Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C
- Autori: Gripp, K.; Hopkins, E.; Sol Church, K.; Stabley, D.; Axelrad, M.; Doyle, D.; Dobyns, W.; Hudson, C.; Johnson, J.; Tenconi, R.; Graham, G.; Sousa, A.; Heller, R.; Piccione, M.; Corsello, G.; Herman, G.; Tartaglia, M.; Lin, A.
- Anno di pubblicazione: 2011
- Tipologia: Articolo in rivista (Articolo in rivista)
- Parole Chiave: Costello syndrome; genotype–phenotype correlation; loose anagen hair; rasopathy.
- OA Link: http://hdl.handle.net/10447/55358
Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings