Аутоімунний полігландулярний синдром І типу як первинний імунодефіцит: спектр клінічних проявів

Healthcare of Republic of Belarus, Minsk, Republic of BelarusAutoimmune polyglandular syndrome type I (APS-1) is a rare autosomal recessive disorder caused by mutation in the autoimmune regulation gene (AIRE), resulting in autoimmune attacks to the various target organs. The article presents the current understanding of the etiology and pathogenesis of APS-1, as well as the spectrum of clinical manifestations of the syndrome based on literature overview and our own clinical observations. The described clinical cases illustrate the phenotypic variability of the disease, including the possible failure of the typical manifestations. Molecular genetic methods allow to extend the diagnostic criteria and make the early diagnosis possible, especially in atypical cases.Аутоиммунный полигландулярный синдром I типа (АПС-1) — это редкое аутосомно-рецессивное заболевание, обусловленное мутацией гена аутоиммунной регуляции (AIRE), следствием чего являются аутоиммунные атаки с разрушением различных органов-мишеней. В статье приведены современные представления об этиологии и патогенезе АПС-1, а также спектр клинических проявлений синдрома на основе данных литературы и собственных наблюдений. Описанные клинические случаи иллюстрируют фенотипическую вариабельность заболевания, в том числе с возможным отсутствием типичных проявлений синдрома. Молекулярно-генетические методы позволяют расширить диагностические критерии и осуществлять раннюю диагностику этой патологии, особенно в атипичных случаях.Аутоімунний полігландулярний синдром І типу (АПС-1) — це рідкісне аутосомно-рецесивне захворювання, пов'язане з мутацією гена аутоімунної регуляції (AIRE), наслідком чого є аутоімунні атаки з руйнуванням різних органів-мішеней. У статті наведені сучасні уявлення про етіологію і патогенез АПС-1, а також спектр клінічних проявів синдрому на основі даних літератури і власних спостережень. Описані клінічні випадки ілюструють фенотипову варіабельність захворювання, у тому числі з можливою відсутністю типових проявів синдрому. Молекулярно-генетичні методи дозволяють розширити діагностичні критерії і здійснювати ранню діагностику цієї патології, особливо в атипових випадках

Хвороба кавасакі у дітей м. Києва. Аналіз 23 випадків

The broadest observation of Kawasaki disease (KD) in children in Ukraine is presented that included 23 clinical cases in Kyiv. The frequency of complete KD was 56% and incomplete one was 44%. The coronary vessel affection rate was 33% and the highest one was revealed in infants — 83%. The symptoms and laboratory manifestations of KD are analyzed. The characteristics of the incomplete KD diagnosis are presented. The prevalence of KD in Kyiv in 2016 is calculated to be 4.6 per 100,000 children under 5 years of age and the expected prevalence of KD in Ukraine in 2016 — 103 cases.Представлено наибольшее в Украине наблюдение болезни Кавасаки (БК) у детей — 23 клинических случая в г. Киеве. Частота полной БК составила 56%, неполной — 44%. Частота поражений коронарных сосудов составила 33% и была наивысшей у детей первого года жизни — 83%. Проанализированы симптомы, лабораторные проявления БК. Описаны особенности постановки диагноза неполной БК. Рассчитана распространенность БК в г. Киеве в 2016 году — 4,6 на 100 000 детей до 5 лет жизни и ожидаемая распространенность БК для Украины в 2016 году — 103 случая.Наведено найширше в Україні спостереження хвороби Кавасакі (ХК) у дітей — 23 клінічні випадки у м. Києві. Частота повної ХК була 56%, неповної — 44%. Частота уражень коронарних судин становила 33% і була найвищою у дітей першого року життя — 83%. Проаналізовано симптоми, лабораторні прояви ХК. Показано особливості постановки діагнозу неповної ХК. Розраховано поширеність ХК у м. Києві у 2016 р. — 4,6 на 100 000 дітей до 5 років життя та очікувану поширеність ХК для України у 2016 р. — 103 випадки

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts

Activated Phosphoinositide 3-Kinase δ Syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background Activated phosphoinositide-3-kinase (PI3K) δ Syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives Report the extended spectrum of disease manifestations in APDS1 versus APDS2, compare these to CTLA-4 deficiency, NFκB1 deficiency, and STAT3 gain-of-function (GOF) disease; identify predictors of severity in APDS. Methods Data collection with the European Society for Immunodeficiencies (ESID)-APDS registry. Comparison with published cohorts of the other IEIs. Results The analysis of 170 APDS patients outlines high penetrance and early-onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA-4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusion APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEI is substantial. Some specific features distinguish APDS1 from APDS2. Early-onset is a risk factor for severe disease course calling for specific treatment studies in younger patients

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

none313siBackground: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.noneThalhammer J.; Kindle G.; Nieters A.; Rusch S.; Seppanen M.R.J.; Fischer A.; Grimbacher B.; Edgar D.; Buckland M.; Mahlaoui N.; Ehl S.; Boztug K.; Brunner J.; Demel U.F.; Forster-Waldl E.; Gasteiger L.M.; Goschl L.; Kojic M.; Schroll A.; Seidel M.G.; Wintergerst U.; Wisgrill L.; Sharapova S.O.; Goffard J.-C.; Kerre T.; Meyts I.; Roosens F.; Smet J.; Haerynck F.; Eric Z.P.; Milenova V.; Gagro A.; Richter D.; Chovancova Z.; Hlavackova E.; Litzman J.; Milota T.; Sediva A.; Elaziz D.A.; Alkady R.S.; El Sayed El Hawary R.; Eldash A.S.; Galal N.; Lotfy S.; Meshaal S.S.; Reda S.M.; Sobh A.; Elmarsafy A.; Brosselin P.; Courteille V.; De Vergnes N.; Kracker S.; Pergent M.; Randrianomenjanahary P.; Ahrenstorf G.; Albert M.H.; Ankermann T.; Atschekzei F.; Baumann U.; Becker B.C.; Behrends U.; Belohradsky B.H.; Biegner A.-K.; Binder N.; Bode S.F.N.; Boesecke C.; Boetticher B.; Borte M.; Borte S.; Classen C.F.; Dirks J.; Duckers G.; El-Helou S.; Ernst D.; Fasshauer M.; Fecker G.; Felgentreff K.; Foell D.; Ghosh S.; Girschick H.J.; Goldacker S.; Graf N.; Graf D.; Greil J.; Hanitsch L.G.; Hauck F.; Heeg M.; Heine S.I.; Henes J.C.; Hoenig M.; Holzer U.; Holzinger D.; Horneff G.; Hundsdoerfer P.; Jablonka A.; Jakoby D.; Joean O.; Kaiser-Labusch P.; Klemann C.; Kobbe R.; Korholz J.; Kramm C.M.; Kruger R.; Landwehr-Kenzel S.; Lehmberg K.; Liese J.G.; Lippert C.F.; Maccari M.E.; Masjosthusmann K.; Meinhardt A.; Metzler M.; Morbach H.; Muller I.; Naumann-Bartsch N.; Neubert J.; Niehues T.; Peter H.