# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=en-US - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260515230752+05'30' - Creator=Adobe InDesign 19.5 (Windows) - ModDate=D:20260515230754+05'30' - Producer=Adobe PDF Library 17.0 - Title=Characteristics and outcomes of patients with pediatric‐onset non‐mastocytosis mast cell activation disorders: A CEREMAST study - Trapped=False - Custom.WPS-ARTICLEDOI=10.1111/pai.70373 - Custom.WPS-JOURNALDOI=10.1111/(ISSN)1399-3038 - Custom.WPS-PROCLEVEL=3 - jav:journal_article_version=VoR - prism:doi=10.1111/pai.70373 - pdfx:wps-articledoi=10.1111/pai.70373 - pdfx:wps-journaldoi=10.1111/(ISSN)1399-3038 - pdfx:wps-proclevel=3 - dc:title=Characteristics and outcomes of patients with pediatric‐onset non‐mastocytosis mast cell activation disorders: A CEREMAST study ## Contents ### Page 1 Pediatr Allergy Immunol. 2026;37:e70373. | 1 of 11https://doi.org/10.1111/pai.70373wileyonlinelibrary.com/journal/paiReceived: 29 April 2025 | Revised: 30 March 2026 | Accepted: 4 May 2026DOI: 10.1111/pai.70373O R I G I N A L A R T I C L E Characteristics and outcomes of patients with pediatric-onset non-mastocytosis mast cell activation disorders: A CEREMAST study M. Weiss1 | J. Rossignol2,3,4 | F. Campeotto5 | E. Foy6 | C. Elbany6 | L. Jaume1 |L. Geroux6 | O. Debeaupuis2 | A. Neuraz7 | L. Bekel1 | G. Lezmi 6 | N. Bellon1 |C. Méni1 | C. Livideanu2,8 | M. Madrange2,4 | D. Condé1,2 | J. Agopian2,9 |C. Michot10 | F. Villard-Truc11 | A. Lachaux11 | C. Greco12 | S. Hadj-Rabia1 |P. Dubreuil2,8 | O. Hermine2,3,4 | C. Bodemer1,2,4 | L. Polivka1,2,41Department of Dermatology, Reference Center for Genodermatoses (MAGEC), AP-HP, Necker- Children's Hospital, Paris Centre University, Paris, France2CEREMAST, Imagine Institute, INSERM U1163, Paris, France3Department of Hematology, Necker- Children's Hospital (AP-HP5), Paris- Centre University, Imagine Institute, Paris, France 4 Paris- Centre University, Imagine Institute, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, INSERM UMR 1163,Paris, France5Department of Gastro-Enterology, Necker-Children's Hospital (AP-HP5), Paris- Centre University, Imagine Institute, Paris, France6Department of Allergology, Necker-Children's Hospital (AP-HP5), Paris- Centre University, Imagine Institute, Paris, France7Department of Bioinformatics, Necker Branch, Necker- Children's Hospital (AP-HP5), Paris- Centre University, Imagine Institute, INSERM U1163, Paris, France8Department of Dermatology, Toulouse University Medical Hospital, Toulouse, France9CRCM [Signaling, Hematopoiesis and Mechanism of Oncogenesis, CEREMAST, AFIRMM], Inserm U1068, Institut Paoli- Calmettes, Aix-Marseille University,UM105, Marseille, France10Department of Genetics, National Reference Centre for Skeletal Dysplasia, Paris University, Necker-Children's Hospital (AP-HP5), Paris- Centre University,Imagine Institute, Paris, France11Department of Pediatric Hepatology and Gastroenterology, Hospices Civils de Lyon, Hôpital Femme Mere Enfant and Lyon 1 University, Inserm 1111, Lyon,France12Department of Pain and Palliative Care, Necker-Children's Hospital (AP-HP5), Paris- Centre University, Imagine Institute, Paris, France This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution inany medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This study was performed on behalf of the French Reference Center for Mastocytosis (CEREMAST) study group.M. Weiss, J. Rossignol, F. Campeotto, E. Foy, C. Bodemer, L. Polivka shared equal contribution.Abbreviations: CEREMAST, Centre de Référence Maladies Rares des Mastocytoses (French National Referral Center for Mast Cell Disorders); ddPCR, droplet digital PCR; HαT, hereditaryalpha tryptasemia; MC, mast cell; MCA, mast cell activation; MCAS, mast cell activation syndrome; MMAS, monoclonal mast cell activation syndrome; SID, sucrase-isomaltasedeficiency.CorrespondenceL. Polivka, Centre University, INSERMU1163, 24 boulevard Montparnasse,F-75015 Paris, France. Email: laura.polivka@institutimagine.orgAbstract Background: Mast cell (MC) activation (MCA) disorders (MCAD) include diseasesin which MCs excessively release mediators leading to recurrent manifestations ofMCA. MCAD encompasses MCA syndrome (MCAS) which is defined by (i) docu- mented systemic symptoms of MCA, (ii) a 20% increase in serum tryptase levelfrom the individual's baseline plus 2 ng/mL and (iii) a symptom response to MC-stabilizing drugs. MCAD not fulfilling mastocytosis or all MCAS criteria are referredEditor: Carmen Riggioni ### Page 2 2 of 11 |WEISS et al.1 | I NTRO D U C TI O NMast cells (MCs) are tissue-bound immune cells involved in physi-ological immune responses but also in the initiation and maintenance of allergic inflammation and other inflammatory conditions.1–4 Theterm “mast cell activation (MCA) disorders” (MCAD) encompassesa group of clinical situations in which MCs inappropriately degranu- late and release excessive amounts of chemical mediators.4–7 Thisexcessive release causes symptoms mimicking IgE-mediated allergyand may significantly impair the patient's quality of life.8 MCAD en- compasses MCA syndrome (MCAS) which is defined by the followingVienna consensus criteria9–11: (i) documented severe, recurrent, sys- temic symptoms of MCA involving at least two organ systems—typi- cal MC–triggered manifestations include gastrointestinal symptoms(nausea, abdominal pain, bloating, cramping, and diarrhea), cutaneoussigns (urticaria, flushing, pruritus, and angioedema), respiratory symp- toms (throat or chest tightness, shortness of breath, and wheezing),and cardiovascular features (hypotension and tachycardia), (ii) a 20%increase in serum tryptase level from the individual's baseline plus2 ng/mL, within a 2–4 h window after the reaction,12 and (iii) a symp- tom response to MC-stabilizing drugs that either target MC-derivedmediators (e.g., H1 and H2 antihistamines and leukotriene receptorantagonists) and/or suppress MC activation (e.g., cromoglycate, ke- totifen, and omalizumab). 