Clinical and Genetic Features of Hereditary Angioedema with and Without C1-inhibitor (C1-INH) Deficiency in Japan.

AllergyVolume 76, Issue 11 p. 3529-3534 LETTEROpen Access Clinical and genetic features of hereditary angioedema with and without C1-inhibitor (C1-INH) deficiency in Japan Chinami Hashimura, Chinami Hashimura Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, JapanSearch for more papers by this authorChikako Kiyohara, Chikako Kiyohara Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanSearch for more papers by this authorJun-Ichi Fukushi, Jun-Ichi Fukushi Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, JapanSearch for more papers by this authorTomoya Hirose, Tomoya Hirose Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, Japan Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, JapanSearch for more papers by this authorIsao Ohsawa, Isao Ohsawa Department of Nephrology, Internal Medicine, Saiyu Soka Hospital, Saitama, JapanSearch for more papers by this authorTomoko Tahira, Tomoko Tahira College of Pharmacy, Kinjo Gakuin University, Nagoya, JapanSearch for more papers by this authorTakahiko Horiuchi, Corresponding Author Takahiko Horiuchi horiuchi@beppu.kyushu-u.ac.jp Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, Japan Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, Japan Correspondence Takahiko Horiuchi, Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, Japan. Email: horiuchi@beppu.kyushu-u.ac.jpSearch for more papers by this author Chinami Hashimura, Chinami Hashimura Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, JapanSearch for more papers by this authorChikako Kiyohara, Chikako Kiyohara Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanSearch for more papers by this authorJun-Ichi Fukushi, Jun-Ichi Fukushi Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, JapanSearch for more papers by this authorTomoya Hirose, Tomoya Hirose Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, Japan Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, JapanSearch for more papers by this authorIsao Ohsawa, Isao Ohsawa Department of Nephrology, Internal Medicine, Saiyu Soka Hospital, Saitama, JapanSearch for more papers by this authorTomoko Tahira, Tomoko Tahira College of Pharmacy, Kinjo Gakuin University, Nagoya, JapanSearch for more papers by this authorTakahiko Horiuchi, Corresponding Author Takahiko Horiuchi horiuchi@beppu.kyushu-u.ac.jp Center for Research, Education, and Treatment of angioEdema, a specified Non-profit Corporation, Fukuoka, Japan Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, Japan Correspondence Takahiko Horiuchi, Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, Japan. Email: horiuchi@beppu.kyushu-u.ac.jpSearch for more papers by this author First published: 03 August 2021 https://doi.org/10.1111/all.15034AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor, Hereditary angioedema with normal C1-inhibitor (HAEnCI) is an umbrella term for several types of HAE that phenotypically resemble HAE but in which variants affecting function have been identified in genes other than the C1-INH gene (SERPING1).1 In contrast to European patients with HAE, we suppose comprehensive clinical and genetic data of HAE are scarcely reported from Asian countries, including Japan. In particular, HAEnCI in Asia has not been clearly characterized. Considering ethnic differences, it would be important to clarify the features of HAE in the Asian population. Here, we