HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

  title={HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation},
  author={Karen W. Gripp and Angela E. Lin and Deborah L. Stabley and Linda Nicholson and Charles I. Scott and Daniel A Doyle and Yoko Aoki and Yoichi Matsubara and Elaine H. Zackai and Pablo Lapunzina and Antonio G{\'o}nzalez-Meneses and Jennifer Holbrook and Cynthia A. Agresta and Iris L. Gonzalez and Katia Sol‐Church},
  journal={American Journal of Medical Genetics Part A},
Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed… 
Costello syndrome associated with novel germline HRAS mutations: An attenuated phenotype?
The medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients were reviewed, and a statistically significantly increased frequency of pyloric stenosis was found compared to the general population frequency.
Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases
These results confirm that mutation testing for HRAS is a reliable diagnostic test for Costello syndrome, and confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS.
Costello syndrome and related disorders
Costello syndrome is caused by heterozygous de-novo point mutations in HRAS, resulting in increased activation of the mitogen-activated protein kinase pathway, which is responsible for Noonan syndrome and the KRAS mutation phenotype.
Somatic mosaicism for an HRAS mutation causes Costello syndrome
This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.
Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome
A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.
Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene
It is emphasized that a subset of patients with Costello syndrome could harbor mutations in other genes involved in the RAS-MAPK signaling, such that all these syndromes constitute a class of disorders caused by deregulated RAS, MAPK signaling.
Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome
The characteristics of these 5 Korean patients with CS are summarized and, along with previous studies, provides clues for genotype-phenotype correlation in patients withCS.
Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C
Novel ectodermal findings in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, suggest a cell type specific effect of this particular mutation.
Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp
The phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, are described, and five previously described cases are reviewed.
Severe neonatal manifestations of Costello syndrome
The diagnosis of Costello syndrome may be difficult in the newborn period, and should be considered in the differential diagnosis of the sick newborn infant with multisystem disease.


Is the locus for Costello syndrome on 11p?
It is suggested that the predisposition to malignancy occurs when a second mutation in the tumour suppressor gene occurs, and demonstration of loss of heterozygosity (LOH) is a proven technique for localisation of tumours suppressor genes.
Further delineation of cardiac abnormalities in Costello syndrome.
All patients with Costello syndrome need a baseline cardiology evaluation with echocardiography and Holter monitoring, and additional prospective evaluations, even in patients without apparent cardiac abnormalities, would be prudent, although data are insufficient to propose a specific schedule.
Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis
It is concluded that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.
The adult phenotype in Costello syndrome
It is recommended that neuro‐imaging be considered in adults with Costello syndrome if they develop symptoms suggestive of a Chiari malformation, and endocrine investigations are indicated and hormone treatment may be required in the event of pubertal delay.
Germline mutations in HRAS proto-oncogene cause Costello syndrome
Four heterozygous de novo mutations of HRAS are identified in 12 of 13 affected individuals, suggesting that germline mutations in HRAS perturb human development and increase susceptibility to tumors.
Tumor predisposition in Costello syndrome
  • K. Gripp
  • Medicine
    American journal of medical genetics. Part C, Seminars in medical genetics
  • 2005
The urine assay for catecholamines is unhelpful as a screening test for neuroblastoma and should not be used in this population of patients with CS, it has since become apparent.
Elevated catecholamine metabolites in patients with Costello syndrome
It appears that in this patient group an elevation above the normal limit is more likely to be a variant, rather than a sign of a neuroblastoma, so it may be prudent not to use this assay as a screening test, and to take the frequently elevated results into consideration when interpreting diagnostic assays.
Genetics of the Costello syndrome.
  • I. Lurie
  • Medicine, Psychology
    American journal of medical genetics
  • 1994
Review of 20 families demonstrated that the 37 sibs of the probands were all normal, and a significant increase of mean paternal age and paternal-maternal age difference suggests sporadic autosomal dominant mutations as a likely cause.
Exclusive paternal origin of new mutations in Apert syndrome
Using a novel application of the amplification refractory mutation system (ARMS), the parental origin of the new mutation in 57 Apert families is determined: in every case, the mutation arose from the father.