Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort

Abstract

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.

Methods: 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.

Keywords: BRAF; MAP2K1; Syndromic immunodeficiency; cardiofaciocutaneous syndrome; hypogammaglobulinemia; inborn errors of immunity; primary immunodeficiency; rasopathy.

Figure 1

Protein domains of BRAF (A), MAP2K1 (B), MAP2K2 (C), KRAS (D) and YWHAZ (E) proteins highlighting the mutations identified in our cohort. The BRAF Q257R and MAP2K1 Y130C variants were modelled through PyMOL based on the PDB structures 7mfe and 3w8q, respectively. Each black dot indicates an affected patient.

Figure 2

Immunoglobulins correlation profile in Cardiofaciocutaneous syndrome. Spearman’s correlation coefficient was used to compare between serum immunoglobulin isotypes and switched memory B (smB) cells (A) or immunoglobulin isotypes (B). smB are depicted as percentages of total B cells. Immunoglobulin isotypes are depicted as per mg/ml.