Di Majo Benedetta Elena, Leoni Chiara, Cartisano Eleonora, Fossati Chiara, Viscogliosi Germana, Trevisan Valentina, Bruno Lucia Pia, Conti Francesca, Moratti Mattia, Monaco Emilia, Rigante Donato, Rivalta Beatrice, Cancrini Caterina, Szczawińska-Popłonyk Aleksandra, Jamsheer Aleksander, Obara-Moszyńska Monika, Zakharova Viktoria, Shcherbina Anna, Rodina Julija, Tüysüz Beyhan, Jamuar Saumya Shekhar, Lim Jiin Ying, Goh Jeannette, Cereda Anna, Agovino Teresa, Contaldo Ilaria, Gambardella Maria Luigia, Balduzzi Adriana Cristina, Cherubino Alessia, Marrocco Giovanni Antonio, Bellesi Silvia, Carusi Valentina, Rumi Gabriele, Biondi Andrea, Zampino Giuseppe, Saettini Francesco
Pediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Dipartimento Di Medicina e Chirurgia, Università Degli Studi Milano-Bicocca, Monza, Italy.
Front Immunol. 2025 Jul 7;16:1598896. doi: 10.3389/fimmu.2025.1598896. eCollection 2025.
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.
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 mutations were predominantly associated with T-cell lymphopenia, whereas 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%).
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.
心脏颜面皮肤综合征（CFCS）是一种由影响RAS/MAPK通路的种系突变引起的罕见综合征性疾病。其特征为独特的颅面畸形、先天性心脏缺陷、皮肤异常、胃肠功能障碍、神经认知障碍和癫痫。新出现的证据表明其与低丙种球蛋白血症有关，但缺乏对CFCS免疫异常的全面描述。
我们进行了一项回顾性、多中心观察性研究，以调查CFCS的免疫表型。分析临床特征、免疫相关表现和实验室参数，以描绘受影响个体的免疫特征。
共纳入56例经临床和分子确诊为CFCS的患者，评估时的中位年龄为13岁（范围：1至39岁）。18/56例患者（32%）报告感染易感性增加，14/56例患者（25%）观察到自身免疫表现。常见的免疫检查结果包括单核细胞增多（32%）、淋巴细胞减少（21%）和低丙种球蛋白血症，分别有21%、40%和35%的患者IgG、IgA或IgM水平降低。基因型-表型分析显示， 突变主要与T细胞淋巴细胞减少有关，而 突变与单核细胞增多、初始和转换记忆B细胞减少以及低丙种球蛋白血症有关。6/56例患者（11%）接受了免疫缺陷相关治疗，包括免疫球蛋白替代治疗、抗生素预防或免疫抑制治疗。
CFCS与复发性但异质性的免疫异常有关，包括淋巴细胞减少、低丙种球蛋白血症和感染易感性增加。鉴于这些发现，应考虑对CFCS患者进行常规免疫评估，以便早期发现和适当管理免疫功能障碍。
