Intra familial expression of Alpha tryptasemia

Intra familial expression of Alpha tryptasemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Intra familial expression of Alpha tryptasemia Paola KAYE NDI, Catherine MBAZOA AMOUGOU, Mehdi MOUNIR, Olivier MICHEL, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8193743/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hereditary alpha- tryptasemia (HαT) is a common genetic disorder resulting from an increased copy number of the TPSAB1 gene that causes persistently elevated basal serum tryptase levels. HαT presents with a broad and heterogeneous clinical spectrum. Although not a disease per se, HαT may act as an amplifying factor in various clinical contexts, particularly in disorders involving mast cell reactivity. We report two cases - mother and daughter - with identical TPSAB1 duplications, but with markedly different clinical profiles. The mother developed moderate symptoms of episodic pruritus, urticaria, and exertional dyspnea that responded to antihistamines and a low-histamine diet. In contrast, the daughter presented with early-onset and persistent symptoms, including angioedema, urticaria, bronchial obstruction, and dysmenorrhea. Neither patient showed evidence of IgE-mediated allergy, systemic inflammation or eosinophilia, and systemic mastocytosis was excluded (absence of cKIT mutation). These observations underscore the symptomatic variability of HαT and highlight the phenotypic heterogeneity of this genetic disorder even within the same family. Introduction Hereditary alpha- tryptasemia (HαT) is a genetic disorder with a prevalence of 4% to 6% in the general population characterized by increased baseline serum tryptase levels due to an increased copy number of the gene coding for alpha-tryptase ( TPSAB1 ) and resulting in chronically elevated basal serum tryptase levels. ( 1 , 2 ). It presents with a broad and heterogeneous clinical spectrum, ranging from asymptomatic individuals to presentations resembling mast cell activation syndromes with multisystem symptoms, including urticaria, angioedema,, gastrointestinal complaints, autonomic dysfunction, and enhanced allergic responses ( 3 ). Importantly, HαT is increasingly regarded not strictly as a distinct disease entity, but rather as a genetic trait that may be associated with various clinical symptoms and may act as a modifier, potentially amplifying the manifestations of mast cell-associated disorders, such as systemic mastocytosis or mast cell activation syndrome (MCAS) ( 4 ). Its presence may also contribute to the severity of anaphylactic reactions in susceptible individuals ( 5 ). Case Presentation We report two intrafamilial cases of HαT exhibiting distinct clinical profiles in a mother (Patient 1) and her only child, a daughter (Patient 2). Notably, the father has no reported history of allergic or atopic disease. Patient 1 A 35-year-old woman with no significant medical history presented to the pulmonary allergy service in 2017 for recurrent episodes of generalized urticaria and isolated pruritus, triggered by the consumption of certain nuts and kiwi. Skin prick testing showed no sensitization to respiratory or food allergens. Blood tests showed no specific IgE to suspected allergens, no evidence of systemic inflammation, and no eosinophilia. A low-histamine diet combined with H1 antihistamines resulted in good symptom control. In 2022, the patient reported recurrent eyelid edema after eating tomatoes, pineapple, kiwi, and mushrooms, along with unusual exertional dyspnea. A new evaluation confirmed the absence of IgE-mediated allergy, normal lung function, and normal exhaled NO. However, a positive histamine bronchial challenge test suggested non-specific bronchial hyperreactivity, explaining the exercise-induced bronchoconstriction. Her serum tryptase level was elevated at 12.7 µg/L (normal < 8.4 µg/L). Systemic mastocytosis was excluded by the absence of a cKIT mutation. The diagnosis of hereditary alpha-tryptasemia was confirmed by the presence of three copies of the TPSAB1 gene encoding alpha-tryptase. A continued low-histamine diet was recommended, along with H1 antihistamines and bronchodilators. She was also prescribed an epinephrine autoinjector to prevent acute reactions. Since then, she has experienced only occasional isolated episodes of pruritus. Patient 2 : Her 13-year-old daughter with no previous significant medical history was seen in 2022 for chronic rhinitis with exertional dyspnea preventing any sports activity, episodes of generalized urticaria and oral angioedema triggered by tomato and orange, perimenstrual labial and eyelid angioedema with dysmenorrhea, non-pruritic maculopapular rashes, and spontaneous bruising. Skin prick tests showed no sensitization to respiratory or food allergens. Lung function tests revealed persistent