United States, United Kingdom, and European Union, a prevalence comparable to the total number of people reported to have elevated basal serum tryptase (BST), which is generally reported by clinical laboratories as >11.4 ng/mL. When individuals with HaT are excluded in population-based evaluations of BST levels, the median value is approximately 4 ng/mL, and the upper limit for BST approaches this clinical laboratory cut-off of 11.4 ng/mL [1]. The term basal serum tryptase refers to the level when the patient is in their usual state of health and not the level that is obtained within hours after an anaphylactic reaction or other severe potentially mast cell-mediated symptoms. It has been estimated that HaT accounts for greater than 90 percent of individuals encountered with elevated BST [2]. Other causes of an elevated tryptase are discussed below. (See 'Differential diagnosis' below.)

It was first reported in 2014 that elevated BST levels could be inherited in an autosomal dominant manner, and HaT was initially recognized in 2016 [3,4]. Thus far, HaT has almost exclusively been reported among White individuals of European descent, although extensive study of other racial or ethnic groups has not been systematically undertaken. While data currently remain limited, racial and ethnic differences in the distribution of structural variation and tryptase isoform-encoding gene composition at TPSAB1 have been reported [5]. In addition, the majority of symptomatic individuals reported have been female, despite the fact that the trait is autosomal dominant, with males and females equally likely to inherit it.

To date, de novo occurrence of HaT has not been observed or reported. Thus, in any family where an individual is identified with HaT, it is very likely that one or more parents also has this trait and that half of the individual's offspring have also inherited it.

TRYPTASES

Relative specificity to mast cells and basophils — Tryptases are serine proteases found predominantly in mature mast cells residing in various tissues and, to a much lesser extent, in blood basophils. Tryptases are the most abundant proteases in the human mast cell, comprising up to 20 percent of the total cell protein [6-8]. Some human mast cells contain up to 35 micrograms of tryptase/106 cells, which is a dramatically higher protease content than any other granulocyte. In contrast, basophils have only very low levels (0.4 percent of the tryptase in mast cells) [9]. (See "Mast cell-derived mediators", section on 'Tryptases'.)

Mast cells are myeloid-lineage granulocytes that are derived from bone marrow precursors. These precursors circulate as immature cells before depositing in the tissues, where they mature in the presence of stem cell factor (SCF) and interleukin (IL-) 3. Mature mast cells are found primarily in the skin and mucosal tissues near blood vessels, although populations of mature mast cells can be found other places, including sites of inflammation and the bone marrow. While several roles for mast cells have been reported in both health and disease, one of the most studied features of mast cells is their contribution to type I allergic immediate hypersensitivity reactions. (See "Mast cells: Development, identification, and physiologic roles".)

The classic mechanism of mast cell activation involves cross-linking of antigen-specific immunoglobulin (Ig)E bound to the high-affinity IgE receptor (FceRI) on the mast cell surface, although IgE-independent mechanisms of mast cell activation also occur. Immediately following activation, mast cells release the contents of secretory granules that contain a number of preformed mediators of inflammation, the most abundant proteins of which are mature enzymatically active tryptases, ultimately leading to symptoms of immediate hypersensitivity. (See "Mast cells: Development, identification, and physiologic roles", section on 'Mast cells in allergy'.)

Functions of tryptases — All tryptases are neutral serine proteases with trypsin-like ("tryptic") activity and the ability to cleave basic amino acids in other proteins. Beta tryptase has been shown to have many actions in vitro, although the relative importance of these in vivo remains unclear [10]. These actions include (see "Mast cell-derived mediators", section on 'Tryptases and other proteases'):

Inactivation of fibrinogen and inhibition of fibrinogenesis, with anticoagulant activity that exceeds that of heparin. Beta tryptase, which is enzymatically active upon release from granules, degrades the alpha chain of fibrinogen and prevents its activation [11,12]. This may explain why some patients with anaphylaxis or mastocytosis develop hemorrhagic disorders (eg, abnormal intraoperative bleeding) and why children with diffuse cutaneous mastocytosis can bleed into the blisters.

Activation of tissue matrix metalloproteinases (MMP), including prostromelysin (MMP-3), which activates collagenase of rheumatoid synovial cells [13].

Inactivation of certain neuropeptides including the bronchodilatory vasoactive intestinal peptide (VIP) [14,15].

