Diverse Clinical Manifestations of Cardiofaciocutaneous Syndrome Type 3 in Two Patients from South East Asia

Abstract

Background: Cardiofaciocutaneous syndrome (CFCS) is a rare genetic condition caused by mutations in BRAF, KRAS, MAP2K1, or MAP2K2. It is characterized by ectodermal abnormalities, cardiac defects, intellectual disability, and distinct craniofacial features. CFCS falls under a group of conditions caused by mutations in the RAS/MAPK pathway called RASopathies which share many features. In particular, CFCS has significant phenotypic overlaps with Costello syndrome (CS) and Noonan syndrome (NS).

Objective: The aim of this study was to assess the patients‧ phenotypic features for syndromic disorders and evaluate the use of molecular testing to clarify the clinical diagnosis.

Method: The patients were recruited for genetic testing with written informed consent. Genomic DNA from venous blood was sequenced and potential variants were identified via targeted next-generation sequencing. Their phenotypic features were compared with other CFCS cases carrying pathogenic variants in the same gene.

Results and discussion: One patient had a de novo variant (c.370C>T; p.P124S) in MAP2K1 and presented with mild and typical features which do not significantly affect her quality of life. The second patient presented with severe features, including failure to thrive, feeding difficulties, epileptic spasms, septal hypertrophy, and global developmental delay, and developed chronic lung disease and sequelae from multiple infections. She had a severe disease course and severe global developmental delay. The discovery of a de novo variant (c.371C>A; p.P124Q) in MAP2K1, which had been reported in another patient with a similar phenotype, clarifies her clinical diagnosis. Her presentations add to existing reports that support expanding the CFCS phenotype to include features previously thought to be more suggestive of CS.

Conclusion: The genetic findings for the 2 patients affirm the use of identified gene mutations to confirm the clinical diagnosis of syndromic disorders and add to the phenotypic spectrum of CFCS.

Keywords: Cardiofaciocutaneous syndrome; Clinical heterogeneity; Costello syndrome; Dysmorphic features; MAP2K1.

Fig. 1

Growth charts for Patient 1 (LL) and Patient 2 (NA). The weight of Patient 1 has stayed between the 3rd and 25th percentile, while her height has stayed between the 3rd to 10th percentile since diagnosis at our genetics clinic. The height and weight of Patient 2 have consistently been below the 3rd percentile since birth. Between the ages of 3−5 years, feeding was increased to improve caloric intake and fast weight gain was noted; however, increased feeds affected her breathing and feeding was reduced, resulting in a weight reduction back below the 3rd percentile at 4 years 9 months.

Fig. 2

Images of craniofacial profiles and extremities of Patient 2. a Frontal view of the face. b Lateral view of the face. c Deep palmar creases on the right hand. d Bilateral overlapping 1st and 5th toes.