Search

BackgroundAbnormal hair growth is a defining feature of RASopathies, syndromes caused by germline mutations in the RAS pathway. However, detailed hair manifestations and the mechanisms of altered hair growth in RASopathies are poorly delineated.ObjectivesTo identify distinguishing clinical features and investigate how the RAS pathway influences hair growth by performing a systematic and detailed side-by-side comparison of hair manifestations in cardio-facio-cutaneous syndrome (CFCS) and Costello syndrome (CS), two RASopathies caused by mutations in the downstream and upstream elements of the RAS pathway, respectively.MethodsSixteen individuals with CFCS and 23 individuals with CS were enrolled. Mutation data were recorded. Scalp hair, eyebrows and eyelashes of individuals with CFCS or CS were examined for texture, colour, density and morphology. Scalp hairs were examined by light microscopy.ResultsWhile both syndromes displayed abnormal hair, striking differences were observed, including darker and thicker scalp hair and sparse eyebrows and eyelashes in CFCS. By contrast, synophrys, trichomegaly and abnormalities of the scalp hair shafts were observed in CS. Possible correlation with straight hair and genotype was observed in CS.ConclusionThe results emphasize the role of the RAS pathway in hair growth, improve accuracy of clinical diagnosis of CFCS and CS and provide a foundation for identification of therapeutic targets.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.

Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated.