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Aleksandra Świeca
Aleksandra Świeca

Public Documents 1
Cardiofaciocutaneous Syndrome Type 4: Expanding the Phenotypic Spectrum with Severe D...
Aleksandra Świeca
Małgorzata  Rydzanicz

Aleksandra Świeca

and 3 more

October 18, 2025
IntroductionCardiofaciocutaneous (CFC) syndrome is a rare RASopathy resulting from pathogenic variants in genes that regulate the RAS/MAPK pathway, which is essential for cellular growth and differentiation. Most cases are associated with BRAF variants, but variants in MAP2K1 ,KRAS , and MAP2K2 have also been identified (1). As this intracellular cascade plays a central role in controlling cell growth, differentiation, and survival, its dysregulation leads to various developmental abnormalities. CFC type 4 (OMIM 615280), caused byMAP2K2 variants, represents one of the rarest molecular subtypes, with limited phenotype-specific data. Characteristic features of CFC include macrocephaly, high forehead, curly or sparse hair, hyperkeratotic skin, segmental hemangiomas, and cardiac defects such as pulmonary stenosis or septal anomalies (2, 3). Neurological involvement, especially hypotonia, seizures, and global developmental delay, is frequent (1). Feeding difficulties in infancy are often severe and may be the earliest clinical manifestation (4). Here, we report an infant with a heterozygous MAP2K2 variant (c.619G>A, p.Glu207Lys), presenting from birth with severe oromotor dysfunction, macrosomia, distinctive craniofacial and cutaneous features, and paroxysmal neurologic episodes, thereby expanding the early phenotypic spectrum of CFC type 4.

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