Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

Abstract

Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

“…Phenotypic features of Costello syndrome include polyhydramnios, increased birth weight, feeding problems, failure to thrive, short stature, developmental delay, pleasant personality, characteristic facial appearance, soft skin, papillomata, spatulate fingerpads, deep palmar creases, joint and skin laxity, kyphoscoliosis, pectus, and splayed fingers with ulnar deviation. Since the discovery that HRAS gene mutations cause Costello syndrome [Aoki et al, 2005], at least 150 genotyped patients have been studied [reviews by Estep et al, 2006;Gripp et al, 2006;Kerr et al, 2006;Zampino et al, 2007]. Consensus expert opinion recommends that Costello syndrome be defined solely by HRAS mutations , which differs from the molecular heterogeneity of CFC syndrome and Noonan syndrome.…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…Of two CS patients with a p.K117R mutation, one patient had an atypical phenotype such as microretrognatism and slightly less-pronounced plantar and palmar creases. 7 The other patient had mild craniofacial manifestations of CS. 13 One patient with the p.A146V mutation showed a mildly coarse face and did not have deep palmar creases.…”

“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

“…Previous studies have also suggested that CS patients with the p.G12A mutation may have an increased risk of malignancy, compared with patients with p.G12S. 7 Patients with the p.G12C mutation had a more severe CS phenotype; these individuals developed severe hypertrophic cardiomyopathy and died in the neonatal period. Patients with p.K117R or p.A146V had a milder and more unusual CS phenotype, compared with patients with mutations in codon 12 or 13.…”

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”