-H.; Rieber N.; Ritterbusch H.; Rockstroh J.K.; Roesler J.; Schauer U.; Scheible R.; Schmalzing M.; Schmidt R.E.; Schneider D.T.; Schreiber S.; Schuetz C.; Schulz A.; Schulze-Koops H.; Schulze-Sturm U.; Schuster V.; Schwaneck E.C.; Schwarz K.; Schwarze-Zander C.; Sirin M.; Skapenko A.; Sogkas G.; Sparber-Sauer M.; Speckmann C.; Steinmann S.; Stiehler S.; Tenbrock K.; von Bernuth H.; Warnatz K.; Wasmuth J.-C.; Weiss M.; Witte T.; Wittke K.; Wittkowski H.; Zeuner R.A.; Farmaki E.; Hatzistilianou M.N.; Kakkas I.; Kanariou M.G.; Kapousouzi A.; Liatsis E.; Maggina P.; Papadopoulou-Alataki E.; Raptaki M.; Speletas M.; Tantou S.; Goda V.; Krivan G.; Marodi L.; Abolhassani H.; Aghamohammadi A.; Rezaei N.; Feighery C.; Leahy T.R.; Ryan P.; Batzir N.A.; Garty B.Z.; Tamary H.; Aiuti A.; Amodio D.; Azzari C.; Barzaghi F.; Baselli L.A.; Cancrini C.; Carrabba M.; Cazzaniga M.; Cesaro S.; Chinello M.; Danieli M.G.; Dellepiane R.M.; Fabio G.; Gambineri E.; Lodi L.; Lougaris V.; Marasco C.; Martire B.; Marzollo A.; Milito C.; Moschese V.; Pignata C.; Plebani A.; Porta F.; Quinti I.; Ricci S.; Soresina A.; Tommasini A.; Vacca A.; Vanessa C.; Blaziene A.; Sitkauskiene B.; Gowin E.; Heropolitanska-Pliszka E.; Pietrucha B.; Szaflarska A.; Wiesik-Szewczyk E.; Wolska-Kusnierz B.; Esteves I.; Faria E.; Marques L.H.; Neves J.F.; Silva S.L.; Teixeira C.; Pereira da Silva S.; Capilna B.R.; Guseva M.N.; Shcherbina A.; Bobcakova A.; Ciznar P.; Gabzdilova J.; Jesenak M.; Kapustova L.; Orosova J.; Petrovicova O.; Raffac S.; Kopac P.; Allende L.M.; Antoli A.; Blanch G.R.; Carbone J.; Dieli-Crimi R.; Garcia-Prat M.; Gil-Herrera J.; Gonzalez-Granado L.I.; Agullo P.L.; Olbrich P.; Parra-Martinez A.; Paz-Artal E.; Pleguezuelo D.E.; Rodriguez N.S.; Sanchez-Ramon S.; Santos-Perez J.L.; Solanich X.; Soler-Palacin P.; Gonzalez-Amores M.; Ekwall O.; Fasth A.; Bitzenhofer-Gruber M.; Candotti F.; Dimitriou F.; Heininger U.; Holbro A.; Jandus P.; Kolios A.G.A.; Marschall K.; Schmid J.P.; Posfay-Barbe K.M.; Prader S.; Reichenbach J.; Steiner U.C.; Truck J.; Bredius R.G.; de Kruijf- Bazen S.; de Vries E.; Henriet S.S.V.; Kuijpers T.W.; Potjewijd J.; Rutgers A.; Stol K.; van Aerde K.J.; Van den Berg J.M.; van de Ven A.A.J.M.; Montfrans J.; Aydemir S.; Baris S.; Dogu F.; Ikinciogullari A.; Karakoc-Aydiner E.; Kilic S.S.; Kiykim A.; Kokcu Karadag S.I.; Kutukculer N.; Ocak S.; UNAL E.; Boyarchuk O.; Hilfanova A.; Kostyuchenko L.V.; Alachkar H.; Arkwright P.D.; Baxendale H.E.; Bernatoniene J.; Coulter T.I.; Garcez T.; Goddard S.; Gompels M.M.; Grigoriadou S.; Herriot R.; Herwadkar A.; Huissoon A.; Ibberson L.; Nademi Z.; Noorani S.; Parvin S.; Steele C.L.; Thomas M.; Waruiru C.; Yong P.F.K.; Bourne