report the clinical and genetic features of Japanese patients with 158 cases from 122 families with HAE-C1-INH and 21 cases from 21 families with HAEnCI. HAEnCI was defined as follows: normal C1-INH activity, no variants affecting function in the SERPING1 gene, at least one relative with recurrent angioedema attacks (i.e., positive family history), no history of urticaria, and lack of efficacy by anti-histamines or corticosteroids. Table 1 shows clinical features of our Japanese patients with HAE-C1-INH and HAEnCI. When compared with HAE-C1-INH, HAEnCI was significantly more predominant among females (95.2% vs. 66.9%, p = .008), more frequently affected in the face (61.9% vs. 32.9%, p = .009) and pharynx/larynx (47.6% vs. 21.5%, p = .009), associated with more frequent exacerbations in the previous year (mean ± SD: 14.4 ± 27.3 vs. 3.66 ± 7.14, p = .0001), associated with higher prevalence of patients with more than six angioedema attacks in the previous year (52.4% vs. 16.5%, p = .0001), and more susceptible to triggers such as physical stress (38.1% vs. 12.7%, p = .007) and upper respiratory infections (URI) (19.0% vs. 5.1%, p = .037). The prevalence of having a positive family history experiencing angioedema attacks was significantly higher in HAEnCI (100%) than in HAE-C1-INH (81.6%) (p = .027). This is because the inclusion criteria of HAEnCI demand a family history of angioedema. There were no differences in most of the clinical features of male and female patients with HAE-C1-INH except the incidence of urological attacks and prodromal symptoms (Table S1). TABLE 1. Clinical features of the Japanese patients with HAE-C1-INH and HAEnCI Variables HAE-C1-INH % (no. affected/observeda a Some of the data are lacking. ) HAEnCI % (no. affected/observeda a Some of the data are lacking. ) p Female 66.9 (105/157) 95.2 (20/21) .008 Comorbid disease AID 3.2 (5/158) 0.0 (0/21) 1.000b b Fisher's exact test. Urticaria 7.6 (12/158) 0.0 (0/21) .365b b Fisher's exact test. Bronchial asthma 5.1 (8/157) 9.5 (2/21) .334b b Fisher's exact test. CVD 3.2 (5/158) 9.5 (2/21) .192b b Fisher's exact test. Arthralgia/arthritis 3.2 (5/158) 0.0 (0/21) 1.000b b Fisher's exact test. Any kinds 27.2 (43/158) 42.9 (9/21) .138 Family history At least another patient in family member 81.6 (129/158) 100.0 (21/21) .027b b Fisher's exact test. Death probably by angioedema 7.6 (12/158) 4.8 (1/21) 1.000b b Fisher's exact test. Age of onset Mean ± SD 23.0 ± 12.6 26.8 ± 22.7 .298 ≤40 95.2 (120/126) 82.4 (14/17) .075b b Fisher's exact test. ≤20 51.6 (65/126) 52.9 (9/17) .916 Age of diagnosis ≤40 69.9 (100/143) 70.0 (14/20) .995 ≤20 13.3 (19/143) 40.0 (8/20) .007b b Fisher's exact test. Site of attacks Extremities 39.2 (62/158) 47.6 (10/21) .462 Tongue 0.6 (1/158) 4.8 (1/21) .221b b Fisher's exact test. Face 32.9 (52/158) 61.9 (13/21) .009 Pharynx/Larynx 21.5 (34/158) 47.6 (10/21) .009 Intestine 35.4 (56/158) 38.1 (8/21) .812 Urogenital 6.3 (10/158) 9.5 (2/21) .636b b Fisher's exact test. Others 7.0 (11/158) 14.3 (3/21) .216b b Fisher's exact test. Frequency of attacks in the previous 1 year Mean ± SD 3.66 ± 7.14 14.4 ± 27.3 .0001 ≧6 times 16.5 (26/158) 52.4 (11/21) .0001 Prodromal symptom 13.3 (21/158) 28.6 (6/21) .097b b Fisher's exact test. Trigger Psychological 13.9 (22/158) 33.3 (7/21) .051b b Fisher's exact test. Physical 12.7 (20/158) 38.1 (8/21) .007b b Fisher's exact test. Menstruation/Pregnancy 19.0 (20/105) 20.0 (4/20) 1.000b b Fisher's exact test. Dental procedure 