Cardiofaciocutaneous syndrome type 4: A comprehensive review of the MAP2K2-related clinical features, diagnostics,...

Cardiofaciocutaneous syndrome type 4 (CFC4) is a rare genetic condition caused by pathogenic variants in the MAP2K2 (MEK2) gene, part of the RAS/MAPK signaling pathway. While the broader phenotype of CFC syndrome has been well described, the features specific to this molecular subtype remain poorly defined due to the limited number of cases and underreporting. We conducted a structured analysis of all available literature on CFC4, focusing on organ-specific manifestations, including cardiac, craniofacial, neurological, integumentary, and gastrointestinal features, as well as developmental outcomes, treatment approaches, imaging findings, and behavioral profiles. Cardiofaciocutaneous syndrome type 4 is associated with a recognizable but variable phenotype. Pulmonary valve stenosis and atrial septal defects (ASDs) are the most common cardiac anomalies. Neurological involvement is nearly universal, often presenting as hypotonia and motor delay, with intellectual disability in a subset of cases. Distinctive craniofacial features and ectodermal abnormalities support clinical recognition. Feeding difficulties, sensory integration disorders, and behavioral challenges are frequently observed. Brain magnetic resonance imaging (MRI) abnormalities such as ventriculomegaly and corpus callosum hypoplasia are also relatively frequent. Notably, some individuals with CFC4 exhibit relatively mild phenotypes, with reports of independent functioning in adulthood and a history of familial transmission. In such cases, only mild learning difficulties were described. Better recognition and understanding of CFC4 require consistent and detailed reporting of new cases. To support this, we propose a concise clinical checklist to standardize case descriptions and support diagnosis.