5,13,14 MCAS can be primary, the so- calledmonoclonal MCAS (MMAS), in which KIT-mutated, clonal MCs aredetected and an underlying mastocytosis is often found; secondary,where an underlying non- neoplastic MC disease is detected (usuallyan IgE-mediated polysensitization, autoimmune disease, or inflamma- tory disorder); or idiopathic (i.e., lacking a clear etiology). The lattertwo are grouped under the term non- clonal MCAS. Data on the serumtryptase level during an acute episode of MCA are often lacking—ex- cept for severe anaphylactic event. Thus, many patients do not fulfillall MCAS criteria, and are referred as “MCA disorder not otherwisespecified (MCAD-NOS)”.15to as MCAD not otherwise specified (MCAD-NOS). The aim was to describe theclinical, laboratory characteristics and outcomes of the first pediatric-onset non-mastocytosis MCAD cohort.Methods: All children with the criteria of non-mastocytosis MCAD managed at theFrench National Referral Center for MCAD were included. Clinical, laboratory data,and outcomes were recorded.Results: Forty-four MCAD patients (mean age at onset: 4.3 years) were identified in- cluding 36 MCAD-NOS and 8 idiopathic MCAS. Hereditary-α-tryptasemia was identi- fied in 5/33 (15.2%) patients. The spectrum of symptoms concerned most frequentlyboth the skin (100% of children, with urticaria, angioedema, pruritus, and/or flushing)and the gastrointestinal tract (93% patients). We identified two clinical profiles, ac- cording to the age at onset. Before 3 years of age, MCAD was associated with per-sistent gastrointestinal symptoms triggered by various foods (leading to a drasticallylimited diet), and after 3 years of age with episodic, recurrent, idiopathic, anaphylacticreactions. The administration of H1 and/or H2 antihistamines drugs +/− a leukotrienereceptor antagonist resulted in a marked reduction in symptoms.Conclusion: The description of the clinical profiles of pediatric-onset non-mastocytosisMCAD may help to avoid diagnostic delay.K E Y W O R D Shereditary alpha tryptasemia, KIT mutation, mast cell, mast cell activation syndrome, tryptaseKey messageThe two most important features of MCAD non specifiedor idiopathic MCAS concern the skin and the gastroin- testinal tract. The clinical profile depended on the age atonset: onset before 3 years of age was characterized bychronic, persistent, food-triggered symptoms in the gas- trointestinal tract at least, whereas onset after 3 years ofage was characterized by recurrent, episodic, idiopathic,anaphylactic-like reactions. In both groups, the combina- tion of an antihistamine with a leukotriene receptor antag- onist was well tolerated, significantly reduced the patient'ssymptoms, and increased quality of life. This study will helpphysicians to better recognize this little-known entity andmay reduce diagnostic delay. The administration of mast-cell-stabilizing drugs constitutes a valuable, safe diagnostictest in children with manifestations of mast cell activation. ### Page 3 | 3 of 11WEISS et al.Pathophysiological mechanism of MCAD is still unknown. Lyonset al. identified an autosomal dominant genetic trait, hereditaryalpha tryptasemia (HαT), related to duplication/amplification of thealpha-1 allele of TPSAB1, which is associated with increased basal serum tryptase levels (>8 ng/mL).16–18 While this genetic trait ap- pears to be present in approximately 5%–6% of the general pop-ulation,19 it has been significantly more prevalent in patient withmastocytosis, idiopathic anaphylaxis, and grade IV venom anaphy- laxis.20 Furthermore, the association of HαT in patients with MMASwas associated with a more severe phenotype of hymenoptera-induced anaphylaxis.18,21,22 However, the prevalence of H αT andthe consequences on the phenotype in non-clonal MCAD are stillunknown. To date, no study has reported a cohort of non-mastocytosisMCAD in children nor the prevalence of HαT and its impact on theclinical presentation of pediatric MCAD patients. Thus, the objec- tives of our study on a cohort of patients with pediatric-onset non-mastocytosis MCAD were to (i) describe the clinical presentation ofthis population, (ii) characterize their clinical profiles, (iii) investigatethe prevalence of HαT in this specific population, and (iv) assessoutcomes.2 | M E TH O DS 2.1 | Study populationWe performed a retrospective study in the dermatology depart- ment at Necker Children's Hospital (Paris, France), which coordi- nates the pediatric branch of the French National Referral Centerfor Mast Cell Disorders (Centre de Référence Maladies Rares des Mastocytoses (CEREMAST)). The CEREMAST was established in2007 and comprises a nationwide network of 20 reference cent- ers in France dedicated to the clinical management of patients withmastocytosis and to advancing research in this field. All childrenaged from 0 to 15 years old consulting with typical signs of MCA be- tween January 1st, 2017, and July 31st, 2022, were considered foreligibility in the study. Patients were selected from the CEREMASTnational cohort involved in pathophysiological studies with infor- mation stored in electronic medical records. The study protocol wasapproved by the local investigational review board (CPPRB GroupeHospitalier de Paris Necker, Paris, France; reference 03-01-05,dated July 7th, 2003, amended in February 2021). Cases of idi- opathic MCAS were defined and classified according to the Viennaconsensus criteria. 