13.9 (22/158) 14.3 (3/21) 1.000b b Fisher's exact test. URI 5.1 (8/158) 19.0 (4/21) .037b b Fisher's exact test. Medication and acute attackc c Icatibant was approved in Japan after the termination of this registration. pdC1-INH 31.0 (49/158) 19.0 (4/21) .259 Tranexamic acid 19.0 (30/158) 38.1 (8/21) .083b b Fisher's exact test. Anti-histamine 6.3 (10/158) 19.0 (4/21) .064b b Fisher's exact test. Prednisolone 3.2 (5/158) 14.3 (3/21) .053b b Fisher's exact test. Epinephrine 1.3 (2/158) 4.8 (1/21) .314b b Fisher's exact test. Danazol 2.5 (4/158) 0.0 (0/21) 1.000b b Fisher's exact test. FFP 0.0 (0/158) 0.0 (0/21) – Intubation/Tracheostomy 3.8 (6/158) 9.5 (2/21) .238b b Fisher's exact test. Prophylaxis Tranexamic acid 31.0 (49/158) 33.3 (7/21) .829 Danazol 5.1 (8/158) 4.8 (1/21) 1.000b b Fisher's exact test. Others 6.3 (10/158) 9.5 (2/21) .636b b Fisher's exact test. Note A total number of registered are 158 for HAE-C1-INH and 21 for HAEnCI. Abbreviations: AID, autoimmune disease; CVD, cardiovascular disease; FFP, fresh frozen plasma; SD, standard deviation; URI, upper respiratory infection. a Some of the data are lacking. b Fisher's exact test. c Icatibant was approved in Japan after the termination of this registration. It is of note that our patients with HAEnCI suffer from edema in the face and pharynx/larynx twice more frequently than those with HAE-C1-INH. In European patients with HAEnCI, facial and oropharyngeal swellings develop more predominantly than those with HAE-C1-INH as well.2 On the other hand, there are a number of differences in the clinical characteristics such as frequency of attacks and triggers between Japanese and European patients with HAEnCI. In particular, hormonal perturbations induced by menstruation/pregnancy or oral contraceptives did not seem to influence attacks in our patients with HAEnCI. This finding is in contrast with European patients with HAEnCI whose angioedema symptoms are frequently deteriorated by oral contraceptives or pregnancies.2 In the case of HAE-C1-INH, the incidence of abdominal attacks was different between our patients and European patients. Abdominal attacks are common clinical manifestations of European patients with HAE-C1-INH, whose incidence reaches over 90% in these patients.3 In contrast, the proportion of patients who had experienced intestinal attack was 35.4% in our 158 patients with HAE-C1-INH (Table 1). Other reports from Asia such as the one from Mainland China4 have shown similar incidence of abdominal attacks with the present study. Genetic analysis directed toward the entire exons for the known causative genes was performed for our Japanese HAEnCI patients (n = 21). Targeted next-generation sequencing for the factor XII gene (F12), the plasminogen (PLG) gene, the angiopoietin-1 (ANGPT1) gene, the kininogen 1 (KNG1) gene, and the SERPING1 gene revealed missense variant: p.Lys330Glu (c.988A>G) in the PLG gene in two patients5 and p.Arg466Ser (c.1396C>A) in the F12 gene in 1 patient. All of these variants were heterozygous. The p.Lys330Glu variant in the PLG gene was originally reported in Europe as causative for HAEnCI.6 The p.Arg466Ser variant identified in the F12 gene has been reported in a patient with factor XII deficiency.7 It is likely that this variant does not have any relationship with angioedema. None of the known variants affecting function in the F12 gene, the ANGPT1 gene, and the KNG1 gene responsible for HAEnCI was identified in our patients. The patients