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

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.

Fibrous dysplasia in cardio-facio-cutaneous syndrome: A case report and review of literature.

Cardio-facio-cutaneous (CFC) syndrome (OMIM #:115150, 615278, 615279, 615280) is a rare genetic condition caused by variants in the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Up to 75% of cases are caused by mutations in the BRAF gene, whereas KRAS gene mutation has only been reported in <2% of cases. CFC syndrome is characterized by cardiac abnormalities, distinctive craniofacial dysmorphism, and various cutaneous abnormalities. Musculoskeletal and orthopedic manifestations are also prevalent in patients with CFC syndrome, among which the most common are skeletal deformities and joint laxities. Dysplastic bone disorders, on the other hand, have not been reported in CFC syndrome before. We report on a case of symmetrical polyostotic fibrous dysplasia (FD) in a patient with CFC syndrome with the KRAS(NM_004985.5):c.57G>C; p.Leu19Phe variant. The FDs were incidentally picked up, and patient was conservatively managed and remained asymptomatic on follow-up. The same variant was reported previously in a patient with Oculoectodermal Syndrome (OES), who developed polyostotic non-ossifying fibroma (NOF). This case explores FD as a possible new clinical feature of CFC syndrome, and when linked to the historical case of OES, explores whether the KRAS(NM_004985.5):c.57G>C; p.Leu19Phe mutation may potentially contribute to the development of dysplastic bone lesions in patients with this particular mutation.

Trajectories of Systolic Blood Pressure in Children: Risk Factors and Cardiometabolic Correlates.

OBJECTIVE: To identify systolic blood pressure (SBP) percentile trajectories in children and to describe the early-life risk factors and cardiometabolic correlates of those trajectories. STUDY DESIGN: Using age-, sex-, and height-specific SBP percentiles based on the American Academy of Pediatrics reference, we examined SBP trajectories using latent class mixed models from ages 3 to 8 years (n = 844) from the Growing Up in Singapore Towards healthy Outcomes-study, a Singaporean mother-offspring cohort study. We analyzed associations between SBP trajectories and early-life risk factors using multinomial logistic regression and differences across trajectories in cardiometabolic outcomes using multiple linear regression. RESULTS: Children were classified into 1 of 4 SBP percentile trajectories: "low increasing" (15%), "high stable" (47%), "high decreasing" (20%), and "low stable" (18%). Maternal hypertension during early pregnancy was a predictor of the "high stable" and "low increasing" SBP trajectories. Rapid child weight gain in the first 2 years of life was only associated with the "high stable" trajectory. Compared with children in the "low stable" trajectory, children in the "high stable" SBP trajectory had greater body mass index z scores, sum of skinfold thicknesses, waist circumference from ages 3 to 8 years, and abdominal adipose tissue (milliliters) at 4.5 years (adjusted mean difference [95% CI]: superficial and deep subcutaneous abdominal adipose tissue: 115.2 [48.1-182.3] and 85.5 [35.2-135.8]). Their fat mass (kilograms) (1.3 [0.6-2.0]), triglyceride levels (mmol/L) (0.10 [0.02-0.18]), and homeostasis model assessment of insulin resistance (0.28 [0.11 0.46]) at age 6 years were also greater but not their arterial thickness and stiffness. CONCLUSIONS: Reducing maternal blood pressure during pregnancy and infant weight gain in the first 2 years of life might help to prevent the development of high SBP.

Maternal Glycemia During Pregnancy and Child Carotid Intima Media Thickness, Pulse Wave Velocity, and Augmentation Index.

BACKGROUND: In women without diabetes, little is known about the consequences of hyperglycemia during pregnancy for the offspring's cardiovascular structure and function. OBJECTIVE: To investigate the association of maternal glycemia during pregnancy with cardiovascular risk markers in their children in GUSTO, a Singaporean birth cohort study. METHODS: Around 26 weeks' gestation, a 75 g oral glucose tolerance test was performed and fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPPG) concentrations were measured. Gestational diabetes mellitus (GDM) was defined using WHO 1999 diagnostic criteria. At 6 years of age, we measured the child's carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), and blood pressure (BP). Association of maternal glycemia during pregnancy with cardiovascular risk markers in their children were analyzed using multiple linear and logistic regressions. RESULTS: Analysis were performed on 479 mother-child dyads. Higher maternal FPG was associated with higher cIMT and, in males, with a higher cfPWV in the offspring (adjusted ß [CI 95%], cIMT: 0.08 per 10mm increase [0.02; 0.15], cfPWV: 0.36 m/s [0.01; 0.70]). Higher 2-hour PPPG was associated with higher cfPWV and AIx. Gestational diabetes mellitus was associated with higher AIx. No association was found between maternal glycemia and their offspring blood pressure. CONCLUSIONS: among mothers without pre-existing diabetes, higher glycemia during pregnancy was associated with mild structural and functional vascular changes in their children at 6 years of age across a continuum. These results support the necessity to monitor maternal glycemia during pregnancy even in the absence of pre-existing diabetes or diagnosed GDM.