5,11 However, in this particular pediatric context,most of the patients did not have a tryptase assay during an epi- sode and were considered as MCAD-NOS according to Valent et al.Idiopathic anaphylactic reactions were defined as acute, potentiallylife-threatening, systemic reactions involving at least two body sys- tems (from among the skin or mucous membranes, respiratory tract,and gastrointestinal tract) for which a triggering factor had not beenidentified.23,242.2 | Patient selection and data collectionThe diagnosis of idiopathic MCAS was retained when there were noarguments for primary and secondary MCAS. In order to rule outcutaneous mastocytosis, all patients underwent a rigorous derma- tological examination by one of the CEREMAST's dermatologists. Allpatients were examined by an allergist. When IgE-mediated allergywas suspected, a careful questioning, skin prick tests and specificIgE assays were performed. The diagnosis of IgE-mediated allergywas confirmed in case of the presence of an immediate reactionto a specific allergen with positive specific IgE and/or positive skinprick tests. All patients with suspected MCAD without mastocyto- sis received MC-stabilizing drugs targeting MC mediator produc-tion, secretion or receptor binding. In order to confirm the evolutionunder treatment, the parents or legal guardian(s) were asked to ratea visual analog scale (VAS) for an improvement in the patient's signsand symptoms after 3 months of treatment. The scale ranged from0 to 3, with 0 corresponding to no improvement, 1 to a slight im-provement, 2 to a moderate improvement, and 3 to a large improve-ment. All patients with slight to large improvement were consideredto have met the third Vienna criteria. Patients who met at least 2out of the 3 Vienna criteria were included in this descriptive study.The study variables were assessed at disease onset (during a con- sultation) and during a study visit, at least 3 months after treatmentinitiation, by the CEREMAST's dermatologists, using an electroniccase report form. All patients who had not been reassessed duringa study visit were excluded. For all identified patients, the data pre-sented in Table S1 were collected.2.3 | Screening for KIT mutationsFor the first 16 enrolled patients, a bone marrow aspirate was col-lected and tested for KIT mutations (using a highly sensitive tech- nique described previously25) after the patient's parents or legalguardian(s) had given their informed consent. Given the absence ofa KIT mutation in these first 16 patients, ethical considerations andthe lack of an elevated basal tryptase level prompted us to refrainfrom performing bone marrow aspiration in the remaining cases as recommended for pediatric patients with mast cell disorders.2.4 | Screening for hereditary α-tryptasemia (HαT)HαT screening was performed only when the child was alreadyundergoing a clinically indicated blood draw during the hospital visit; no additional venipuncture was performed solely for this genetictest. Genomic DNA was extracted from peripheral blood using theQIAamp DNA Mini Kit (Qiagen, Hilden, Germany). TPSAB1 CNVwas assessed by droplet digital PCR (ddPCR) with probes targetingspecifically α- and β-tryptase sequences as described by Lyons et al.26In brief, genomic DNA was quantified with the Nanodrop 2000 ### Page 4 4 of 11 |WEISS et al.TA B L E 1 Main characteristics of the study population and the different subgroups, according to the age at onset.Characteristic Total = 44 (%) Age at onset <3 years (N = 23)Age at onset >or = 3 years (N = 21) q Value aSex ratio (female/male) 25/19 (1.3) 10/13 (0.77) 15/6 (2.6) .20Age (years) at onset, mean (range) 4.3 (0–14) — — — Age (years) at diagnosis, mean (range) 7.3 (1–16) — — — Congenital MCAS 13 (29.5) — — — Personal historyAtopy b 18 (40.9) 9 (39.1) 9 (42.9) .94 CMPAc 3 (10.7) 1 (7.1) 2 (14.3) .79Familial history Clinical manifestations of MCAsymptoms11 (25) 7 (30.4) 4 (19) .60Mastocytosis 0 (0) 0 (0) 0 (0) 1Urticaria 12 (27.3) 6 (26.1) 6 (28.6) .95 Inflammatory bowel disease 5 (11.4) 3 (13) 2 (9.5) 1 Inflammatory rheumatism 4 (9.1) 1 (4.3) 3 (14.3) .56 Atopy 22 (50) 12 (53.2) 10 (47.6) .92 Anaphylactic reaction (includedQuincke's edema) 11 (25) 6 (26.1) 5 (23.8) .95 Chronology of symptoms Chronic persistent 33 (75) 22 (95.7) 11 (52.4) <.01Episodic recurrent 11 (25) 1 (4.3) 10 (47.6) <.01 Cutaneous signsPruritus 17 (38.6) 8 (34.8) 9 (42.9) .79Flushing 25 (56.8) 14 (60.9) 11 (52.4) .79Urticaria (wheals)d 30 (68.2) 15 (65.2) 15 (71.4) .84Angioedema 21 (47.7) 8 (34.8) 13 (61.9) .22 Gastrointestinal signs Abdominal pain and cramps 38 (86.3) 21 (91.3) 17 (81) .60 Diarrhea 29 (65.9) 23 (100) 6 (28.6) <.01Nausea/vomiting 18 (40.9) 11 (47.8) 7 (33.3) .56Gastroesophageal reflux 11 (25) 9 (39.1) 2 (9.5) .09 Reaction to at least one food 26 (59.1) 20 (87%) 6 (28.6) <.01 Reactions to >5 foods 22 (50) 17 (73.9) 5 (23.8) <.01ENT signs Quincke's edema 8 (18.2) 1 (4.3) 7 (33.3) .08Laryngeal blockage 2 (4.5) 0 (0) 2 (9.5) .44 Nasal congestion/pruritus 23 (52.3) 16 (69.6) 7 (33.3) .08Neuropsychological signs Headache 10 (22.7) 3 (13.6) 7 (33.3) .33Sleep disorders 21 (47.7) 16 (69.6) 5 (23.8) .01 Agitation 9 (20.5) 5 (21.7) 4 (19) 1Anxiety/mood sadness 6 (13.6) 1 (4.3) 5 (23.8) .25 Cardiorespiratory signsFainting or loss of consciousness 17 (38.6) 7 (30.4) 10 (47.6) .46 Palpitations 7 (15.9) 1 (5.3) 6 (28.6) .15 Cough 5 (11.4) 3 (13) 2 (9.5) 1 ### Page 5 | 5 of 11WEISS et al.instrument (Thermo Fisher Scientific, USA) and adjusted to 20 ng/μL per sample. After DNA digestion with high-fidelity restrictionenzyme BamHI (New England BioLabs, Ipswich, MA), ddPCRreaction mix (Bio-Rad Laboratories, Munich, Germany) was preparedusing published primers and probes for α- and β-tryptase genes andprimers and probes for AP3B1 as a reference gene. Droplets weregenerated with the QX200 AutoDG Droplet Generator, and PCR wasperformed on T100 Thermal Cycler (Bio-Rad Laboratories, Munich,Germany). Quantification of the allelic α- and β-tryptase copies wasperformed on the QX-200 Droplet Reader and calculated usingQuantaSoft Software (Bio-Rad Laboratories, Munich, Germany) asdescribed. 