Stimulation of fibroblast proliferation and mRNA synthesis for procollagen in human culture systems [16,17].

Chemotactic activity for eosinophils [18]. Recruitment of eosinophils contributes to the late phase of an allergic reaction (or allergen challenge), which is important in disorders such as asthma. (See "Pathogenesis of asthma", section on 'Early and late phase reactions'.)

Upregulation of IL-8 synthesis and intercellular adhesion molecule 1 (ICAM-1) expression in bronchial epithelial cells [19].

A pruritogenic effect as well as induction of endothelial cell permeability by tryptase has been found in mice and human umbilical vein endothelial cells, respectively, through the proteinase-activated receptor 2 (PAR2) [20,21].

Tryptase catalytic activity can trigger mast cell degranulation in a feedforward manner [22].

Genes encoding tryptase — The human tryptase locus is situated near the end (sub-telomeric region) of the short arm of chromosome 16, at position 16p13.3. There are four known human tryptase orthologs or genes that evolved from a common ancestor: TPSAB1, TPSB2, TPSD1, and TPSG1 [23].

TPSAB1 can encode for any of the two major isoforms of alpha-tryptase (aI- or aII-tryptase) or for any of the three major isoforms of beta-tryptase (bI-, bII-, or bIII-tryptase). TPSB2 has only been reported to encode for beta-tryptases.

In the general population, TPSAB1 and TPSB2 are in near complete linkage disequilibrium, such that individuals inherit tryptases encoded at these two loci together as a haplotype from each parent [5,23]. In the majority (>90 percent) of the general population, each locus encodes a single gene product, resulting in a total of four tryptase protein-encoding copies.

In the remaining individuals, copy number variants (CNVs) at TPSAB1 and/or TPSB2 have been reported. The most common CNV identified to date is increased TPSAB1 gene copy number encoding alpha-tryptase; this defines HaT and is present in approximately 5.7 percent of the Western populations from the United States, European Union, and United Kingdom where this has been studied. While increased beta-tryptase-encoding gene copy number and decreased total tryptase-encoding gene copy number have also been identified, these appear to be less common, and increased beta-tryptase CNVs have not been associated with inherited increases in basal serum tryptase (BST) levels.

TPSD1 encodes either of the two reported delta (d)-tryptase isoforms (dI- or dII-tryptase).

TPSG1 encodes either gamma I- or gamma II-tryptase.

Additional variants of all four isoforms likely exist, as has been shown for alpha-tryptase [1].

Isoforms of tryptase — The five known major secreted isoforms (aI-, aII-, bI-, bII-, and bIII-tryptase) of human tryptases all appear to be expressed in vivo, and they are largely restricted to mature, tissue-resident mast cells and, to a much lesser extent, blood basophils. (See 'Relative specificity to mast cells and basophils' above.)

Alpha- and beta-tryptases – Of the two secreted tryptase isoforms, only beta-tryptases are enzymatically active, although there is a common nonsense variant of beta-tryptase that is nonfunctional if it is expressed [5]. In the past, alpha-tryptases were shown to be inactive, but the identification of HaT has revealed that alpha-tryptases do impact tryptase function when combined with beta-tryptases in heterotetramers. (See 'Tryptase tetramers' below.)

Secreted alpha- and beta-tryptases, like many other serine proteases, are first generated as zymogens, called pro-tryptases. Pro-tryptases require step-wise proteolytic processing in order to become fully mature enzymes. Alpha-tryptases have variants in their pro-peptide domains that interfere with their being processed into fully mature proteins, although it has been demonstrated that alpha-tryptases can be processed to full maturity in vitro and in vivo.

Delta-tryptases – Delta-tryptases are the dominant biologically relevant secreted forms of tryptase in certain nonhuman primates, although little is known about the function of delta-tryptases in humans, including whether they have in vivo activity. They are believed to be secreted in humans, but coding sequences contain a premature stop codon and thus lack a large portion (39 amino acids) of the C-terminal sequence present in major alpha- and beta-tryptase isoforms, likely limiting their enzymatic function.

Gamma-tryptases – There are two membrane-anchored tryptases called gamma tryptases: gamma I- or gamma II-tryptase. These are believed to be the first to evolve in humans from other ancestral type-1 membrane-anchored proteases of the prostasin family. The biological function(s) of gamma-tryptases are largely unknown, although their structure suggests they would have tryptic enzymatic activity.

