Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort
IntroductionCardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairmen...
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2025-07-01
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| author | Benedetta Elena Di Majo Benedetta Elena Di Majo Chiara Leoni Eleonora Cartisano Eleonora Cartisano Chiara Fossati Germana Viscogliosi Valentina Trevisan Lucia Pia Bruno Francesca Conti Mattia Moratti Emilia Monaco Donato Rigante Donato Rigante Beatrice Rivalta Beatrice Rivalta Caterina Cancrini Caterina Cancrini Aleksandra Szczawińska-Popłonyk Aleksander Jamsheer Aleksander Jamsheer Monika Obara-Moszyńska Viktoria Zakharova Anna Shcherbina Julija Rodina Beyhan Tüysüz Saumya Shekhar Jamuar Saumya Shekhar Jamuar Jiin Ying Lim Jeannette Goh Anna Cereda Teresa Agovino Ilaria Contaldo Maria Luigia Gambardella Adriana Cristina Balduzzi Adriana Cristina Balduzzi Alessia Cherubino Giovanni Antonio Marrocco Silvia Bellesi Valentina Carusi Gabriele Rumi Andrea Biondi Giuseppe Zampino Giuseppe Zampino Francesco Saettini Francesco Saettini |
| author_facet | Benedetta Elena Di Majo Benedetta Elena Di Majo Chiara Leoni Eleonora Cartisano Eleonora Cartisano Chiara Fossati Germana Viscogliosi Valentina Trevisan Lucia Pia Bruno Francesca Conti Mattia Moratti Emilia Monaco Donato Rigante Donato Rigante Beatrice Rivalta Beatrice Rivalta Caterina Cancrini Caterina Cancrini Aleksandra Szczawińska-Popłonyk Aleksander Jamsheer Aleksander Jamsheer Monika Obara-Moszyńska Viktoria Zakharova Anna Shcherbina Julija Rodina Beyhan Tüysüz Saumya Shekhar Jamuar Saumya Shekhar Jamuar Jiin Ying Lim Jeannette Goh Anna Cereda Teresa Agovino Ilaria Contaldo Maria Luigia Gambardella Adriana Cristina Balduzzi Adriana Cristina Balduzzi Alessia Cherubino Giovanni Antonio Marrocco Silvia Bellesi Valentina Carusi Gabriele Rumi Andrea Biondi Giuseppe Zampino Giuseppe Zampino Francesco Saettini Francesco Saettini |
| author_sort | Benedetta Elena Di Majo |
| collection | DOAJ |
| description | IntroductionCardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairment, and epilepsy. Emerging evidence suggests an association with hypogammaglobulinemia, but a comprehensive characterization of immunological abnormalities in CFCS is lacking.MethodsWe conducted a retrospective, multicenter observational study to investigate the immunological phenotype of CFCS. Clinical features, immune-related manifestations, and laboratory parameters were analyzed to delineate the immunological profile of affected individuals.ResultsA total of 56 patients with a confirmed clinical and molecular diagnosis of CFCS were included, with a median age at evaluation of 13 years (range: 1–39 years). Increased susceptibility to infections was reported in 18/56 patients (32%), while autoimmune manifestations were observed in 14/56 patients (25%). Common immunological findings included monocytosis (32%), lymphopenia (21%), and hypogammaglobulinemia, with decreased IgG, IgA, or IgM levels in 21%, 40%, and 35% of patients, respectively. Genotype-phenotype analysis revealed that BRAF mutations were predominantly associated with T-cell lymphopenia, whereas MAP2K1 mutations were linked to monocytosis, reduced naïve and switched-memory B cells, and hypogammaglobulinemia. Immunodeficiency-related treatments, including immunoglobulin replacement therapy, antibiotic prophylaxis, or immunosuppressive therapy, were administered to 6/56 patients (11%).ConclusionsCFCS is associated with recurrent yet heterogeneous immunological abnormalities, including lymphopenia, hypogammaglobulinemia, and increased infection susceptibility. Given these findings, routine immunological assessment should be considered in CFCS patients to facilitate early detection and appropriate management of immune dysfunction. |
| format | Article |
| id | doaj-art-cc871e706c88495bb8d945dd3a49bde0 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-cc871e706c88495bb8d945dd3a49bde02025-08-20T02:42:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.15988961598896Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohortBenedetta Elena Di Majo0Benedetta Elena Di Majo1Chiara Leoni2Eleonora Cartisano3Eleonora Cartisano4Chiara Fossati5Germana Viscogliosi6Valentina Trevisan7Lucia Pia Bruno8Francesca Conti9Mattia Moratti10Emilia Monaco11Donato Rigante12Donato Rigante13Beatrice Rivalta14Beatrice Rivalta15Caterina Cancrini16Caterina Cancrini17Aleksandra Szczawińska-Popłonyk18Aleksander Jamsheer19Aleksander Jamsheer20Monika Obara-Moszyńska21Viktoria Zakharova22Anna Shcherbina23Julija Rodina24Beyhan Tüysüz25Saumya Shekhar Jamuar26Saumya Shekhar Jamuar27Jiin Ying Lim28Jeannette Goh29Anna Cereda30Teresa Agovino31Ilaria Contaldo32Maria Luigia Gambardella33Adriana Cristina Balduzzi34Adriana Cristina Balduzzi35Alessia Cherubino36Giovanni Antonio Marrocco37Silvia Bellesi38Valentina Carusi39Gabriele Rumi40Andrea Biondi41Giuseppe Zampino42Giuseppe Zampino43Francesco Saettini44Francesco Saettini45Pediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyDipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyPediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyDipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, ItalyPediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyDipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, ItalyPediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyPediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyDepartment of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ItalyUniversità Cattolica Sacro Cuore, Rome, ItalyResearch and Clinical Unit of Primary Immunodeficiencies, IRCCS Bambino Gesù Children’s Hospital, Rome, ItalyClinical Unit of Clinical Immunology and Vaccinology, IRCCS Bambino Gesù Children’s Hospital, Rome, ItalyResearch and Clinical Unit of Primary Immunodeficiencies, IRCCS Bambino Gesù Children’s Hospital, Rome, ItalyChair of Pediatrics, Department of Systems Medicine, University of Rome “Tor Vergata”, Roma, Italy0Department of Pediatric Pneumonology, Allergy and Clinical Immunology, Institute of Pediatrics, Poznań University of Medical Sciences, Poznań, Poland1Department of Medical Genetics, Poznań University of Medical Sciences, Poznań, Poland2Diagnostyka GENESIS, Poznań, Poland3Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland4Clinical Data Analysis Department, National Medical Research Center for Endocrinology, Moscow, Russia5Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia5Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia6Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Türkiye7Genetics Service, KK Women’s and Children’s Hospital, Singapore, Singapore8International Rare Disease Research Consortium, Paris, France7Genetics Service, KK Women’s and Children’s Hospital, Singapore, Singapore7Genetics Service, KK Women’s and Children’s Hospital, Singapore, Singapore9Department of Pediatric, “Papa Giovanni XXIII” Hospital, Bergamo, Italy9Department of Pediatric, “Papa Giovanni XXIII” Hospital, Bergamo, Italy0Child Neurology and Psychiatric Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy0Child Neurology and Psychiatric Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyPediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyDipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy1Dipartimento di Scienze di Laboratorio ed Ematologiche, Fondazione Policlinico Gemelli, IRCCS, Rome, Italy2UOSD Allergologia ed Immunologia Clinica, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy3Unità Operativa Semplice Malattie Infiammatorie Croniche Intestinali, Inflammatory Bowel Disease (IBD) Unit, CEMAD, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy4Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico A. Gemelli, IRCCS, Rome, ItalyUniversità Cattolica Sacro Cuore, Rome, ItalyPediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy4Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyIntroductionCardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairment, and epilepsy. Emerging evidence suggests an association with hypogammaglobulinemia, but a comprehensive characterization of immunological abnormalities in CFCS is lacking.MethodsWe conducted a retrospective, multicenter observational study to investigate the immunological phenotype of CFCS. Clinical features, immune-related manifestations, and laboratory parameters were analyzed to delineate the immunological profile of affected individuals.ResultsA total of 56 patients with a confirmed clinical and molecular diagnosis of CFCS were included, with a median age at evaluation of 13 years (range: 1–39 years). Increased susceptibility to infections was reported in 18/56 patients (32%), while autoimmune manifestations were observed in 14/56 patients (25%). Common immunological findings included monocytosis (32%), lymphopenia (21%), and hypogammaglobulinemia, with decreased IgG, IgA, or IgM levels in 21%, 40%, and 35% of patients, respectively. Genotype-phenotype analysis revealed that BRAF mutations were predominantly associated with T-cell lymphopenia, whereas MAP2K1 mutations were linked to monocytosis, reduced naïve and switched-memory B cells, and hypogammaglobulinemia. Immunodeficiency-related treatments, including immunoglobulin replacement therapy, antibiotic prophylaxis, or immunosuppressive therapy, were administered to 6/56 patients (11%).ConclusionsCFCS is associated with recurrent yet heterogeneous immunological abnormalities, including lymphopenia, hypogammaglobulinemia, and increased infection susceptibility. Given these findings, routine immunological assessment should be considered in CFCS patients to facilitate early detection and appropriate management of immune dysfunction.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1598896/fullprimary immunodeficiencyinborn errors of immunitycardiofaciocutaneous syndromerasopathyhypogammaglobulinemiaBRAF |
| spellingShingle | Benedetta Elena Di Majo Benedetta Elena Di Majo Chiara Leoni Eleonora Cartisano Eleonora Cartisano Chiara Fossati Germana Viscogliosi Valentina Trevisan Lucia Pia Bruno Francesca Conti Mattia Moratti Emilia Monaco Donato Rigante Donato Rigante Beatrice Rivalta Beatrice Rivalta Caterina Cancrini Caterina Cancrini Aleksandra Szczawińska-Popłonyk Aleksander Jamsheer Aleksander Jamsheer Monika Obara-Moszyńska Viktoria Zakharova Anna Shcherbina Julija Rodina Beyhan Tüysüz Saumya Shekhar Jamuar Saumya Shekhar Jamuar Jiin Ying Lim Jeannette Goh Anna Cereda Teresa Agovino Ilaria Contaldo Maria Luigia Gambardella Adriana Cristina Balduzzi Adriana Cristina Balduzzi Alessia Cherubino Giovanni Antonio Marrocco Silvia Bellesi Valentina Carusi Gabriele Rumi Andrea Biondi Giuseppe Zampino Giuseppe Zampino Francesco Saettini Francesco Saettini Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort Frontiers in Immunology primary immunodeficiency inborn errors of immunity cardiofaciocutaneous syndrome rasopathy hypogammaglobulinemia BRAF |
| title | Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort |
| title_full | Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort |
| title_fullStr | Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort |
| title_full_unstemmed | Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort |
| title_short | Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort |
| title_sort | cardiofaciocutaneous syndrome and immunodeficiency data from an international multicenter cohort |
| topic | primary immunodeficiency inborn errors of immunity cardiofaciocutaneous syndrome rasopathy hypogammaglobulinemia BRAF |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1598896/full |
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