26 Increased α-tryptase encoding TPSAB1 copy numberconsistent with HαT was defined as ≥3 α-tryptase copies or 2 α-tryptase copies in the presence of 3 β-tryptase copies.2.5 | Statistical analysesDescriptive statistical analyses were performed using the chi-squaretest or Fisher's exact test for categorical variables, as appropriate.Continuous variables were compared using the Mann–Whitney Utest. Changes in paired binary outcomes before and after treatmentCharacteristic Total = 44 (%) Age at onset <3 years (N = 23)Age at onset >or = 3 years (N = 21) q Value aBronchoconstriction 9 (20.5) 3 (13) 6 (28.6) .50 General symptoms Anaphylactic reactions 17 (38.6) 3 (13) 14 (66.7) <.01 Recurrent fever e 11 (25) 2 (11.8) 9 (39.1) .05 Drained feeling 14 (31.8) 5 (21.7) 9 (42.9) .31 Bone and joint pain 13 (29.5) 6 (26.1) 7 (33.3) .79Fatigue 14 (31.8) 5 (21.7) 9 (42.9) .31 Concentration disorders 10 (22.7) 3 (13) 7 (33.3) .33School absenteeismf 20 (50) 13 (61.9) 7 (33.3) .31Break in the growth curveg 8 (18.2) 5 (21.7) 3 (14.3) .87Laboratory findingsBasal serum tryptase level (median(range)) 3.5 (1.2–14.5) 4.0 (1.6–13.5) 3.3 (1.2–14.5) .21TPSAB1 germline copy number variants gain (n = 33) 5 (15.2) 2 (10) (n = 20) 3 (23) (n = 13) .58Treatment received H1 antihistamines 42 (95.5) — — — H2 antihistamines 32 (72.7) — — — Leukotriene receptor antagonists 29 (65.9) — — — Combinations of H1 antihistaminesand H2 antihistamines 32 (72.7) — — — Combinations of H1 antihistamines,H2 antihistamines, andanti-leukotrienes 26 (59.1) — — — Abbreviations: CMPA, cow's milk protein allergy; ENT, ear, nose, and throat; MCAS, mast cell activation syndrome.aTo account for multiple testing, p values were adjusted using the Benjamini–Hochberg procedure to control the false discovery rate.bNone of the 18 patients with a medical history of atopy (either mild atopic dermatitis, intermittent asthma, or mild allergic rhinoconjunctivitis) werereceiving systemic treatments for atopy. Flare-ups of atopy were not obviously linked to flare-ups of MCA.cFor these three patients the MCA symptoms did not improve after the children moved to a dairy-free diet. None of the other patients displayedallergic manifestations; food-allergen-specific IgE assays and skin prick tests to food allergens were negative in all cases (data not shown).dUrticaria (wheals) correspond to recurrent acute urticaria (intermittent, short-lived flares—wheals—occurring a few times per year). No cases metcriteria for chronic urticaria (symptoms on most days for >6 weeks) per current guidelines.eRecurrent fever was reported by patients or families as low-grade fever episodes (38°C–38.5°C), occurring without signs of infection and frequentlyassociated with other mast cell activation symptoms such as urticaria flares, fatigue, diarrhea, or abdominal pain, often described by families astypical MCAD flares.fSchool absenteeism was common: 20 of the 40 children of school age (50%) had taken at least 1 day off from school per month as a result of MCAmanifestations. Three of these children (15%) missed school once a week, on average, and 9 (45%) missed school several times a week.gEight patients (18.2%) presented with a break in the growth curve, although the clinical examination and the usual biological exploration werenormal in all cases.TA B L E 1 (Continued) ### Page 6 6 of 11 |WEISS et al.were evaluated with McNemar's test. To account for multiple test-ing, p values were adjusted using the Benjamini–Hochberg proce- dure to control the false discovery rate (FDR). A two-sided p value or q value <.05 were considered statistically significant. Statisticalanalyses were performed in R (version 4.4.1, R Foundation forStatistical Computing, Vienna, Austria). Symptom prevalence inchildren younger than 3 years and those aged 3 years or older wasvisualized using a radar chart generated in R (version 4.4.1, packagestidyverse and fmsb).3 | R E S U LT SBetween January 1st, 2017, and July 31st, 2022, a total of 76 patientswere referred to the CEREMAST with suspected non-mastocytosisMCAD. Thirty-two patients were excluded because of an incorrectdiagnosis (n = 7) and/or because they did not come at the study visit(due to loss to follow-up, refusal to participate or refusal to take thetreatment (n = 14)) and/or because they didn't fulfill at least two ofthe three Vienna criteria, making the diagnosis of MCAD less likely(n = 11). Overall, 44 of the remaining patients had non-mastocytosisMCAD and so were selected for the study: 8 MCAS (including 6 withanaphylactic episodes) for which the three criteria were fulfilled and36 MCAD-NOS (who did not meet the tryptase criterion but met thetreatment response criterion) (Figure S1). As required by the inclu-sion criteria, none of these included patients presented with cutane- ous lesions of mastocytosis. The bone marrow aspirate (performedin 16 patients, 36.4%) did not reveal any signs of mastocytosis: atypi- cal MCs, as well as CD2+ and/or CD25+ MCs, were not detected byflow cytometry (FcER1 and CD117). No KIT mutations (in exons 8 to13 or exon 17) were found in these patients.3.1 | Characteristics of the study populationThe main characteristics of the study population (n = 44) are sum-marized in Table 1. The mean (range) age at onset of symptoms was4.3 years (0–14), and 13 patients had clinical manifestations of MCAsince the first month of life (congenital MCAD, 29.5%). The mean(range) age at diagnosis was 7.3 years.1–16 The female to male ratiowas 1.3. There was a family history of clinical