Cardiofaciocutaneous Syndrome (CFCS) and Immunodeficiency: Data From an International Multicenter Cohort

Benedetta Elena Di Majo¹Chiara Leoni²Eleonora Cartisano¹Chiara Fossati³Germana Viscogliosi²Valentina Trevisan²Lucia Pia Bruno¹Francesca Conti⁴Mattia Moratti⁴Emilia Monaco²Donato Rigante^5,6Beatrice Rivalta^7,8Caterina Cancrini^7,8Aleksandra Szczawińska-Popłonyk⁹Aleksander Jamsheer^10,11Monika Obara-Moszynska¹²Viktoria Zakharova¹³Anna Shcherbina¹⁴Julija Rodina¹⁴Beyhan Tüysüz¹⁵Saumya Shekhar Jamuar^16,17Jiin Ying Lim¹⁶Jeannette Goh¹⁶Anna Cereda¹⁸Teresa Agovino¹⁸Ilaria Contaldo¹⁹Maria Luigia Gambardella¹⁹Adriana Balduzzi^1,3Alessia Cherubino²Giovanni Antonio Marrocco²Silvia Bellesi²⁰Valentina Carusi²¹GABRIELE RUMI^2,6Andrea Biondi²²Giuseppe Zampino^2,6Francesco Saettini^22,3*

• ¹Dipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, Italy, Monza, Italy
• ²Center for Rare Diseases and Birth Defects, Department of Women's Health, Children's Health and Public Health, Agostino Gemelli University Polyclinic (IRCCS), Rome, Sicily, Italy
• ³Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori Hospital, Monza, Italy
• ⁴Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁵Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
• ⁶Università Cattolica Sacro Cuore, Rome, Italy
• ⁷Research and Clinical Unit of Primary Immunodeficiencies, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
• ⁸Unit of Clinical Immunology and Vaccinology, University Hospital Pediatric Department, Bambino Gesù Children's Hospital (IRCCS), Rome, Lazio, Italy
• ⁹Department of Pneumonology, Pediatric Allergology and Clinical Immunology, Poznań University of Medical Sciences, Poznań, Greater Poland, Poland
• ¹⁰Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
• ¹¹Diagnostyka GENESIS, Poznan, Poland
• ¹²Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland
• ¹³Clinical Data Analysis Department, National Medical Research Center for Endocrinology, Moscow, Russia
• ¹⁴Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Moscow Oblast, Russia
• ¹⁵Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Türkiye
• ¹⁶Genetics service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore, Singapore
• ¹⁷International Rare Disease Research Consortium, Paris, France
• ¹⁸Department of Pediatrics, Papa Giovanni XXIII Hospital, Bergamo, Lombardy, Italy
• ¹⁹Child Neurology and Psychiatric Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
• ²⁰Dipartimento di Scienze di Laboratorio ed Ematologiche, Fondazione Policlinico Gemelli, Rome, Italy
• ²¹UOSD Allergologia ed Immunologia Clinica, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
• ²²Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

Introduction: Cardiofaciocutaneous 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.We 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.Results: A 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%).Conclusions: CFCS 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.