Tryptase tetramers — Fully mature tryptases exist as tetrameric, toroidal (ie, donut-shaped) proteins that are stabilized by heparin under low pH conditions. Both alpha- and beta-tryptases have been shown to assemble into either homo- or heterotetramers. The active sites from each monomeric subunit are positioned within the hole of the donut, which functionally limits their substrate specificity and prevents natural protease inhibitors from neutralizing their activity (figure 1).

Alpha- and beta-tryptase homotetramers – Beta-tryptases contain a highly conserved residue adjacent to the active site of the enzyme (p.Glu216). Beta-tryptase homotetramers require stabilization by heparin and rapidly dissociate at neutral pH. In contrast, alpha-tryptases contain two missense changes (p.Glu216Asp and p.Asp189Lys), which result in conformational changes that block peptide substrates from accessing the active site, and thus render alpha-tryptase essentially inactive. However, alpha-tryptases form stable homotetramers in the absence of heparin and can remain intact under neutral pH conditions. Thus, alpha-tryptase homotetramers, although enzymatically inactive, are more stable.

Alpha-/beta-tryptase heterotetramers – It was initially unclear how over-expression of alpha-tryptase in patients with HaT might lead to clinical symptoms if alpha-homotetramers were enzymatically inactive. However, in 2019, it was discovered that alpha- and beta-tryptases could also form heterotetramers [24]. Alpha-/beta-tryptase heterotetramers have properties of both mature tryptases that may contribute to unique activities: they are relatively stable while retaining enzymatic activity.

PROPOSED PATHOPHYSIOLOGY — Higher levels of basal serum tryptase (BST) alone are not known to cause symptoms, because the tryptases that make up BST are enzymatically inactive pro-peptides. Tryptases, like many proteases, are initially formed as inactive pro-peptides, some of which undergo stepwise intracellular proteolysis to form tetrameric tryptases that are stored in secretory granules within mature mast cells. However, some of the immature, enzymatically inactive pro-tryptases are constitutively secreted via undefined pathways. It is these enzymatically inactive pro-alpha- and pro-beta-tryptases that comprise BST.

The proposed clinical implications of HaT are believed to be related to the properties of alpha-/beta-tryptase heterotetramers. To date, these heterotetramers are known to cleave at least two protein targets under predicted physiologic conditions [21,23,24]:

EMR2 – Epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 2

and

PAR-2 - Protease activated receptor-2

Enhanced mechanoreceptor activity — EMR2 is a mechanosensing G protein-coupled receptor (GPCR) that is highly expressed on the surface of mast cells and other cells of the myeloid lineage. It appears to contribute to the activation of mast cells in response to specific physical stimuli, such as vibration and shearing forces. EMR2 is encoded by adhesion G protein-coupled receptor E2 (ADGRE2) and comprised of two non-covalently bound domains. The EMR2a subunit binds to proteoglycans in the extracellular space, tethering the integral cell membrane serpentine EMR2b subunit, and thus the cell, to the interstitium. EMR2a tonically inhibits EMR2b signaling. However, in response to shearing forces, the subunits are separated and signaling occurs, leading to mast cell degranulation.

The importance of this receptor on mast cells and associated clinical phenotypes was recognized in a 2016 report of two multigenerational Lebanese families with severe vibratory urticaria associated with a pathogenic missense variant c.1475G>A in ADGRE2 [25]. The resulting p.C492Y amino acid substitution in EMR2 appeared to interfere with the non-covalent interaction of the two EMR subunits, resulting in enhanced in vitro activation of mast cells in response to vibration and severe urticaria in response to vibratory stimuli in the patients.

Similar to the effect of the pathogenic ADGRE2 variant in these two families, alpha-/beta-tryptase heterotetramers have been shown to be uniquely capable of cleaving EMR2a in vitro [24]. Furthermore, an increasing relative abundance of alpha-tryptase- relative to beta-tryptase-encoding gene copies at TPSAB1 and TPSB2 was associated with an increase in symptom response scores following cutaneous vibratory challenge in symptomatic individuals with HaT, as well as in volunteers without HaT [24].