carrying variants affecting function in the F12 gene (HAE-F12) account for about 30% of HAEnCI in European countries.8 Lack of the F12 gene findings in our Japanese HAEnCI patients might reflect ethnic difference, or limitation of our approach focused only on small variants of the exons. In addition, the recently reported variants affecting function of the myoferlin (MYOF) gene (p.Arg217Ser) and of the heparin sulfate 3-O-sulfotransferase 6 (HS3ST6) gene (p.Thr144Ser) were not identified in our patients. Ninety-two percent (112/122) of the studied families with HAE-C1-INH were positive for the SERPING1 variant affecting function (Table 2). Missense variants were the most common (45 families), followed by small insertions/deletions (30 families), large insertions/deletions (15 families), nonsense variants (13 families), and splicing defects (nine families). Nineteen variants were recurrent, at least in two different families. Twenty-five variants affecting function had not been reported in LOVD v.3.0 Leiden Open Variation Database9 (https://databases.lovd.nl/shared/genes/SERPING1) as of April 2021. All the novel sequence variants except two (#17, #23) were predicted to be pathogenic by in silico analysis (Table S2). The variants #17 (c.461_465delACCACinsTCAGGGAGGCTCTTCAA) and #23 (c.554_555insTGTTGCAGGGGC) were in frame insertion/deletion and were predicted as variants of uncertain significance (VUS). There were no correlations between the types of SERPING1 variants (missense vs. other variant) and the markers of severity of disease, such as the age of onset, frequency of attacks, and C1-INH activity (Table S3). TABLE 2. SERPING1 mutations in our Japanese 112 families of HAE-C1-INH Alteration (physical location on chromosome 11)a a GRCh37/hg19 genomic chromosomal coordinates are shown. cDNA numbering (NM_000062.2) Location Effect on protein Families Referenceb b The mutations previously reported in LOVD v.3.0 (https://databases.lovd.nl/shared/genes/SERPING1) as of April 2021 are shown (*). (LOVD) 1 g.57365720A>G c.-22-2A>G Intron1 Splicing defect 1 * 2 g.57365746G>A c.3G>A Exon2 p.Met1Ile 1 * 3 g.57365748_57365749del c.5_6delCC Exon2 p.Ala2Valfs*17 1 4 g.57365760_57365767dup c.17_24dupCCCTGCTG Exon2 p.Thr9Profs*3 1 5 g.57365795G>T c.51+1G>T Intron2 Splicing defect 1 * 6 g.57367351G>A c.52-1G>A Intron2 Splicing defect 1 * 7 g.57367406_57367407del c.106_107delAG Exon3 p.Ser36Phefs*21 3 * 8 g.57367416_57367417insGGATC c.116_117insGGATC Exon3 p.Asp39Glufs*42 1 9 g.57367438_57367507del c.138_207del Exon3 p.Thr47Glnfs*9 1 * 10 g.57367447del c.147delT Exon3 p.Ile50Serfs*29 1 11 g.57367504del c.204delC Exon3 p.Asn69Thrfs*10 1 12 g.57367526del c.226delA Exon3 p.Thr76Profs*3 1 13 g.57367646C>T c.346C>T Exon3 p.Gln116* 2 * 14 g.57367700_57367704del c.400_404delGAGAG Exon3 p.Glu134Serfs*121 1 15 g.57367703_57367704del c.403_404delAG Exon3 p.His136Phefs*120 1 * 16 g.57367749C>T c.449C>T Exon3 p.Ser150Phe 2 * 17 g.57367761_57367765delins TCAGGGAGGCTCTTCAA c.461_465delACCACins TCAGGGAGGCTCTTCAA Exon3 p.Tyr154_His155delins PheArgGluAlaLeuGln 1 18 g.57367767C>A c.467C>A Exon3 p.Ala156Asp 2 * 19 g.57367775del c.475delG Exon3 p.Ala159Glnfs*2 1 20 g.57367848T>C c.548T>C Exon3 p.Leu183Pro 2 * 21 g.57367850G>A c.550G>A Exon3 p.Gly184Arg 2 * 22 g.57369507G>C c.551-1G>C intron3 Splicing defect 1 * 23 g.57369500-57369511dup c.554_555ins TGTTGCAGGGGC Exon4 p.Ala185_Gly186ins ValAlaGlyAla 1 24 g.57369510del c.553delG Exon4 p.Ala185Leufs*26 1 * 25 g.57369523C>A