H.Thalhammer, J.; Kindle, G.; Nieters, A.; Rusch, S.; Seppanen, M. R. J.; Fischer, A.; Grimbacher, B.; Edgar, D.; Buckland, M.; Mahlaoui, N.; Ehl, S.; Boztug, K.; Brunner, J.; Demel, U. F.; Forster-Waldl, E.; Gasteiger, L. M.; Goschl, L.; Kojic, M.; Schroll, A.; Seidel, M. G.; Wintergerst, U.; Wisgrill, L.; Sharapova, S. O.; Goffard, J. -C.; Kerre, T.; Meyts, I.; Roosens, F.; Smet, J.; Haerynck, F.; Eric, Z. P.; Milenova, V.; Gagro, A.; Richter, D.; Chovancova, Z.; Hlavackova, E.; Litzman, J.; Milota, T.; Sediva, A.; Elaziz, D. A.; Alkady, R. S.; El Sayed El Hawary, R.; Eldash, A. S.; Galal, N.; Lotfy, S.; Meshaal, S. S.; Reda, S. M.; Sobh, A.; Elmarsafy, A.; Brosselin, P.; Courteille, V.; De Vergnes, N.; Kracker, S.; Pergent, M.; Randrianomenjanahary, P.; Ahrenstorf, G.; Albert, M. H.; Ankermann, T.; Atschekzei, F.; Baumann, U.; Becker, B. C.; Behrends, U.; Belohradsky, B. H.; Biegner, A. -K.; Binder, N.; Bode, S. F. N.; Boesecke, C.; Boetticher, B.; Borte, M.; Borte, S.; Classen, C. F.; Dirks, J.; Duckers, G.; El-Helou, S.; Ernst, D.; Fasshauer, M.; Fecker, G.; Felgentreff, K.; Foell, D.; Ghosh, S.; Girschick, H. J.; Goldacker, S.; Graf, N.; Graf, D.; Greil, J.; Hanitsch, L. G.; Hauck, F.; Heeg, M.; Heine, S. I.; Henes, J. C.; Hoenig, M.; Holzer, U.; Holzinger, D.; Horneff, G.; Hundsdoerfer, P.; Jablonka, A.; Jakoby, D.; Joean, O.; Kaiser-Labusch, P.; Klemann, C.; Kobbe, R.; Korholz, J.; Kramm, C. M.; Kruger, R.; Landwehr-Kenzel, S.; Lehmberg, K.; Liese, J. G.; Lippert, C. F.; Maccari, M. E.; Masjosthusmann, K.; Meinhardt, A.; Metzler, M.; Morbach, H.; Muller, I.; Naumann-Bartsch, N.; Neubert, J.; Niehues, T.; Peter, H. -H.; Rieber, N.; Ritterbusch, H.; Rockstroh, J. K.; Roesler, J.; Schauer, U.; Scheible, R.; Schmalzing, M.; Schmidt, R. E.; Schneider, D. T.; Schreiber, S.; Schuetz, C.; Schulz, A.; Schulze-Koops, H.; Schulze-Sturm, U.; Schuster, V.; Schwaneck, E. C.; Schwarz, K.; Schwarze-Zander, C.; Sirin, M.; Skapenko, A.; Sogkas, G.; Sparber-Sauer, M.; Speckmann, C.; Steinmann, S.; Stiehler, S.; Tenbrock, K.; von Bernuth, H.; Warnatz, K.; Wasmuth, J. -C.; Weiss, M.; Witte, T.; Wittke, K.; Wittkowski, H.; Zeuner, R. A.; Farmaki, E.; Hatzistilianou, M. N.; Kakkas, I.; Kanariou, M. G.; Kapousouzi, A.; Liatsis, E.; Maggina, P.; Papadopoulou-Alataki, E.; Raptaki, M.; Speletas, M.; Tantou, S.; Goda, V.; Krivan, G.; Marodi, L.; Abolhassani, H.; Aghamohammadi, A.; Rezaei, N.; Feighery, C.; Leahy, T. R.; Ryan, P.; Batzir, N. A.; Garty, B. Z.; Tamary, H.; Aiuti, A.; Amodio, D.; Azzari, C.; Barzaghi, F.; Baselli, L. A.; Cancrini, C.; Carrabba, M.; Cazzaniga, M.; Cesaro, S.; Chinello, M.; Danieli, M. G.; Dellepiane, R. M.; Fabio, G.; Gambineri, E.; Lodi, L.; Lougaris, V.; Marasco, C.; Martire, B.; Marzollo, A.; Milito, C.; Moschese, V.; Pignata, C.; Plebani, A.; Porta, F.; Quinti, I.; Ricci, S.; Soresina, A.; Tommasini, A.; Vacca, A.; Vanessa, C.; Blaziene, A.; Sitkauskiene, B.; Gowin, E.; Heropolitanska-Pliszka, E.; Pietrucha, B.; Szaflarska, A.; Wiesik-Szewczyk, E.; Wolska-Kusnierz, B.; Esteves, I.; Faria, E.; Marques, L. H.; Neves, J. F.; Silva, S. L.; Teixeira, C.; Pereira