bronchial obstruction, with normal exhaled NO. Blood tests showed no specific IgE, no systemic inflammation, and no eosinophilia. Serum tryptase was elevated at 13.1 ng/mL (normal < 8.4 µg/L). While mast cell hyperactivation syndrome was suspected, systemic mastocytosis was excluded by the absence of cKIT mutation. The diagnosis of hereditary alpha tryptasemia was confirmed by a duplication of TPSAB1/TPSAB2 ( TPSAB1 [alpha]: 3 copies; TPSAB2 [beta]: 2 copies). Treatment included a combination of anti-H1 anti-H2 histamines, inhaled corticosteroids, anti-leukotrienes, long-acting bronchodilators, and a low-histamine diet. Since then, there has been partial improvement in symptoms, but persistent obstructive ventilatory disorder remains, with an FEV1 < 60% of predicted. Discussion HαT is increasingly recognized as a common inherited trait that may contribute to mast cell activation in predisposed individuals but is not associated with clinical specific phenotypes ( 6 , 7 ). The present reported cases highlight the phenotypic variability even within a single family. The mother exhibits a relatively mild and late-onset phenotype, with cutaneous and respiratory symptoms well-controlled by standard interventions. In contrast, her daughter demonstrates a much more complex and severe presentation from adolescence, involving persistent bronchial obstruction, mucosal edema, and cutaneous and gynecological symptoms. Measurement of basal serum tryptase should be considered in patients with symptoms suggestive of allergic or mast cell-mediated processes. If elevated, it should prompt evaluation for HαT, especially in the absence of clear IgE-mediated mechanisms or systemic mastocytosis ( 8 ). HαT can mimic several diseases, including mast cell activation syndrome (MCAS), which is characterized by paroxysmal symptoms associated with an acute increase in serum tryptase (> 20% + 2 ng/mL) a few hours after a typical symptomatic episode ( 9 ) and a good response to combined therapy with anti-H1 and anti-H2 antihistamines in combination with an anti leukotriene medication ( 10 ). Our cases do not meet these criteria as they have persistently elevated tryptase levels and only a partial response to treatment. Another possible diagnosis could be chronic spontaneous urticaria (CSU) with angioedema which typically involves daily urticaria, often with angioedema, usually of autoimmune or allergic origin ( 11 ). In our cases, the absence of specific IgE, elevated exhaled NO and autoimmune markers suggests an alternative diagnosis. In addition, the severe respiratory involvement observed in the daughter is not consistent with classic CSU. HαT is increasingly recognized as a common inherited trait that may contribute to mast cell activation in predisposed individuals ( 4 ). This striking intra-familial contrast in clinical expression of our presented cases underscores the heterogeneity of HαT and supports its classification not as a disease entity, but as a genetic background capable of modulating individual responses to environmental and physiological triggers. Both patients lacked indicators of IgE-mediated allergy or systemic mastocytosis, emphasizing the role of non- IgE pathways, possibly involving MRGPRX2 or PAR2 receptor signaling, in driving symptomatology ( 12 ). Initially, Lyons et al described HαT as a monogenic cause of multisystem mast cell–associated symptoms, suggesting a pathogenic disease entity linked to TPSAB1 copy number variation ( 2 ). However, subsequent studies from the same group revised this interpretation, emphasizing that HαT is better characterized as a common genetic trait that may modulate symptom severity in various clinical contexts without constituting a disease in itself ( 5 ). Such interpretations remain controversial ( 13 ) Treatment of hereditary alpha- tryptasemia currently relies on an individualized symptomatic approach, as no curative therapy targeting the TPSAB1 gene duplication is available ( 14 ). Patients benefit primarily from a low-histamine diet combined with H1 and H2 antihistamines to manage cutaneous, gastrointestinal, and respiratory symptoms ( 15 ). In cases of asthma or exertional dyspnea, bronchodilators and inhaled corticosteroids may be indicated, sometimes supplemented with anti-leukotrienes ( 11 ). More severe or refractory forms, especially those with chronic urticaria, pseudo anaphylaxis, or persistent bronchial obstruction, may warrant the use of omalizumab (anti-IgE) ( 1 , 16 ). An epinephrine autoinjector is often prescribed to prevent severe acute reactions ( 1 ) Although tryptase inhibitors and receptor antagonists are under investigation, these therapeutic options remain experimental. Management should be multidisciplinary and tailored to the fluctuating and often complex symptomatology of this condition. Conclusion Hereditary alpha-tryptasemia (HαT) can mimic chronic allergic or mast cell–mediated conditions without exhibiting their typical immunologic hallmarks. These cases underscore the importance of considering TPSAB1 gene duplication in the diagnostic workup of unexplained pseudo-allergic symptoms, particularly in familial contexts. A multidisciplinary approach and longitudinal follow-up are essential, especially when respiratory manifestations are progressive and lack a clear etiology. Learning Points : Hereditary alpha tryptasemia is a genetic trait with variable clinical expression. It may amplify mast cell reactivity in non-IgE contexts. Phenotypic variability can be striking even within families. Diagnosis relies on elevated basal tryptase and TPSAB1 copy number. Management is symptomatic and should be personalized. Declarations Author information Authors and affiliations Department of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium Paola KAYE NDI , Md. Department of pulmonology and allergology , Edith Cavell Interregional Hospital , Brussels , Belgium Catherine MBAZOA AMOUGOU , Md . Department of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium Mehdi MOUNIR , Md. Department of pulmonology and allergology , Edith Cavell Interregional Hospital , Brussels , Belgium Olivier MICHEL ,Phd. Department of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium Elie COGAN , Phd. Corresponding authors Correspondence to Paola Kaye Ndi , [email protected] . Funding The authors declare that no financial support was recieved for the research,autorship, and/or publication of this article. Clinical trial number Not applicable. Data Availability All data generated or analysed during this study are included in this article. Ethics approval Ethical approval for this study was waived by the Ethics Committee of the CHIREC Hospital Group , 201 Boulevard du Triomphe, 1160 Brussels, Belgium, as this work is based on the retrospective analysis and description of clinical data collected during routine medical care, with no additional diagnostic or therapeutic procedures performed for research purposes. The study was conducted in accordance with the ethical standards of the above-mentioned ethics committee and with the principles of the Declaration of Helsinki. Consent to participate Informed consent to participate was obtained from the patients and from the patients parent’s /legal guardian’s for the publication of any data included in this article. Consent to publish Written informed consent for publication of this case report was from the patients. For minors, written informed consent was obtained from their parents or legal guardians. Competing interest The authors declare that they have no competing interests. References Luskin KT, White AA, Lyons JJ. The Genetic Basis and Clinical Impact of Hereditary Alpha-Tryptasemia. J Allergy Clin Immunol Pract. 2021;9(6):2235–42. 10.1016/j.jaip.2021.03.005 . Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016;48(12):1564–9. 10.1038/ng.3696 . Robey RC, Wilcock A, Bonin H, Beaman G, Myers B, Grattan C, et al. Hereditary Alpha-Tryptasemia: UK Prevalence and Variability in Disease Expression. J Allergy Clin Immunol Pract. 2020;8(10):3549–56. 10.1016/j.jaip.2020.05.057 . Shin H, Lyons JJ. Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell-Mediated Reactions. Curr Allergy Asthma Rep. 2024;24(4):199–209. 10.1007/s11882-024-01136-y . Wu R, Lyons JJ. Hereditary Alpha-Tryptasemia: a Commonly Inherited Modifier of Anaphylaxis. Curr Allergy Asthma Rep. 2021;21(5):33. 10.1007/s11882-021-01010-1 . Chollet MB, Akin C. Hereditary alpha tryptasemia is not associated with specific clinical phenotypes. J Allergy Clin Immunol . (2022);149(2):728 – 35 e2. 10.1016/j.jaci.2021.06.017 Giannetti MP, Weller E, Bormans C, Novak P, Hamilton MJ, Castells M. Hereditary alpha-tryptasemia in 101 patients with mast cell activation-related symptomatology including anaphylaxis. Ann Allergy Asthma Immunol. 2021;126(6):655–60. 10.1016/j.anai.2021.01.016 . Spoerl D, Docquier M, Coattrenec Y, Seebach JD. Patients with elevated basal tryptase serum levels should be tested for hereditary alpha-tryptasemia. Eur Ann Allergy Clin Immunol. 2022;54(5):242–4. 10.23822/EurAnnACI.1764-1489.220 . Gulen T, Akin C, Bonadonna P, Siebenhaar F, Broesby-Olsen S, Brockow K, et al. Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review. J Allergy Clin Immunol Pract. 2021;9(11):3918–28. 10.1016/j.jaip.2021.06.011 . Weiler CR, Austen KF, Akin C, Barkoff MS, Bernstein JA, Bonadonna P, AAAAI Mast Cell Disorders Committee Work Group Report, et al. Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol. 2019;144(4):883–96. 10.1016/j.jaci.2019.08.023 . Kolkhir P, Munoz M, Asero R, Ferrer M, Kocaturk E, Metz M, et al. Autoimmune chronic spontaneous urticaria. J Allergy Clin Immunol. 2022;149(6):1819–31. 10.1016/j.jaci.2022.04.010 . Wang Z, Babina M. MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis? Exp Dermatol. 2020;29(11):1104–11. 10.1111/exd.14182 . Couto ML, Silva M, Barbosa MJ, Ferreira F, Fragoso AS, Azenha Rama T. Defining hereditary alpha-tryptasemia as a risk/modifying factor for anaphylaxis: are we there yet? Eur Ann Allergy Clin Immunol. 2023;55(4):152–60. 10.23822/EurAnnACI.1764-1489.288 . Sprinzl B, Greiner G, Uyanik G, Arock M, Haferlach T, Sperr WR, et al. Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond. Int J Mol Sci. 2021;22(5). 10.3390/ijms22052458 . Kranyak A, Shuler M, Lee LW. Cutaneous Manifestations in Hereditary Alpha Tryptasemia. Cutis. 2023;111(1):49–52. 10.12788/cutis.0682 . Mendoza Alvarez LB, Barker R, Nelson C, DiMaggio T, Stone KD, Milner JD, et al. Clinical response to omalizumab in patients with hereditary alpha-tryptasemia. Ann Allergy Asthma Immunol. 2020;124(1):99–e1001. 10.1016/j.anai.2019.09.026 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8193743","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":587495733,"identity":"a57e9a9d-e015-462d-8d1a-adba0aba5a44","order_by":0,"name":"Paola KAYE NDI","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYHACxgMMDMw8/MyMjY/BfGbmBoJ6wFok25sPGzMwGADZjMRpYTA4cyxNGqyFgYAWc/bDBw783GEtw3Ajx6y6oOJPNH87UMuPim04tVj2pCUc7D2TzsM4I8fs9owzBrkzDjM2MPacuY1Ti8GBHIMDvG2HeZglgFp42wxyG4BamBnb8Gg5/8bg4F+gFjaglmKQlvkEtdzIMTgMsoWH51gaM0jLBkJaLGc8Szgs25bOI8HefFia54xx7kagloP4/GLOn3zw4ds2a3v7w4yNn3kq5HLnnT988MGPCjwOwyp6AKd6nFpGwSgYBaNgFCADADsoWzaem4M8AAAAAElFTkSuQmCC","orcid":"","institution":"Edith Cavell Interregional Hospital","correspondingAuthor":true,"prefix":"","firstName":"Paola","middleName":"KAYE","lastName":"NDI","suffix":""},{"id":587495735,"identity":"514c6494-ae2a-461b-92b2-ec935f9c6112","order_by":1,"name":"Catherine MBAZOA AMOUGOU","email":"","orcid":"","institution":"Edith Cavell Interregional Hospital","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"MBAZOA","lastName":"AMOUGOU","suffix":""},{"id":587495739,"identity":"b5022129-5ef2-42b3-8548-31546296fbca","order_by":2,"name":"Mehdi MOUNIR","email":"","orcid":"","institution":"Edith Cavell Interregional Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mehdi","middleName":"","lastName":"MOUNIR","suffix":""},{"id":587495740,"identity":"d30f1de7-5d09-4f42-b52a-55b452674fb7","order_by":3,"name":"Olivier MICHEL","email":"","orcid":"","institution":"Edith Cavell Interregional Hospital","correspondingAuthor":false,"prefix":"","firstName":"Olivier","middleName":"","lastName":"MICHEL","suffix":""},{"id":587495741,"identity":"2ad3e11c-134c-46d0-ba24-4c2e61770f64","order_by":4,"name":"Elie COGAN","email":"","orcid":"","institution":"Edith Cavell Interregional Hospital","correspondingAuthor":false,"prefix":"","firstName":"Elie","middleName":"","lastName":"COGAN","suffix":""}],"badges":[],"createdAt":"2025-11-24 13:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8193743/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8193743/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108085071,"identity":"4bd9206b-29ff-48c1-b0a0-f464e4f3b578","added_by":"auto","created_at":"2026-04-29 08:26:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":159036,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8193743/v1/dd483626-ea21-48b1-9c7a-530432da32a5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intra familial expression of Alpha tryptasemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHereditary alpha- tryptasemia (HαT) is a genetic disorder with a prevalence of 4% to 6% in the general population characterized by increased baseline serum tryptase levels due to an increased copy number of the gene coding for alpha-tryptase (\u003cem\u003eTPSAB1\u003c/em\u003e) and resulting in chronically elevated basal serum tryptase levels. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). It presents with a broad and heterogeneous clinical spectrum, ranging from asymptomatic individuals to presentations resembling mast cell activation syndromes with multisystem symptoms, including urticaria, angioedema,, gastrointestinal complaints, autonomic dysfunction, and enhanced allergic responses (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Importantly, HαT is increasingly regarded not strictly as a distinct disease entity, but rather as a genetic trait that may be associated with various clinical symptoms and may act as a modifier, potentially amplifying the manifestations of mast cell-associated disorders, such as systemic mastocytosis or mast cell activation syndrome (MCAS) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Its presence may also contribute to the severity of anaphylactic reactions in susceptible individuals (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eWe report two intrafamilial cases of HαT exhibiting distinct clinical profiles in a mother (Patient 1) and her only child, a daughter (Patient 2). Notably, the father has no reported history of allergic or atopic disease.