c.566C>A Exon4 p.Thr189Asn 1 * 26 g.57369586T>C c.629T>C Exon4 p.Leu210Pro 1 * 27 g.57369610T>A c.653T>A Exon4 p.Val218Asp 1 * 28 g.57369623_57369624del c.666_667delTC Exon4 p.Gln223Aspfs*33 1 * 29 g.57369631_57369632delinsAA c.674_675delinsAA Exon4 p.Phe225* 2 * 30 g.57373482G>T c.686-1G>T intron4 Splicing defect 1 31 g.57373492T>A c.695T>A Exon5 p.Ile232Lys 1 * 32 g.57373549T>A c.752T>A Exon5 p.Leu251Gln 1 33 g.57373617A>G c.820A>G Exon5 p.Ile274Val 3 * 34 g.57373649dup c.852dupT Exon5 p.Thr285Tyrfs*20 1 35 g.57373687G>A c.889+1G>A intron5 Splicing defect 1 * 36 g.57373886T>G c.895T>G Exon6 p.Trp299Gly 1 * 37 g.57373928T>C c.937T>C Exon6 p.Phe313Leu 1 * 38 g.57373956T>G c.965T>G Exon6 p.Val322Gly 2 39 g.57373962T>G c.971T>G Exon6 p.Met324Arg 1 * 40 g.57373989C>A c.998C>A Exon6 p.Ala333Asp 1 * 41 g.57379188A>G c.1030-2A>G intron6 Splicing defect 1 42 g.57379189G>C c.1030-1G>C intron6 Splicing defect 1 * 43 g.57379189G>A c.1030-1G>A intron6 Splicing defect 1 * 44 g.57379193G>A c.1033G>A Exon7 p.Gly345Arg 1 * 45 g.57379194G>A c.1034G>A Exon7 p.Gly345Glu 1 * 46 g.57379216dup c.1056dup Exon7 p.Leu353Serfs*16 1 * 47 g.57379241C>T c.1081C>T Exon7 p.Gln361* 1 * 48 g.57379279_57379302del c.1119_1142del Exon7 p.Leu374_Ala381del 1 49 g.57379317del c.1157delT Exon7 p.Leu386Argfs*11 1 * 50 g.57379317_57379318del c.1157_1158delTG Exon7 p.Leu386Argfs*38 2 51 g.57379344_57379345 c.1184_1185delTC Exon7 p.Leu395Profs*29 3 52 g.57379355C>T c.1195C>T Exon7 p.Pro399Ser 1 * 53 g.57379379C>T c.1219C>T Exon7 p.Gln407* 2 54 g.57379395T>A c.1235T>A Exon7 p.Ile412Asn 1 * 55 g.57381820T>G c.1269T>G Exon8 p.Tyr423* 1 * 56 g.57381835T>A c.1284T>A Exon8 p.Cys428* 1 * 57 g.57381891T>C c.1340T>C Exon8 p.Leu447Pro 1 * 58 g.57381919_57381921del c.1368_1370delGGC Exon8 p.Ala457del 1 59 g.57381920G>C c.1369G>C Exon8 p.Ala457Pro 1 * 60 g.57381947C>T c.1396C>T Exon8 p.Arg466Cys 7 * 61 g.57381947del c.1396delC Exon8 p.Arg466Alafs*110 2 62 g.57381948G>T c.1397G>T Exon8 p.Arg466Leu 3 * 63 g.57381982C>G c.1431C>G Exon8 p.Phe477Leu 1 * 64 p.57381996G>A c.1445G>A Exon8 p.Trp482* 1 65 g.57382026T>A c.1475T>A Exon8 p.Met492Lys 1 * 66 g.57382028G>A c.1477G>A Exon8 p.Gly493Arg 1 * 67 g.57382029G>A c.1478G>A Exon8 p.Gly493Glu 1 * 68 g.57382031C>T c.1480C>T Exon8 p.Arg494* 3 * 69 g.57382034_57382036del c.1483_1485delGTA Exon8 p.Val495del 1 70 g.57382044C>A c.1493C>A Exon8 p.Pro498His 1 * 71 g.57382044C>T c.1493C>T Exon8 p.Pro498Leu 1 * 72 Deletion of exon 1 to 4 1 * 73 Deletion of exon 1 to 8 2 * 74 Deletion of exon 4 5 * 75 Deletion of exon 4 to 8 1 76 Deletion of exon 5 to 6 1 * 77 Deletion of exon 5 to 8 3 * 78 Duplication of exon 3 1 79 Duplication of exon 4 1 * a GRCh37/hg19 genomic chromosomal coordinates are shown. b The mutations previously reported in LOVD v.3.0 (https://databases.lovd.nl/shared/genes/SERPING1) as of April 2021 are shown (*). In conclusion, we demonstrated the clinical and genetic features of the patients with HAE-C1-INH and HAEnCI in Japan. When compared with European patients with HAE-C1-INH, the clinical features of our Japanese patients with HAE-C1-INH were almost similar, but the frequency of abdominal pain in our patients was considerably low. The clinical features of our Japanese patients with HAEnCI were significantly different from those of HAE-C1-INH in a number of aspects such as female-male ratio and sites of attacks. Lack of the F12 gene variants affecting function in our HAEnCI patients might indicate that the genetic background is different