Exploring the clinical complexity of cardio-facio-cutaneous syndrome: insights from a pediatric case series

Abstract

Background: Cardio-Facio-Cutaneous syndrome (CFCS) is a rare autosomal dominant genetic disorder primarily caused by BRAF gene mutations, posing diagnostic challenges due to its multifaceted clinical presentation.

Objective: To elucidate the clinical characteristics of pediatric CFCS patients, expanding the phenotypic spectrum to enhance early diagnostic capabilities, while also presenting the relationship between genotye and corresponding phenotype severity.

Methods: From January 2015 to March 2022, four children diagnosed with CFCS in Children's Hospital of Chongqing Medical University were included for analysis. Whole exome sequencing (WES) was conducted to identify the types and locations of possible gene mutations. Neurological development was assessed using electroencephalography (EEG), magnetic resonance imaging (MRI) and Gesell developmental evaluation.

Results: All four CFCS patients exhibited de novo BRAF gene mutations, manifesting with cardiac malformations, distinctive facial features, skin and hair changes, and neurological abnormalities. WES revealed that the specific BRAF mutations were closely linked to their clinical severity. Three patients displayed milder symptoms (case 1-3, genotype I or II), demonstrating stability or slight improvement, whereas one patient (case 4, genotype III) suffered from a severe phenotype characterized by profound neurological and digestive system impairments, leading to a significantly reduced quality of life and a grim prognosis.

Conclusion: In CFCS patients, severe developmental delay and seizures are predominant neurological features, possibly accompanied by continuous spike-and-wave during sleep (CSWS) and severe sleep disturbances. CFCS generally carries a poor prognosis, underscoring the importance of disease awareness and early genetic testing.

Keywords: BRAF gene; RASopathies; cardio-facio-cutaneous syndrome; developmental delay; seizures.

Figure 1

Domain organization of BRAF in CFCS. The top row depicts the positions of the 18 exons of the BRAF gene, the second row shows the corresponding amino acid numbers, and the third row presents the key structural domains of BRAF. The N-terminal CR1 domain contains the region mediating binding with activated RAS (RAS-binding domain, RBD) and the cysteine-rich domain (CRD), which serves a regulatory function. The C-terminal CR3 region encompasses the catalytic site and Ser 729, which serves as a binding site for 14-3-3 proteins when phosphorylated. The CR2 region contains a second 14-3-3 binding site (Ser 365), which plays a critical role in regulating the switch between the catalytically inactive and active conformations. CFCS, cardio-facio-cutaneous syndrome; RBD, RAS-binding domain; CRD, cysteine-rich domain; CR1, cysteine-rich 1; CR2, cysteine-rich 2; CR3, cysteine-rich 3.

Figure 2

Gene mutation-RAS pathway abnormality-clinical syndrome relationship. The first column lists the gene names causing RAS pathway abnormalities, the middle column represents RAS pathway abnormalities, and the last column lists the clinical syndromes associated with RAS pathway abnormalities. CFCS, cardio-facio-cutaneous syndrome; NS, noonan syndrome; NSML, noonan syndrome with multiple lentigines; NF1, neurofibromatosis type I; CS, costello syndrome; LS, legius syndrome; CM-AVM, capillary malformation–arteriovenous malformation syndrome.