Increased vascular permeability — Protease activated receptor 2 (PAR-2) is one of four receptors in a unique family of mammalian GPCRs wherein proteolytic cleavage of the extracellular N-terminal domain of the protein yields a peptide ligand for the same receptor, leading to its activation in an autocrine manner. PAR-2 is also expressed on mast cells and other myeloid lineage cells but is best characterized in cells from other organs and tissues, including mesodermally derived lineages such as smooth muscle and vascular endothelial cells.

Previous studies examining the activity of beta-tryptases on PAR-2 have been conflicting, ostensibly due to the specific in vitro conditions required for activity, which are unlikely to occur in vivo. However, two studies examining the impacts of alpha-/beta-tryptase heterotetramers have demonstrated a similar ability of these enzymes to activate PAR-2 in a selective manner, similar to that observed with EMR2a [24]. In one study, selective activation of PAR-2 by alpha-/beta-tryptase heterotetramers was shown to result in permeabilization of a vascular endothelial (HUVEC) monolayer in vitro [21]. Such activity might contribute to enhanced vascular permeability in vivo and result in the modifying effects on the severity of immediate hypersensitivity reactions reported in the study.

CLINICAL MANIFESTATIONS — The majority of individuals (estimates are that up to two-thirds) with HaT appear to be asymptomatic or have few symptoms. Among individuals presenting to medical attention, HaT is associated with an increased prevalence and/or severity of anaphylaxis among patients with systemic mastocytosis, stinging insect venom allergy, idiopathic anaphylaxis, and potentially other disorders. In addition, there is an increased prevalence of HaT among patients with systemic mastocytosis.

Evolving clinical picture — There were several other signs and symptoms attributed to HaT in early studies that have not been found in subsequent studies. Because HaT is a common genetic trait present in about 1 in 20 people, it will take time and large numbers of subjects to understand what additional clinical manifestations, if any, are truly associated.

Signs and symptoms that were associated with HaT in initial studies included cutaneous symptoms such as flushing, pruritus, and, in some cases, hives; gastrointestinal (GI) symptoms such as bloating, pain, and diarrhea; connective tissue abnormalities including joint hypermobility, deformity and associated pain, primary tooth retention; and symptoms suggestive of autonomic dysfunction, including in some individuals with postural orthostatic tachycardia syndrome (POTS).

In the years since those earliest descriptions, several studies have begun the process of refining the phenotype of what has now become accepted as a common genetic trait. However, this process has been limited by the relatively high prevalence of HaT in the general population, the modest reported effect size (odds ratio [OR] approximately 2 for immediate hypersensitivity reactions), and the absence of symptoms in the majority of individuals with HaT. Ignoring variable penetrance, to estimate with 95 percent confidence a change in the prevalence of HaT in any given population or phenotype within a margin of error of 1 percent would require an examination of approximately 2000 individuals for a single phenotype, and examining several phenotypes at the same time (multiple comparisons) would require a sample size that is orders of magnitude larger.

Augmented immediate hypersensitivity reactions — The presence of HaT appears to increase the frequency and severity of immediate hypersensitivity reactions in patients with at least three disorders:

Systemic mastocytosis (SM)

Anaphylaxis due to Hymenoptera (bees, wasps, etc) venom allergy, and

Idiopathic anaphylaxis

It remains to be determined if HaT can also enhance other mast cell-mediated disorders.

Systemic mastocytosis — The disorder with the most striking association with HaT to date is systemic mastocytosis. SM is a clonal myeloid neoplastic disorder of mast cells that is frequently indolent in nature and often presents with symptoms of mast cell activation ranging from flushing to syncopal anaphylaxis. Individuals with SM are approximately three times more likely to have HaT compared with healthy controls [26]. In studies that have performed tryptase genotyping among individuals with SM, HaT was found in 12 to 18 percent of individuals. In the two larger studies, it was also found that HaT was associated with a twofold increase in prevalence of anaphylaxis compared with those with SM without HaT [21,26,27]. Although a third smaller, subsequent study did not report this association, individuals with SM and HaT were approximately three times more likely to have been prescribed epinephrine for insect sting reactions than those with SM alone [26,28]. In the largest study of individuals with SM to date, increasing copy numbers of genes encoding alpha-tryptase were associated with increased mast cell mediator-associated symptoms [26,27]. These findings were consistent with the gene-dosage effect on symptoms that was reported in the initial cohort describing HaT, as well as in symptom scores in response to vibratory stimuli among individuals with and without HaT. Most reported individuals with both HaT and SM have had indolent SM. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