between Japanese and European patients with HAEnCI. ACKNOWLEDGEMENTS Dr. Horiuchi reports grants from the Ministry of Health, Labour and Welfare (MHLW) (H29-013), Japan, grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) (16K09246, 19H03564), Japan, during the conduct of the study, grants and personal fees from Takeda Pharmaceutical Company, grants and personal fees from CSL Behring, outside the submitted work. CONFLICT OF INTEREST As for COI, Dr. Hashimura has nothing to disclose. Dr. Kiyohara has nothing to disclose. Dr. Fukushi has nothing to disclose. Dr. Hirose is a consultant for Takeda Pharmaceutical Company (without salary). Dr. Ohsawa reports personal fees from Takeda Pharmaceutical Company, personal fees from CSL Behring, personal fees from Torii Pharmaceutical Company, personal fees from BioCryst Pharmaceuticals, outside the submitted work. Dr. Tahira has nothing to disclose. Dr. Horiuchi reports personal fees from Takeda Pharmaceutical Company, personal fees from CSL Behring, personal fees from Torii Pharmaceutical Company, outside the submitted work. AUTHOR CONTRIBUTIONS CH contributed to conception, performed data acquisition and analysis, and wrote the initial draft of the manuscript. CK and TT performed data analysis and drafted the manuscript. THirose, JIF, and IO were involved in data collection. THoriuchi designed the study, performed data acquisition and analysis, and wrote the manuscript. All authors contributed to drafting the article, revised the manuscript critically for important intellectual content, and approved the final version. Supporting Information Filename Description all15034-sup-0001-Supinfo.docxWord document, 46.3 KB Table S1, S3 all15034-sup-0002-TableS2.xlsxapplication/excel, 17.6 KB Table S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020; 382(12): 1136- 1148. CrossrefCASPubMedWeb of Science®Google Scholar 2Riedl MA. Hereditary angioedema with normal C1-INH (HAE type III). J Allergy Clin Immunol Pract. 2013; 1: 427- 432. CrossrefPubMedWeb of Science®Google Scholar 3Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006; 119(3): 267- 274. CrossrefPubMedWeb of Science®Google Scholar 4Xu Y-Y, Jiang Y, Zhi Y-X, et al. Clinical features of hereditary angioedema in Chinese patients: new findings and differences from other populations. Eur J Dermatol. 2013; 23(4): 500- 504. CrossrefPubMedWeb of Science®Google Scholar 5Yakushiji H, Hashimura C, Fukuoka K, et al. A missense mutation of the plasminogen gene in hereditary angioedema with normal C1 inhibitor in Japan. Allergy. 2018; 73(11): 2244- 2247. Wiley Online LibraryPubMedWeb of Science®Google Scholar 6Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018; 73(2): 442- 450. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 7Matsukuma E, Gotoh Y, Kuroyanagi Y, et al. A case of atypical hemolytic uremic syndrome due to anti-factor H antibody in a patient presenting with a factor XII deficiency identified two novel mutations. Clin Exp Nephrol. 2011; 15(2): 269- 274. CrossrefPubMedWeb of Science®Google Scholar 8Bork K, Wulff K, Witzke G, Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy. 2015; 70(8): 1004- 1012. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 9Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD vol 2.0: the next generation in gene variant databases. Hum Mutat. 2011; 32(5): 557- 563. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume76, Issue11November 2021Pages 3529-3534 ReferencesRelatedInformation