Camila Lopes Veronez1, Adriana S Moreno2, Rosemeire Navickas Constantino-Silva3, Luana S M Maia2, Mariana P L Ferriani2, Fábio F M Castro4, Solange Rodrigues Valle5, Victor Koji Nakamura1, Nathália Cagini1, Rozana Fátima Gonçalves6, Eli Mansour7, Faradiba Sarquis Serpa8, Gabriela Andrade Coelho Dias9, Miguel Alberto Piccirillo10, Eliana Toledo11, Marli de Souza Bernardes12, Sven Cichon13, Christiane Stieber14, L Karla Arruda2, João Bosco Pesquero1, Anete Sevciovic Grumach15. 1. Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil. 2. Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil. 3. Division of Clinical Immunology, Faculdade de Medicina ABC, Santo André, SP, Brazil. 4. Division of Allergy and Clinical Immunology, School of Medicine of the University of São Paulo, São Paulo, SP, Brazil. 5. Federal University of Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ, Brazil. 6. Private Allergy and Immunology Clinic, Belo Horizonte, MG, Brazil. 7. Division of Clinical Allergy and Immunology, School of Medicine, State University of Campinas, Campinas, SP, Brazil. 8. School of Medicine of Santa Casa de Misericordia of Vitoria, Vitoria, ES, Brazil. 9. Division of Allergy and Immunology, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. 10. Private Allergy and Immunology Clinic, Londrina, PR, Brazil. 11. School of Medicine, State University of São José do Rio Preto, São José do Rio Preto, SP, Brazil. 12. Private Allergy and Immunology Clinic, Foz do Iguaçu, PR, Brazil. 13. Division of Medical Genetics, University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland; Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 14. Institute of Human Genetics, University of Bonn School of Medicine & University Hospital of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Center for Rare Diseases Bonn, University Hospital of Bonn, Bonn, Germany. 15. Division of Clinical Immunology, Faculdade de Medicina ABC, Santo André, SP, Brazil. Electronic address: asgrumach@gmail.com.
Abstract
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES: Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS: We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS: Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS: Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.
BACKGROUND:Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES: Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS: We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS: Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS: Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.
Authors: Marcel Gutierrez; Camila L Veronez; Solange O Rodrigues Valle; Rozana Fátima Gonçalves; Mariana Paes Leme Ferriani; Adriana S Moreno; L Karla Arruda; Marcelo Vivolo Aun; Pedro Giavina-Bianchi; Maria Luiza Oliva Alonso; Joao B Pesquero; Anete S Grumach Journal: Clin Rev Allergy Immunol Date: 2021-03-23 Impact factor: 8.667
Authors: Ursula Waack; Mark Warnock; Andrew Yee; Zachary Huttinger; Sara Smith; Ayush Kumar; Alban Deroux; David Ginsburg; Harry L T Mobley; Daniel A Lawrence; Maria Sandkvist Journal: mBio Date: 2018-12-18 Impact factor: 7.867
Authors: Camila Lopes Veronez; Anne Aabom; Renan Paulo Martin; Rafael Filippelli-Silva; Rozana Fátima Gonçalves; Priscila Nicolicht; Agatha Ribeiro Mendes; Jane Da Silva; Mar Guilarte; Anete Sevciovic Grumach; Eli Mansour; Anette Bygum; João Bosco Pesquero Journal: Front Med (Lausanne) Date: 2019-02-21
Authors: Itahisa Marcelino-Rodriguez; Ariel Callero; Alejandro Mendoza-Alvarez; Eva Perez-Rodriguez; Javier Barrios-Recio; Jose C Garcia-Robaina; Carlos Flores Journal: Front Genet Date: 2019-09-27 Impact factor: 4.599
Authors: Jörg Scheffel; Niklas A Mahnke; Zonne L M Hofman; Steven de Maat; Jim Wu; Hanna Bonnekoh; Reuben J Pengelly; Sarah Ennis; John W Holloway; Marieluise Kirchner; Philipp Mertins; Martin K Church; Marcus Maurer; Coen Maas; Karoline Krause Journal: Nat Commun Date: 2020-01-10 Impact factor: 14.919
Authors: Ivan Ivanov; Anton Matafonov; Mao-Fu Sun; Bassem M Mohammed; Qiufang Cheng; S Kent Dickeson; Suman Kundu; Ingrid M Verhamme; Andras Gruber; Keith McCrae; David Gailani Journal: Blood Date: 2018-12-27 Impact factor: 25.476
Authors: Stephen Betschel; Jacquie Badiou; Karen Binkley; Rozita Borici-Mazi; Jacques Hébert; Amin Kanani; Paul Keith; Gina Lacuesta; Susan Waserman; Bill Yang; Emel Aygören-Pürsün; Jonathan Bernstein; Konrad Bork; Teresa Caballero; Marco Cicardi; Timothy Craig; Henriette Farkas; Anete Grumach; Connie Katelaris; Hilary Longhurst; Marc Riedl; Bruce Zuraw; Magdelena Berger; Jean-Nicolas Boursiquot; Henrik Boysen; Anthony Castaldo; Hugo Chapdelaine; Lori Connors; Lisa Fu; Dawn Goodyear; Alison Haynes; Palinder Kamra; Harold Kim; Kelly Lang-Robertson; Eric Leith; Christine McCusker; Bill Moote; Andrew O'Keefe; Ibraheem Othman; Man-Chiu Poon; Bruce Ritchie; Charles St-Pierre; Donald Stark; Ellie Tsai Journal: Allergy Asthma Clin Immunol Date: 2019-11-25 Impact factor: 3.406