da Silva, S.; Capilna, B. R.; Guseva, M. N.; Shcherbina, A.; Bobcakova, A.; Ciznar, P.; Gabzdilova, J.; Jesenak, M.; Kapustova, L.; Orosova, J.; Petrovicova, O.; Raffac, S.; Kopac, P.; Allende, L. M.; Antoli, A.; Blanch, G. R.; Carbone, J.; Dieli-Crimi, R.; Garcia-Prat, M.; Gil-Herrera, J.; Gonzalez-Granado, L. I.; Agullo, P. L.; Olbrich, P.; Parra-Martinez, A.; Paz-Artal, E.; Pleguezuelo, D. E.; Rodriguez, N. S.; Sanchez-Ramon, S.; Santos-Perez, J. L.; Solanich, X.; Soler-Palacin, P.; Gonzalez-Amores, M.; Ekwall, O.; Fasth, A.; Bitzenhofer-Gruber, M.; Candotti, F.; Dimitriou, F.; Heininger, U.; Holbro, A.; Jandus, P.; Kolios, A. G. A.; Marschall, K.; Schmid, J. P.; Posfay-Barbe, K. M.; Prader, S.; Reichenbach, J.; Steiner, U. C.; Truck, J.; Bredius, R. G.; de Kruijf- Bazen, S.; de Vries, E.; Henriet, S. S. V.; Kuijpers, T. W.; Potjewijd, J.; Rutgers, A.; Stol, K.; van Aerde, K. J.; Van den Berg, J. M.; van de Ven, A. A. J. M.; Montfrans, J.; Aydemir, S.; Baris, S.; Dogu, F.; Ikinciogullari, A.; Karakoc-Aydiner, E.; Kilic, S. S.; Kiykim, A.; Kokcu Karadag, S. I.; Kutukculer, N.; Ocak, S.; Unal, E.; Boyarchuk, O.; Hilfanova, A.; Kostyuchenko, L. V.; Alachkar, H.; Arkwright, P. D.; Baxendale, H. E.; Bernatoniene, J.; Coulter, T. I.; Garcez, T.; Goddard, S.; Gompels, M. M.; Grigoriadou, S.; Herriot, R.; Herwadkar, A.; Huissoon, A.; Ibberson, L.; Nademi, Z.; Noorani, S.; Parvin, S.; Steele, C. L.; Thomas, M.; Waruiru, C.; Yong, P. F. K.; Bourne, H

Activated Phosphoinositide 3-Kinase δ Syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

BACKGROUND: Activated phosphoinositide-3-kinase (PI3K) δ Syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: Report the extended spectrum of disease manifestations in APDS1 versus APDS2, compare these to CTLA-4 deficiency, NFκB1 deficiency, and STAT3 gain-of-function (GOF) disease; identify predictors of severity in APDS. METHODS: Data collection with the European Society for Immunodeficiencies (ESID)-APDS registry. Comparison with published cohorts of the other IEIs. RESULTS: The analysis of 170 APDS patients outlines high penetrance and early-onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA-4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSION: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEI is substantial. Some specific features distinguish APDS1 from APDS2. Early-onset is a risk factor for severe disease course calling for specific treatment studies in younger patients

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations. (J Allergy Clin Immunol 2021;148:1332-41.