manifestations of MCAin 11 patients (25%). When considering the medical history of first-and second- degree family members, we noted anaphylactic reac- tions (including Quincke's edema) for 11 (25%). The distribution ofMCA manifestations was as follows: chronic (daily or persistent, e.g.,occurring at least twice per week, for example digestive symptoms orchronic rhinitis) in 33 patients (75%), and episodic, recurrent symp- toms involving at least two organs, interspersed with symptom-freeperiods, in 11 patients (25%). All of these 11 patients presented withepisodic recurrent idiopathic anaphylactic reactions. In the cohort as a whole, the spectrum of symptoms concernsmost frequently the skin (in 100% of patients). Patients presentedwith recurrent acute urticaria (intermittent, short-lived flares— wheals—occurring a few times per year) (n = 30, 68.2%), flushing(n = 25, 56.8%), angioedema (n = 21, 47.7%), pruritus (apart fromatopy, n = 17, 38.6%), and/or unspecific rashes (n = 3, 6.8%) (Table 1 and Figure 1). Regarding urticaria, symptomatic dermographismwas observed in two patients, whereas no cases of cold urticariaor other inducible forms of urticaria were identified. Symptoms as-sociated with the gastrointestinal tract were the second most fre- quently observed (93%). Patients presented with abdominal painor cramps (n = 38, 86.3%), chronic diarrhea (n = 29, 65.9%), nauseaor vomiting (n = 18, 40.9%), and/or gastroesophageal reflux (n = 11,25.0%) (Table 1). An endoscopy of the upper gastrointestinal tractwas performed in 12 children (27.3%), six presented a secondary (i.e.,without germline genetic anomalies) sucrase-isomaltase deficiency(SID, diagnosed by enzymatic assay) and six did not present any sig- nificant anomalies. For the six patients with SID, the gastrointestinalsymptoms and skin symptoms were triggered by a broad spectrumof foods (for example histamine-rich or histamine-releasing foods)and not just by sucrose and starch (data not shown). The other mainsymptoms included sleep disorders, defined by more than 3 awak- enings/night before 3 years old or 1 after 3 years old (often wakingup every 30 min at night for the infants), asthenia, headache, andconcentration disorders (Table 1). School absenteeism, definedby at least 1 day off from school per month as a result of MCAF I G U R E 1 Examples of skin manifestations in patients from our pediatric MCAD cohort. (A) Angioedema of the eyelid; (B) Angioedema ofthe lips; (C, D) Redness and angioedema of the ears; (E) Urticaria; (F) Flush; (G) Angioedema of the right side of the face.G(A) (B) (C) (D) (E) (F) (G) ### Page 7 | 7 of 11WEISS et al.Symptom/item Before treatmentN (%)After treatmentN (%) q Value aGeneralPersistent fatigue 27 (71.1) 17 (44.7) <.01 Recurrent fever 11 (28.9) 2 (5.3) .01 Drained feeling 27 (71.1) 19 (50) .08 CutaneousPruritus 26 (68.4) 10 (26.3) <.01Flushes 31 (81.6) 17 (44.7) <.01Urticaria 32 (84.2) 14 (36.8) <.01 Angioedema 20 (52.6) 5 (13.2) <.01 Another unusual rash 24 (63.2) 9 (23.7) <.01 Gastrointestinal Abdominal pain 33 (86.8) 19 (50) <.01 Diarrhea 31 (81.6) 10 (26.3) <.01Nausea and/or vomiting 21 (55.3) 6 (15.8) <.01Gastroesophageal reflux 28 (73.7) 11 (28.9) <.01Pollakiuria 15 (39.5) 5 (13.2) <.01Food avoidancec 30 (78.9) 25 (65.8) .08ENT Quincke's edema 8 (21.1) 3 (7.9) .14 Laryngeal blockage 14 (36.8) 2 (5.3) <.01 Chronic rhinitis/nasal pruritus 23 (60.5) 6 (15.8) <.01 Cardiorespiratory signsPalpitations 18 (47.4) 7 (18.4) <.01Unexplained cough 20 (52.6) 7 (18.4) <.01 Dyspnea 17 (44.7) 17 (44.7) 1Severe anaphylactic reaction 15 (39.5) 2 (5.3) <.01 Bone and joints Bone, joint, or muscle pain 31 (81.6) 12 (31.6) <.01Neuropsychological and social Headache 18 (47.4) 8 (21.1) <.01Night-time awakening 31 (81.6) 0 (0) <.01 Difficulty falling asleep 28 (73.7) 15 (39.5) <.01Irritability/anxiety/mooddisorders33 (86.8) 25 (65.8) .03 Concentration disorders 17 (44.7) 14 (36.8) .71School absenteeism 18 (47.4) 10 (26.3) .01Factors triggering the symptoms Food reactionc 30 (78.9) 26 (68.4) .14 Temperature change 26 (68.4) 21 (55.3) .20Medication 20 (52.6) 12 (31.6) .05 Other triggering factors 22 (57.9) 19 (50) .49aTo account for multiple testing, p values were adjusted using the Benjamini–Hochberg procedureto control the false discovery rate. bSix of the 44 patients were not included in this analysis because they had recurrent episodes ofMCA but were not receiving long-term treatment.cFood reactions and food avoidance were slightly less frequent after treatment (mean reductionsof 13.3% and 30.3%, respectively) but the manifestations were less severe than before treatment.This was evidenced by the reductions in gastrointestinal signs and symptoms, which were the mainfood-induced symptoms.TA B L E 2 Clinical symptoms before andafter treatment (n = 38 patientsb). ### Page 8 8 of 11 |WEISS et al.manifestations, was common (50%, Table 1). Overall, 17 of 44 pa- tients (38.6%) experienced idiopathic anaphylaxis, and 15 of thesepatients were treated with epinephrine.The most frequent trigger was food (59.1%) and more than fivefoods were implicated in 50% of the patients—leading to a drasticallylimited diet (Table 1). The foods varied widely among patients anddid not systematically involve histamine-rich foods. No immediatesystemic reactions were reported after food ingestion. Symptomsappeared from 6 to 48 h after the ingestion of the suspected incrim- inated food (by parents and doctors). Symptoms improve markedlybut do not completely disappear with the exclusion diet. Seventeenpatients (38.6%) experienced anaphylactic reactions; in all cases,review of the medical history—non-immediate onset, absence of aplausible food trigger (no ingestion within the preceding 2 h)—andnegative allergy testing (skin prick testing and serum specific IgE)did not support an IgE-mediated mechanism; these episodes weretherefore classified as idiopathic anaphylaxis. After the first consultation at the CEREMAST reference center,the prescribed treatments included second-generation H1 antihis- tamines in 95.5% of cases, H2 antihistamines in 72.7%, and leukot- riene receptor antagonists in 65.9%. The mean (range) baseline serum tryptase level was 4.4 ng/ mL (1.2; 14.5) overall. Data on the serum tryptase level duringan acute episode of MCA were available for 8 patients (18.2%),all diagnosed with idiopathic MCAS; the mean (range) value was21.6 ng/mL (17.9; 25.2), which corresponds to a mean increase of412%.3.2 | Genetic analysisTPSAB1 germline copy number variants were assessed in 33 pa- tients for whom DNA samples were available. HαT was identifiedin 5/33 patients (15.2%). Among the 11 patients not tested, one hada baseline serum tryptase >8 ng/mL, raising suspicion for HαT; themean (range) baseline tryptase in this untested subgroup was 4.8 ng/ mL (1.1–23.8). Among tested patients, the mean (range) baselineserum tryptase level was 9.7 ng/mL (3; 14.5) in patients with HαTand 3.7 ng/mL (1.2; 6.5) in patients without HαT (p < .01). No othersignificant differences were observed between the two groups, par- ticularly in terms of family history of MCA or other clinical charac- teristics (data not shown).3.3 | Patient profiles as a function of age at onsetBased on clinical rationale, we prespecified two age-at-onset groups(<3 vs. ≥3 years). The cohort split accordingly: 23 patients (52.3%)had onset before age 3, and 21 (47.7%) at age 3 or later (Figure S2).The main differences between the two groups of patients aresummarized in Table 1. We found that chronic persistent symptomswere more prevalent in the earlier- onset group (n = 22/23, 95.7%)than in the later-onset group (n = 11/21, 52.4%, q < .01). Theearlier-onset group of patients was homogeneous, with a highproportion of individuals with gastrointestinal symptoms such as chronic diarrhea (n = 23, 100% vs. n = 6, 28.6% in the later-onsetgroup; q < .01) and sleep disorders (n = 16, 69.6% vs. n = 5, 23.8%,q = .01) triggered by foods in 87.0% of cases (vs. 28.6% in the later-onset group, q < .01), and more than five foods were frequentlyincriminated (n = 17, 73.9% vs. n = 5, 23.8% in the later-onsetgroup; q < .01). None of these patients fulfilled the criteria of foodprotein-induced enterocolitis syndrome. In the later-onset group,the symptoms were episodic recurrent in 10 patients (47.6%).The episodic or acute symptoms consisted of abdominal cramps(n = 17, 81%), urticaria (wheals) (n = 15, 71.4%), angioedema (n = 13,61.9%), Quincke's edema (n = 7, 33.3% in the later-onset group vs.n = 1, 4.3% in the earlier-onset group; q = .08) and correspondedto idiopathic anaphylactic reactions in 14 patients (66.7% vs.3 patients (13.0%) in the earlier-onset group, q < .01). Six of theeight patients with idiopathic MCAS belonged to the older-onsetgroup and experienced anaphylactic reactions. No anaphylacticreactions were observed in the two confirmed idiopathic MCAScases from the early- onset group.3.4 | Response to treatmentSix of the 44 patients were not included in this analysis because theyhad recurrent episodes of MCA but were not receiving long-termtreatment. The mean (IQR) improvement in the visual analog scalescore (ranging from 0 (no improvement) to 3 (large improvement))upon treatment was 2.1 (1.4–2.8). The score was 1 for 7 patients(18%), 2 for 20 patients (53%) and 3 for 11 patients (29%). The MCAsigns that responded best to treatment were all gastrointestinal signs (Table 2). Night-time awakenings were dramatically reducedwith treatment (100%). The frequency of anaphylactic-like episodeswas also significantly lower after treatment. Table 2 summarized all the symptoms.4 | D I S CUS S I O NHere, we report the first series describing the clinical andlaboratory features of a cohort of children (n = 44) diagnosedwith pediatric-onset non-mastocytosis MCAD. Our demographicanalysis revealed a female predominance (female/male ratio:1.3), an early disease onset (mean age at onset: 4.3 years), anda relatively high frequency of congenital forms (29.5%). Theprevalence of HαT was 15.2% which is significantly higher than inthe general population published by Robey et al. (p = .04).19 Apartfrom a significant elevation of basal tryptase in the HαT group, thesmall size of our study did not allow us to identify other significantdifferences between the two groups. In this context, testing forHαT may be considered in patients with elevated baseline tryptaselevels rather than performed systematically in all patients withsuspected MCAD. ### Page 9 | 9 of 11WEISS et al.The mean diagnostic delay was 3 years: this is particularly longin a young child and highlights the diagnostic difficulties and lack ofawareness of MCAD among physicians. The symptoms associatedto skin and gastrointestinal tract were the two most frequently ob- served in over 90% of patients, which is consistent with the litera- ture data on adult-onset MCAD.5,27 Figure S3 summarizes the signsand symptoms of pediatric-onset MCAD. We identified two clinical profiles for pediatric-onset MCAD,depending on whether the disease had started before or after theage of 3 years (Figure S2). The younger group was homogeneous andwas characterized by chronic, persistent symptoms that affectedthe gastrointestinal tract (diarrhea, gastroesophageal reflux, andabdominal cramps) and were triggered by foods (albeit not throughan IgE-mediated allergic mechanism). More than five foods were in- volved in 73.9% of cases; this had resulted in a drastically limited dietand a break in the growth curve in 21.7% of the patients. In the oldergroup, the symptoms were episodic and recurrent in almost half thecases, and chronic persistent in 52.4% of the cases. All these epi-sodes corresponded to idiopathic, anaphylactic reactions, includingn = 6 patients with a final diagnosis of idiopathic MCAS. Therefore,as in adults, idiopathic MCAS should be considered as a cause ofrecurrent, idiopathic anaphylaxis.28 The small number of includedpatients prevented us from performing cluster analysis.The absence of signs of clonality in the bone marrow aspiratesof the first 16 pediatric patients in our cohort led us to discontinuethis invasive procedure in children. We acknowledge that KIT clonal- ity in the 28 unassessed patients cannot be entirely excluded; how- ever, the risk–benefit ratio did not justify further invasive testing,and any positive result would have altered classification rather thansymptom-directed management. These findings, together with datafrom the literature, suggest that isolated clonal bone marrow MCsare likely exceptional in childhood, in contrast to adults.29Non-mastocytosis MCAD may be mistaken for an IgE-mediatedallergy and especially a food allergy. The large number of incrimi-nated foods, the absence of any immediate reactions, and the neg- ative specific IgE assay and skin prick tests make the diagnosis ofan IgE-mediated allergy unlikely. These manifestations constitute amajor problem, especially when they occur at the age of food diver- sification. Treatment with antihistamines and an MC degranulationblocker limited the severity of food reactions and enabled diversi- fication of the concerned children's diets (Table 2). In addition, pa-tient and family education is essential to ensure trigger avoidance, adherence to treatment, and appropriate management of acute re-actions, including the use of epinephrine in patients with a historyof anaphylaxis. Furthermore, we struggled to obtain data on the serum tryptaselevel during acute MCA episodes in most of our patients; this wasfrequently due to practical problems, such as the difficulty of ob- taining a blood sample during the children's short episodes of MCAand within the following 1–4 h. Consequently, the Vienna Consensustryptase criteria were not met in most patients, who were thereforeclassified as MCAD-NOS; however, idiopathic MCAS cannot be ex-cluded in some cases, introducing verification bias and diagnosticmisclassification. Given that our cohort includes well-defined phe- notypes (e.g., idiopathic MCAS) alongside a less-defined category(MCAD-NOS), is retrospective with inherent limitations (includingF I G U R E 2 Algorithm for the diagnosis of pediatric- onset MCAD. *Non-mastocytosis monoclonal MCAS (i.e., patients presenting with aKIT D816V mutation but only two minor systemic mastocytosis criteria) or SM without cutaneous involvement is extremely rare in children,and further details are therefore not provided here. **MCAS criteria: (i) documented systemic symptoms of MCA, (ii) a 20% increase inserum tryptase level from the individual's baseline plus 2 ng/mL and (iii) a symptom response to MC-stabilizing drugs. ***For these cases,the provisional diagnosis “probable MCAS” may be appropriate. This diagnosis may then change in follow-up. For example, if a patient withclinical symptoms of MCAS and a diagnostic increase in tryptase did not respond to first-line therapy such as antihistamines but did respondto second-line therapy such as an anti-IgE antibody, the initial diagnosis would be “probable MCAS” and would change to MCAS when aresponse to second-line therapy has been documented. DCM, diffuse cutaneous mastocytosis; MC, mast cell; MCA, mast cell activation;MCAD, mast cell activation disorder; MCAD-NOS, MCA disorder not otherwise specified; MCAS, mast cell activation syndrome; MPCM,maculo-papular mastocytosis; WHO, World Health Organization.Primary MCAS/Mastocytosis* (according to WHO criteria)Presence of skin lesions of mastocytosis in almost all cases:Mastocytoma MPCM DCM Secondary MCAS Mast cell activation of inflammatory origin:- IgE-mediated allergy - Autoimmune diseases - Acute or chronic infections - Inflammatory disordersIdiopathic MCAS Lacking of a clear etiology MCA disorder not otherwise specified (MCAD-NOS)1/ The patient presented with classical symptoms of MCA in 2 or more organs but did not meet either of the two additional criteria (biological confirmation or response to treatment) = Probable MCAS*** 2/ Patients with clinical/laboratory signs of MCA in one or more organs but without firm evidence of mast-cell involvement typically have chronic, milder, recurrent, mono-organ symptoms with variable response to anti- MC/mediator therapy, and because MCAS criteria are not met, this label should not be used as the primary or final diagnosis for multisystem complaints.Pediatric MCADThe 3 MCAS criteria are fulfilled** Only one or two MCAS criteria are fulfilled ### Page 10 10 of 11 |WEISS et al.data completeness and selection bias), and that some subgroup anal-yses were conducted with very small sample sizes, a larger, dedi- cated prospective study in non-mastocytosis MCAD phenotypesis warranted to better characterize clinical phenotypes and deriverobust biological, molecular, and metabolic biomarkers. These signa- tures should be trained and analytically validated in the well-definedgroups and then prospectively applied to MCAD-NOS to testwhether they reduce diagnostic uncertainty and enable data-drivenreclassification. Such biomarkers could enable earlier identification(thereby reducing diagnostic delay) and help prevent the overdiag- nosis of MCAD. The absence of standardized treatment in children promptedus to suggest a combination of mediator blocking drugs (second-generation H1 and H2 antihistamines and leukotriene receptorantagonists) modeled on MCAS management in adults. 