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePatient 1\u003c/strong\u003e \u003cp\u003eA 35-year-old woman with no significant medical history presented to the pulmonary allergy service in 2017 for recurrent episodes of generalized urticaria and isolated pruritus, triggered by the consumption of certain nuts and kiwi.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eSkin prick testing showed no sensitization to respiratory or food allergens. Blood tests showed no specific IgE to suspected allergens, no evidence of systemic inflammation, and no eosinophilia. A low-histamine diet combined with H1 antihistamines resulted in good symptom control.\u003c/p\u003e \u003cp\u003eIn 2022, the patient reported recurrent eyelid edema after eating tomatoes, pineapple, kiwi, and mushrooms, along with unusual exertional dyspnea.\u003c/p\u003e \u003cp\u003eA new evaluation confirmed the absence of IgE-mediated allergy, normal lung function, and normal exhaled NO. However, a positive histamine bronchial challenge test suggested non-specific bronchial hyperreactivity, explaining the exercise-induced bronchoconstriction. Her serum tryptase level was elevated at 12.7 \u0026micro;g/L (normal\u0026thinsp;\u0026lt;\u0026thinsp;8.4 \u0026micro;g/L). Systemic mastocytosis was excluded by the absence of a \u003cem\u003ecKIT\u003c/em\u003e mutation. The diagnosis of hereditary alpha-tryptasemia was confirmed by the presence of three copies of the \u003cem\u003eTPSAB1\u003c/em\u003e gene encoding alpha-tryptase.\u003c/p\u003e \u003cp\u003eA continued low-histamine diet was recommended, along with H1 antihistamines and bronchodilators. She was also prescribed an epinephrine autoinjector to prevent acute reactions. Since then, she has experienced only occasional isolated episodes of pruritus.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003ePatient 2\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eHer 13-year-old daughter with no previous significant medical history was seen in 2022 for chronic rhinitis with exertional dyspnea preventing any sports activity, episodes of generalized urticaria and oral angioedema triggered by tomato and orange, perimenstrual labial and eyelid angioedema with dysmenorrhea, non-pruritic maculopapular rashes, and spontaneous bruising. Skin prick tests showed no sensitization to respiratory or food allergens. Lung function tests revealed persistent bronchial obstruction, with normal exhaled NO. Blood tests showed no specific IgE, no systemic inflammation, and no eosinophilia. Serum tryptase was elevated at 13.1 ng/mL (normal\u0026thinsp;\u0026lt;\u0026thinsp;8.4 \u0026micro;g/L). While mast cell hyperactivation syndrome was suspected, systemic mastocytosis was excluded by the absence of \u003cem\u003ecKIT\u003c/em\u003e mutation. The diagnosis of hereditary alpha tryptasemia was confirmed by a duplication of \u003cem\u003eTPSAB1/TPSAB2\u003c/em\u003e (\u003cem\u003eTPSAB1\u003c/em\u003e [alpha]: 3 copies; \u003cem\u003eTPSAB2\u003c/em\u003e [beta]: 2 copies).\u003c/p\u003e \u003cp\u003eTreatment included a combination of anti-H1 anti-H2 histamines, inhaled corticosteroids, anti-leukotrienes, long-acting bronchodilators, and a low-histamine diet. Since then, there has been partial improvement in symptoms, but persistent obstructive ventilatory disorder remains, with an FEV1\u0026thinsp;\u0026lt;\u0026thinsp;60% of predicted.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHαT is increasingly recognized as a common inherited trait that may contribute to mast cell activation in predisposed individuals but is not associated with clinical specific phenotypes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The present reported cases highlight the phenotypic variability even within a single family. The mother exhibits a relatively mild and late-onset phenotype, with cutaneous and respiratory symptoms well-controlled by standard interventions. In contrast, her daughter demonstrates a much more complex and severe presentation from adolescence, involving persistent bronchial obstruction, mucosal edema, and cutaneous and gynecological symptoms.\u003c/p\u003e \u003cp\u003eMeasurement of basal serum tryptase should be considered in patients with symptoms suggestive of allergic or mast cell-mediated processes. If elevated, it should prompt evaluation for HαT, especially in the absence of clear IgE-mediated mechanisms or systemic mastocytosis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHαT can mimic several diseases, including mast cell activation syndrome (MCAS), which is characterized by paroxysmal symptoms associated with an acute increase in serum tryptase (\u0026gt;\u0026thinsp;20% + 2 ng/mL) a few hours after a typical symptomatic episode (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and a good response to combined therapy with anti-H1 and anti-H2 antihistamines in combination with an anti leukotriene medication (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Our cases do not meet these criteria as they have persistently elevated tryptase levels and only a partial response to treatment.\u003c/p\u003e \u003cp\u003eAnother possible diagnosis could be chronic spontaneous urticaria (CSU) with angioedema which typically involves daily urticaria, often with angioedema, usually of autoimmune or allergic origin (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In our cases, the absence of specific IgE, elevated exhaled NO and autoimmune markers suggests an alternative diagnosis. In addition, the severe respiratory involvement observed in the daughter is not consistent with classic CSU. HαT is increasingly recognized as a common inherited trait that may contribute to mast cell activation in predisposed individuals (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis striking intra-familial contrast in clinical expression of our presented cases underscores the heterogeneity of HαT and supports its classification not as a disease entity, but as a genetic background capable of modulating individual responses to environmental and physiological triggers. Both patients lacked indicators of IgE-mediated allergy or systemic mastocytosis, emphasizing the role of non- IgE pathways, possibly involving MRGPRX2 or PAR2 receptor signaling, in driving symptomatology (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInitially, Lyons et al described HαT as a monogenic cause of multisystem mast cell\u0026ndash;associated symptoms, suggesting a pathogenic disease entity linked to \u003cem\u003eTPSAB1\u003c/em\u003e copy number variation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, subsequent studies from the same group revised this interpretation, emphasizing that HαT is better characterized as a common genetic trait that may modulate symptom severity in various clinical contexts without constituting a disease in itself (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Such interpretations remain controversial (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTreatment of hereditary alpha- tryptasemia currently relies on an individualized symptomatic approach, as no curative therapy targeting the \u003cem\u003eTPSAB1\u003c/em\u003e gene duplication is available (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Patients benefit primarily from a low-histamine diet combined with H1 and H2 antihistamines to manage cutaneous, gastrointestinal, and respiratory symptoms (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In cases of asthma or exertional dyspnea, bronchodilators and inhaled corticosteroids may be indicated, sometimes supplemented with anti-leukotrienes (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMore severe or refractory forms, especially those with chronic urticaria, pseudo anaphylaxis, or persistent bronchial obstruction, may warrant the use of omalizumab (anti-IgE) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). An epinephrine autoinjector is often prescribed to prevent severe acute reactions (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAlthough tryptase inhibitors and receptor antagonists are under investigation, these therapeutic options remain experimental. Management should be multidisciplinary and tailored to the fluctuating and often complex symptomatology of this condition.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHereditary alpha-tryptasemia (HαT) can mimic chronic allergic or mast cell\u0026ndash;mediated conditions without exhibiting their typical immunologic hallmarks. These cases underscore the importance of considering TPSAB1 gene duplication in the diagnostic workup of unexplained pseudo-allergic symptoms, particularly in familial contexts. A multidisciplinary approach and longitudinal follow-up are essential, especially when respiratory manifestations are progressive and lack a clear etiology.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLearning Points\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e Hereditary alpha tryptasemia is a genetic trait with variable clinical expression.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e It may amplify mast cell reactivity in non-IgE contexts.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Phenotypic variability can be striking even within families.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Diagnosis relies on elevated basal tryptase and TPSAB1 copy number.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Management is symptomatic and should be personalized.