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.
"It typically encompasses severe failure to thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, a predisposition to papillomata and malignant tumors, and neurologic abnormalities including Chiari 1 malformation and tethered cord, nystagmus, hypotonia and intellectual disability [Gripp and Lin, 2006, 2012]. Most patients have an HRAS mutation affecting the glycine residue in position 12 [Gripp et al., 2006; Kerr et al., 2006], and the glycine in position 13 is the second most commonly altered amino acid [Gripp et al., 2011a]. Specific amino acid substitutions, particularly those strongly inducing oncogenic cell transformation, may result in an early lethal phenotype [Lo et al., 2008]. "
"Rarer HRAS germline changes, including p.G12C, may be associated with a more severe phenotype [van der Burgt et al., 2007; Lo et al., 2008]; whereas others, such as p.G13C, may result in a milder phenotype [Gripp et al., 2008, 2011]. Because the growth parameters of individuals with HRAS p.G13C may be closer to the range for typical individuals than those of patients with p.G12S [Gripp et al., 2011], it is important to note that data from Costello syndrome patients with rare mutations are included in our analysis (Table I). Limitations of our study are largely due to the small number of patients with Costello syndrome, and are compounded by the lack of reliable growth data as exemplified by our inability to generate OFC centiles past age 36 months. "
"Common clinical features include prenatal overgrowth and polyhydramnios, severe postnatal failure to thrive, short stature, developmental delay, congenital heart disease, and cardiomyopathy [Kerr, 2009]. Whilst CS often has a relatively homogenous phenotype, both milder and more severe phenotypes are now recognized, which often arise due to less common mutations [Kerr et al., 2006; van der Burgt et al., 2007; Gripp et al., 2011]. "
[Show abstract][Hide abstract] ABSTRACT: De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition.
American Journal of Medical Genetics Part A 05/2012; 158A(5):1102-10. DOI:10.1002/ajmg.a.35296 · 2.16 Impact Factor
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