Hymenoptera venom anaphylaxis — HaT was found to be at least twice as prevalent among individuals with severe Hymenoptera venom-associated anaphylaxis (HVA) compared with patients with less severe systemic reactions in both a blinded retrospective and a prospective study [21,29]. In both studies, all individuals identified with both HaT and SM had Mueller grade IV anaphylaxis (ie, involving cardiovascular symptoms such as hypotension, shock, arrhythmia). HaT also accounted for the majority of individuals with elevated basal serum tryptase (BST), particularly among those with grade IV anaphylaxis. Of note, the prevalence of HaT among all venom-allergic individuals was not higher than the general population, indicating that while HaT may modify the severity of HVA, it does not appear to increase the risk for the development of venom allergy.

Idiopathic anaphylaxis — A greater prevalence of HaT has also been found in patients with idiopathic anaphylaxis (IA). Among carefully recruited individuals with IA, in whom SM was excluded with bone marrow biopsy, 17 percent of individuals had HaT, a level comparable to that seen in SM. In this cohort, HaT accounted for all BST levels >9.5 ng/mL [21]. (See "Idiopathic anaphylaxis".)

Associations requiring further study — Disorders that have not proven to be definitively associated with HaT include classical irritable bowel syndrome (IBS), hypermobility disorders, and autonomic instability.

Classical IBS – One of the most common symptoms reported among symptomatic individuals with HaT are seemingly functional GI manifestations similar to irritable bowel syndrome (IBS). The individuals included in the first reports of HaT had symptoms largely consistent with Rome III criteria for IBS (table 1) [3,4]. However, an association with classical IBS was not confirmed in a subsequent study that performed tryptase genotyping of individuals from a much larger cohort of individuals with well-characterized and diagnosed IBS [30]. Despite this lack of association with classical IBS, this study identified a specific kind of inflammation (pyroptosis) in the GI mucosa of symptomatic individuals with HaT that was comparable to quiescent inflammatory bowel disease patients and was associated with evidence of cellular activation and adaptive immunologic changes in the GI mucosae. The clinical relevance and generalizability of these findings require additional study.

Congenital hypermobility syndromes – Among the other phenotypes initially reported in association with HaT, subsequent reports have suggested that hypermobility disorders and autonomic instability may not be linked. The prevalence of HaT was not increased among individuals with congenital hypermobility phenotypes, including hypermobile Ehlers-Danlos syndrome (hEDS), hypermobility spectrum disorders (HSD), and those with undefined joint hypermobility associated with severe scoliosis or Chiari malformation, in studies from two independent centers [31]. However, dysphagia and retained primary dentition (ie, phenotypes previously identified to be associated with HaT in unselected volunteers) were significantly associated with HaT. Anaphylaxis and cutaneous flushing and pruritus were also positively associated with HaT, though they did not reach statistical significance after correcting for multiple comparisons given the limited sample size.

Postural orthostatic tachycardia syndrome – In a study examining the potential prevalence of HaT in a well characterized cohort of individuals with POTS, only 7.2 percent of individuals with POTS had BST >8 ng/mL, and only 6.4 percent had BST >11.4 ng/mL [32]. Thus, it appears unlikely that HaT is associated with POTS. Whether it may modify phenotypes associated with this disorder remains to be determined.

Small fiber neuropathy – In a small study of patients with physician-diagnosed mast cell activation syndrome, 80 percent of those with and without HaT were found to have small fiber neuropathy associated with autonomic dysfunction distinct from POTS [33]. Additional studies are needed to examine this association in more detail.

Elevated serum total tryptase — Approximately 80 percent of individuals with HaT have BST levels over 11.4 ng/mL and ranging as high as >100 ng/mL [26]. In contrast, the median BST level in the general population is 4.1 ng/mL. At some point, the dominant effect of tryptase genotype on BST levels in the population will likely require adjustment in clinical laboratory reports.