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor information\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors and affiliations\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePaola KAYE NDI , Md.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of pulmonology and allergology , Edith Cavell Interregional Hospital , Brussels , Belgium\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCatherine MBAZOA AMOUGOU , Md .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMehdi MOUNIR , Md.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of pulmonology and allergology , Edith Cavell Interregional Hospital , Brussels , Belgium\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOlivier MICHEL ,Phd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of internal medicine, Edith Cavell Interregional Hospital , Brussels , Belgium\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eElie COGAN , Phd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Paola Kaye Ndi , [email protected].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no financial support was recieved for the research,autorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was waived by the \u003cstrong\u003eEthics Committee of the CHIREC Hospital Group\u003c/strong\u003e,\u0026nbsp;201 Boulevard du Triomphe, 1160 Brussels, Belgium, as this work is based on the retrospective analysis and description of clinical data collected during routine medical care, with no additional diagnostic or therapeutic procedures performed for research purposes.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the ethical standards of the above-mentioned ethics committee and with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent to participate\u0026nbsp; was obtained from the patients and\u0026nbsp;from the patients parent’s /legal guardian’s for the publication of any data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of this case report was from the patients. For minors, written informed consent was obtained from their parents or legal guardians.\u003c/p\u003e\n\u003cp\u003eCompeting interest\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing \u0026nbsp;interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLuskin KT, White AA, Lyons JJ. The Genetic Basis and Clinical Impact of Hereditary Alpha-Tryptasemia. J Allergy Clin Immunol Pract. 2021;9(6):2235\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaip.2021.03.005\u003c/span\u003e\u003cspan address=\"10.1016/j.jaip.2021.03.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. 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Ann Allergy Asthma Immunol. 2020;124(1):99\u0026ndash;e1001. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.anai.2019.09.026\u003c/span\u003e\u003cspan address=\"10.1016/j.anai.2019.09.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8193743/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8193743/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHereditary alpha- tryptasemia (HαT) is a common genetic disorder resulting from an increased copy number of the \u003cem\u003eTPSAB1\u003c/em\u003e gene that causes persistently elevated basal serum tryptase levels. HαT presents with a broad and heterogeneous clinical spectrum. Although not a disease per se, HαT may act as an amplifying factor in various clinical contexts, particularly in disorders involving mast cell reactivity. We report two cases - mother and daughter - with identical \u003cem\u003eTPSAB1\u003c/em\u003e duplications, but with markedly different clinical profiles. The mother developed moderate symptoms of episodic pruritus, urticaria, and exertional dyspnea that responded to antihistamines and a low-histamine diet. In contrast, the daughter presented with early-onset and persistent symptoms, including angioedema, urticaria, bronchial obstruction, and dysmenorrhea. Neither patient showed evidence of IgE-mediated allergy, systemic inflammation or eosinophilia, and systemic mastocytosis was excluded (absence of \u003cem\u003ecKIT\u003c/em\u003e mutation). These observations underscore the symptomatic variability of HαT and highlight the phenotypic heterogeneity of this genetic disorder even within the same family.\u003c/p\u003e","manuscriptTitle":"Intra familial expression of Alpha tryptasemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 14:29:05","doi":"10.21203/rs.3.rs-8193743/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3a3143a4-96d5-410c-b15f-97cc7538635f","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Withdrawn","date":"2026-04-29T08:11:20+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T08:24:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 14:29:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8193743","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8193743","identity":"rs-8193743","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}