5,13,14 Thecombination of antihistamines and a leukotriene receptor antagonistwas effective on MCA symptoms in our population. It is important tonote that after an average of 3 years of serial misdiagnosis, this wasthe first time that our patients had received a treatment that reducedtheir symptoms and improved their quality of life. One limitation ofour study was the wide range of heterogeneous symptoms that arenot specific to pediatric-onset MCAD. Therefore, we have devel-oped algorithms designed to assist clinicians in optimizing the diag- nosis and management of pediatric-onset MCAD, including guidanceon the different drugs to use and their dosages (Figures 2 and 3). Itis important to always consider a differential diagnosis, namely con- ditions not involving MCs like endocrine disorders (hypothyroidism,hypoglycemia, etc.), gastrointestinal disorders (chronic inflammatorybowel disease, celiac disease, etc.), and cutaneous disorders (e.g., he- reditary or acquired angioedema).5 | CO N C LUS I O NPediatric-onset non-mastocytosis MCAD has a broad clinical spec- trum. The diagnosis is based on the combination of symptoms af- fecting at least two organs, the symptoms' time scale, durationand/or recurrence, the elimination of differential diagnoses andthe often-dramatic response to antihistamines. Greater awarenessof pediatric-onset MCAD should lead to a reduction in diagnos- tic wandering and an improvement in the quality of life of thesechildren.AC K N OW L E D G M E N T SThe authors acknowledge the contributions and participation of thepatients and their families, the pediatric mastocytosis study group,and the French Association for Research Initiatives on Mast Cellsand Mastocytoses (AFIRMM). Dr. Laura Polivka and Dr. OrianneDebeaupuis were funded by the Bettencourt Schueller Foundation.Open access publication funding provided by COUPERIN CY26.F I G U R E 3 Clinical algorithm for evaluating suspected pediatric- onset MCAD *If the baseline serum tryptase level is >8 μg/L, a hereditaryalpha tryptasemia is highly probable. **In case of multiple medication reactions, treatments should be given as a medical preparation withoutexcipient (or cellulose alone). ***MCAS criteria: (i) documented systemic symptoms of MCA, (ii) a 20% increase in serum tryptase levelfrom the individual's baseline plus 2 ng/mL and (iii) a symptom response to MC-stabilizing drugs. ENT, ear, nose, and throat; MCA, mast cellactivation; MCAD, mast cell activation disorder; MCAS, mast cell activation syndrome.When can pediatric-onset MCAD be suspected?- Recurrent episodic idiopathic anaphylactic reactions - Chronic persistent symptoms of MCA, involving at least two organs - Multiple food reactions with digestive and skin manifestations in infants without identified allergens, leading to a drastically restricted dietWhat should the physician do when faced with a suspected case of pediatric-onset MCAD ?- Clinical examination : a meticulous examination of the skin (to rule out mastocytosis) and detailed questioning about any signs or symptoms of secondary MCAS (allergy or other inflammatory processes)- Blood tests, comprising :- the serum tryptase level at baseline and during an attack*- specific assays as a function of the clinical findings (poor growth: renal, liver and thyroid function tests, a check for celiac disease, IGF1; specific IgE assay; CRP and fecal calprotectin level). Any abnormal findings: refer the patient to a specialistWhich first-line treatment should be prescribed? H1 antihistamines (e.g., desloratadine 1.25–2.5 mg/day or cetirizine 2.5–5 mg/day in children <6 years)** plus (if required) H2 antihistamines (digestive symptoms: cimetidine, 10 to 20 mg/kg/day) plus (if required) a leukotriene receptor antagonist (ENT symptoms, flushes): montelukast 4 mg (2-4 years of age), 5 mg (5-14 years of age) or 10 mg (15 and over]Highly probable MCAS : 2 out of 3 criteria are met (1 and 2, or 1 and 3), with no other obvious diagnoses:- Progressively increase H1 antihistamines dose and/or add a mast cell stabilizer (e.g., oral cromolyn sodium 100 mg 3–4 times daily before meals).- AND/OR assay the tryptase level during an episode of MCAConfirmed MCAS(All three criteria are met) Continue the treatment and monitor the outcomes at 3 months. Intensify the treatment if the response is only partial.Only one criterion*** is met :- Recheck differential diagnoses- If the clinical presumption is strong, possibility of trying to change anti- histamine treatment, subject to minor toxicity ### Page 11 | 11 of 11WEISS et al.F U N D I N G I N FO R M AT I O NThis research did not receive any specific funding from agencies ororganizations in the public, commercial, or not-for-profit sectors. L.P.and O.D. were funded by the Bettencourt Schueller Foundation.CO N FL I C T O F I N T E R E S T S TAT E M E N TThe authors declare no conflicts of interest for this study.P E E R R E V I E WThe peer review history for this article is available at https://www.webof scien ce. com/api/gatew ay/ wos/ peer- review/10. 1111/ pai.70373.O R C I DC. Livideanu https://orcid.org/0000-0002-5275-6868C. Greco https://orcid.org/0000-0003-4259-6861R E F E R E N C E S1. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and re-lated disorders. 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EClinicalMedicine. 2025;80:103043.S U P P O R T I N G I N FO R M AT I O NAdditional supporting information can be found online in theSupporting Information section at the end of this article.How to cite this article: Weiss M, Rossignol J, Campeotto F,et al. Characteristics and outcomes of patients withpediatric-onset non- mastocytosis mast cell activationdisorders: A CEREMAST study. Pediatr Allergy Immunol. 2026;37:e70373. doi:10.1111/pai.70373