Note that BST levels among individuals with HaT are not universally above 11.4 ng/mL. Some individuals have been reported with BST levels as low as 6.5 ng/mL, although, in these cases, beta-tryptase replications (which are not associated with inherited elevations in BST) were not excluded.

Increased tissue mast cell numbers — Several independent studies have demonstrated increased mast cell numbers and other distinct immunologic findings in the bone marrow or GI mucosa of symptomatic individuals with HaT [3,30,34,35] (see 'Associations requiring further study' above). Such findings are intriguing given the association of HaT with SM and clonal mast cell disease. It is most likely that association with clonal mast cell disorders result from a modifying effect of HaT on symptoms associated with these presentations, such that patients are more likely to seek medical attention if they have both HaT and SM. Nevertheless, given that HaT is associated with increased mast cell numbers in tissues in the absence of clonal mast cell disease, there remains a possibility that alpha-tryptase overexpression may somehow impact mast cell homeostasis. Were this to be true, however, this effect seems to be limited to mast cells since the prevalence of HaT has not been reported to be increased in other non-mast cell-related myeloid neoplasms [27].

DIAGNOSIS

When to suspect — An elevated basal serum tryptase (BST) is the primary reason to suspect HaT. Tryptase levels are usually obtained following apparent allergic reactions or anaphylaxis or in the evaluation of patients with Hymenoptera venom allergy or symptoms suggestive of mastocytosis or certain hematologic malignancies. The diagnosis of HaT should be suspected in individuals with a BST above 8 ng/mL, although nearly 80 percent of people with the trait have BST levels above the upper limit of normal cited by most laboratories, which is 11.4 ng/mL.

Instructions for obtaining an accurate tryptase level are shown in the table (table 2).

If a patient has been found to have an elevated tryptase following an apparent allergic reaction or anaphylaxis, a repeat tryptase level should be obtained at least 24 hours after the patient has returned to their baseline state. This level represents the patient's BST.

Referral — The diagnosis of HaT and evaluation for other causes of an elevated BST are usually carried out by allergy/immunology or hematology specialists. Referral is appropriate if the BST is elevated >8 ng/mL.

Tryptase levels — Approximately 80 percent of individuals with HaT have BST levels >11.4 ng/mL, as stated previously. The range of BST levels reported in individuals with HaT is dependent upon the number of TPSAB1 replications encoding alpha-tryptase. Most individuals with HaT have one replication (often stated as a "duplication" in the literature). However, individuals with HaT and BST levels >100 ng/mL have also been identified [1,26].

Each TPSAB1 replication encoding alpha-tryptase results in an increase in BST by approximately 9 ng/mL:

The median BST level associated with one replication of TPSAB1 (alpha-tryptase duplication) is 13.6 ng/mL with the modeled upper limit of normal being 36.2 ng/mL.

The median BST level associated with two replications (alpha triplication) is 23.4 ng/mL with the modeled upper limit of normal being 62.2 ng/mL.

Tryptase genotyping — In patients with an elevated BST, the presence of the trait is then confirmed by a droplet digital polymerase chain reaction (ddPCR) assay demonstrating increased copy number of the TPSAB1 gene encoding alpha-tryptase. Note that tryptase gene composition or copy number cannot be characterized with routinely available next-generation sequencing modalities, including exome sequencing (WES), genome sequencing (WGS), and microarray-based comparative genomic hybridization (aCGH). The ddPCR assay is currently only available in one Clinical Laboratory Improvement Amendments (CLIA)College of American Pathologists (CAP)-certified lab in the United States [36]. The lab is accessible to international clinicians as well as those in the United States.

Rarely, concomitant inheritance of tryptase gene copy loss and HaT have been reported in individuals with "normal" genotyping but a mild elevation in BST [37]. This can confound correct interpretation of BST and tryptase genotyping results. However, because haplotype inheritance is nearly universal, examination of tryptase genotypes within pedigrees can clarify conflicting results. This is important since elevated BST >11.4 ng/mL in the absence of HaT or renal disease is principally indicative of myeloid neoplasia. (See 'Differential diagnosis' below.)

Further evaluation in very symptomatic patients — Because HaT is common and many patients are asymptomatic, coexisting disorders should be suspected in highly symptomatic individuals, in particular those with signs and symptoms suggestive of mastocytosis or clonal myeloid diseases, including the following [26]:

Lymphadenopathy

Hepatosplenomegaly

Abnormalities on complete blood count

Thrombocytopenia

Anemia

Pancytopenia

Polycythemia

Neutrophilia

Hypereosinophilia (absolute eosinophil count >1500 cells/mcL)

Eosinophilic tissue infiltration and/or inflammation

Anaphylaxis, especially hypotensive (idiopathic, Hymenoptera venom)

Urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis)/Darier's sign (picture 1)

DIFFERENTIAL DIAGNOSIS — It has been estimated that approximately 90 percent of individuals with basal serum tryptase (BST) levels >11.4 ng/mL have HaT as the cause. However, clonal myeloid diseases (including mastocytosis) and advanced renal disease are the other two groups of disorders in which elevations of BST are seen [2,38].

In several carefully screened cohorts, HaT accounted for all individuals with BST over 10 ng/mL who did not have the two other most common causes of an elevated BST, which are clonal myeloid neoplasms (including mastocytosis) or advanced kidney disease. Similarly, in a retrospective study of a regional health system, these three disorders accounted for 93.1 percent of individuals with BST >11.4 ng/mL. There are some other less common disorders that occasionally lead to elevated tryptase [38].

Mastocytosis — BST levels can be normal patients with systemic mastocytosis (SM) or be elevated into the 1000s of ng/mL [39]. The various forms of mastocytosis are discussed in detail separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

Other myeloid neoplasms — Elevated BST has been reported in 30 to 40 percent of patients with other myeloid neoplasms including those with:

Myelodysplastic syndrome (see "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)")

Myeloproliferative disease (see "Overview of the myeloproliferative neoplasms")

Chronic myeloid leukemia (see "Clinical manifestations and diagnosis of chronic myeloid leukemia")

Chronic myelomonocytic leukemia (see "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis")

Hypereosinophilic syndrome/chronic eosinophilic leukemia (see "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis")

Patients with these disorders may have very high BST levels, although many individuals have normal levels [39].

Advanced kidney disease — BST levels increase gradually with decreasing renal function, ranging from an average of 11.25 ng/mL in stage III chronic kidney disease to the range of 13 to 15 ng/mL in stage V chronic kidney disease and in patients on hemodialysis.

MANAGEMENT — The majority of individuals with HaT have been reported to have few symptoms and thus do not require medical intervention. However, among individuals with HaT who come to medical attention, many respond to therapies that inhibit or reduce the effects of various mast cell mediators.

Overview — Outside of specific clinical presentations (eg, venom anaphylaxis), there are few current expert recommendations for changes in treatment or monitoring, specifically:

In the context of Hymenoptera venom-associated anaphylaxis (HVA), lifelong venom immunotherapy (VIT) has been recommended by some experts, but it has yet to be prospectively examined.

Among individuals with concomitant systemic mastocytosis (SM), the identification of HaT may help anticipate future symptom severity.

Bone density monitoring among symptomatic adults has also been advocated, though prospective data are lacking.

Pharmacotherapy — Treatment strategies for symptomatic individuals with HaT are currently identical to those used in clonal mast cell disorders such as indolent mastocytosis: H1- and H2-antihistamines as well as other mast cell stabilizers such as compounded oral ketotifen or cromolyn sodium, leukotriene modifiers, and, in certain patients, aspirin or intermittent courses of oral corticosteroids [23,40]. In addition, patients with anaphylaxis should be supplied with at least two epinephrine autoinjectors and instructed on how and when to use them. The use of these medications in the treatment of mast cell disorders is reviewed in detail elsewhere. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Therapies to control symptoms'.)

Omalizumab — A small number of studies of symptomatic individuals with HaT have examined the effect of omalizumab on clinical symptoms:

Cutaneous and respiratory symptoms – In retrospective studies, cutaneous and respiratory symptoms attributed to mast cell activation improved, but many other symptoms, including gastrointestinal manifestations, did not [40,41].

Anaphylaxis – In a prospective, randomized placebo-controlled trial of omalizumab in patients with idiopathic anaphylaxis, two of the trial participants were retrospectively identified as having HaT [42]. The HaT participant in the omalizumab arm had a reduction in episodes of anaphylaxis, whereas the HaT participant receiving placebo did not. A reduction in anaphylaxis episodes was also reported in a retrospective study that included HaT patients with anaphylaxis from various triggers [40].

Monitoring for bone loss — Symptomatic individuals with HaT may be at risk for premature bone loss based upon the following:

Clinical reports linking high BST due to unknown cause(s) with premature osteopenia and osteoporosis

The identification of distinct populations of bone marrow mast cells and eosinophils that are increased in symptomatic individuals with HaT

The fact that symptomatic individuals with HaT frequently receive high-dose systemic corticosteroids

We assess symptomatic adult patients (female and male) for osteopenia and osteoporosis with bone densitometry, as described elsewhere. (See "Evaluation and treatment of premenopausal osteoporosis".)

SUMMARY AND RECOMMENDATIONS

Definition and epidemiology – Hereditary alpha-tryptasemia (HaT) is a common autosomal dominant genetic trait, first recognized in 2016, which affects 5 to 6 percent of White populations in the United States, Europe, and the United Kingdom. Studies of other populations are needed. HaT is defined by an increased TPSAB1 gene copy number encoding alpha-tryptase and characterized by elevated basal serum levels of total tryptase (BST). In the populations studied so far, HaT is the most common cause for an elevated BST, accounting for an estimated 90 percent of individuals with elevated levels. (See 'Introduction and definition' above and 'Epidemiology' above.)

Pathophysiology – Tryptases are serine proteases found almost exclusively in mature tissue-resident mast cells. Tryptases have many functions, but the presence of higher BST levels alone is not believed to cause symptoms since the tryptases that make up BST are inactive pro-peptides. Instead, the presence of more alpha-tryptases results in the formation of heterotetramers with beta-tryptases. These alpha-/beta-tryptase heterotetramers have unique enzymatic functions that promote vascular permeability and make mast cells activate more easily in response to certain physical stimuli. (See 'Tryptases' above and 'Proposed pathophysiology' above.)

Clinical manifestations – The majority of individuals (up to two-thirds) with HaT appear to be asymptomatic. In symptomatic patients, the presence of HaT appears to increase the frequency and severity of immediate hypersensitivity reactions and is associated with at least three disorders: systemic mastocytosis, Hymenoptera venom allergy (ie, allergy to the stings of bees and related insects), and idiopathic anaphylaxis. Other phenotypes initially reported in association with HaT, including connective tissue hypermobility and dysautonomia, do not appear to be linked to this common genetic trait based on available evidence, but more study is needed. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis of HaT should be suspected in individuals with a BST above 8 ng/mL, although nearly 80 percent of people with the trait have BST levels above the upper limit of normal cited by most laboratories, which is 11.4 ng/mL. BST levels can range from 6.5 ng/mL to values in the hundreds of ng/mL. It is unclear if these levels correlate with the severity of clinical manifestations among symptomatic individuals, but they do correlate directly with the number of TPSAB1 replications encoding alpha-tryptase. The presence of the trait is confirmed by a droplet digital polymerase chain reaction (ddPCR) assay demonstrating increased copy numbers of the TPSAB1 gene encoding alpha-tryptase. (See 'Diagnosis' above.)

Differential diagnosis – Elevated BST (>11.4 ng/mL) in the absence of HaT is predominantly caused by either significant renal impairment, which is easily identified, or by clonal myeloid neoplasms, including systemic mastocytosis. The presence of various "red flag" signs and symptoms or discordance between the number of alpha-tryptase copies and the BST level should prompt an evaluation for the latter. (See 'Further evaluation in very symptomatic patients' above and 'Differential diagnosis' above.)

Management – The majority of individuals with HaT have few symptoms and thus often do not require medical intervention. Among symptomatic individuals, many respond to therapies that inhibit or reduce the effects of various mast cell mediators, including H1- and H2-antihistamines, oral ketotifen or cromolyn sodium, leukotriene modifiers, and, in certain patients, aspirin or intermittent courses of oral corticosteroids. In addition, patients with anaphylaxis should be supplied with at least two epinephrine autoinjectors and instructed on how and when to use them, and patients with allergy to Hymenoptera venom should receive venom immunotherapy. The anti-IgE monoclonal antibody omalizumab has been used successfully to manage cutaneous and respiratory symptoms and to lessen episodes of anaphylaxis. (See 'Management' above.)

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Topic 135236 Version 2.0

References

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