Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C

Abstract

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 cohortcomparison 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.

Assessing genotype–phenotype correlation in Costello syndrome using a severity score

“…The differing results of comparisons between those with p.G13C and p.G12S in these two studies may be due to the larger number of individuals studied in Gripp et al; 13 not all of these individuals were included in the current study. Furthermore, Gripp et al 13 focused solely on the phenotypic description of individuals with p.G13C and did not use a standardized approach as applied here.…”

“…By contrast, a cohort of 12 individuals with the p.G13C HRAS mutation was recently characterized and Original research article compared with individuals with the p.G12S HRAS mutation. 13 In that study, those with p.G13C had significantly lower rates of neurological abnormalities requiring surgery, lack of multifocal atrial tachycardia and papillomata, and a higher likelihood of dolichocilia, or extremely long eyelashes requiring trimming.…”

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…In this study 11 and others conducted by colleagues, we have avoided duplicated reporting of this rare syndrome. 21 Recently, 12 individuals with p.Gly13Cys change were identified, 8 making this the most common amino acid change affecting the glycine in Position 13. Other mutations ( A suspected clinical diagnosis of Costello syndrome is confirmed through the identification of a specific germline mutation in the proto-oncogene HRAS, which is the only gene associated with Costello syndrome according to a review by expert clinicians.…”

“…24 Distinctive phenotypic findings are associated with the p.Gly13Cys change and include dolichocilia (extremely long eye lashes, often requiring trimming) and loose anagen hair. 8 Papillomata or multifocal atrial tachycardia have not yet been seen in individuals with p.Gly13Cys, and fewer have short stature. Compared with individuals with the most common p.Gly12Ser, these differences are statistically significant.…”

“…In addition, no individual with p.Gly13Cys has developed a malignant tumor. 8 The two individuals reported with p.Glu37dup share phenotypic findings including very sparse hair and facial features that appear less coarse than in most other Costello syndrome individuals, but a detailed clinical description was not provided. 25 Of 146 patients with HRAS mutations whose cardiovascular status was reviewed, there was no apparent correlation between the specific mutation and the variables studied (HCM, multifocal tachycardia, and aortic dilation; Table 5 in Lin et al 42 ).…”