Case Report A Rare Cause of Cardiofaciocutaneous Syndrome—KRAS p.Pro34arg: Clinical Delineation, Diagnostic Challenges, and Implications for RASopathy Classification

Abstract

Background and Clinical Significance: Cardiofaciocutaneous syndrome (CFC) is a rare autosomal dominant RASopathy characterized by craniofacial dysmorphism, congenital heart defects, cutaneous abnormalities, growth impairment, and neurodevelopmental delay. Pathogenic variants in KRAS account for a minority of cases and define cardiofaciocutaneous syndrome type 2 (CFC2). Establishing a molecular diagnosis is often challenging because of the substantial clinical overlap among RASopathies, including Noonan and Costello syndromes. Case Presentation: We describe a one-year-old boy presenting with macrocephaly, ventriculomegaly, hypotonia, developmental delay, hypertrophic cardiomyopathy, gastroesophageal reflux, and mild dermatological abnormalities. To clarify the diagnosis, a custom next-generation sequencing panel targeting RASopathy-associated genes was performed. Genetic analysis identified a heterozygous KRAS variant, NM_033360.4:c.101C>G, p.(Pro34Arg), which was confirmed by Sanger sequencing and shown to have arisen de novo through parental testing. Additional variants of uncertain significance were detected in ABCC9, CACNA1G, and DES; however, these were considered unlikely to account for the phenotype because of limited clinical concordance and current ACMG/AMP classification. The KRAS variant was classified as pathogenic based on its de novo occurrence, absence from population databases, localization within a critical functional domain, supportive computational evidence, and previously reported pathogenic substitutions affecting the same residue. Conclusions: This case provides additional evidence supporting the pathogenicity of KRAS p.(Pro34Arg), a variant reported only rarely in association with CFC. The observed phenotype further expands the clinical spectrum of KRAS-associated CFC and highlights the value of comprehensive molecular testing for the differential diagnosis of RASopathies and the refinement of genotype–phenotype correlations.