Case Report A Rare Cause of Cardiofaciocutaneous Syndrome-KRAS p.Pro34arg: Clinical Delineation, Diagnostic Challenges, and Implications for RASopathy Classification.
5 affiliations
- 1Department of Genetic, Málaga Regional University Hospital, 29011 Málaga, Spain.
- 2Department of Biochemistry, Molecular Biology and Immunology, University of Málaga, 29071 Málaga, Spain.
- 3Gerona Institute of Biomedical Research (IDIBGI), 17190 Gerona, Spain.
- 4Clinical Genetics Department, GENinCode SLU (Affiliate of GENinCode UK), 08244 Barcelona, Spain.
- 5Department of Genetic, Gerona University Hospital Santa, Caterina, 17190 Gerona, Spain.
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.
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BibTeX
@article{torre2026case,
title = {{Case Report A Rare Cause of Cardiofaciocutaneous Syndrome-KRAS p.Pro34arg: Clinical Delineation, Diagnostic Challenges, and Implications for RASopathy Classification.}},
author = {Francisco J Mérida De Ia Torre and Mónica Coll Vidal and Ivette Rubio Martínez and Lucía Quintana Tello and Ramón Brugada Terradellas},
journal = {Reports (MDPI)},
year = {2026},
month = oct,
doi = {10.3390/reports9040335},
url = {https://europepmc.org/article/MED/42924787},
note = {CC BY},
}
RIS
TY - JOUR
TI - Case Report A Rare Cause of Cardiofaciocutaneous Syndrome-KRAS p.Pro34arg: Clinical Delineation, Diagnostic Challenges, and Implications for RASopathy Classification.
AU - Francisco J Mérida De Ia Torre
AU - Mónica Coll Vidal
AU - Ivette Rubio Martínez
AU - Lucía Quintana Tello
AU - Ramón Brugada Terradellas
PY - 2026
DA - 2026/10/05
JO - Reports (MDPI)
DO - 10.3390/reports9040335
UR - https://europepmc.org/article/MED/42924787
AB - 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.
SN - 2571-841X
ER -