Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

Bertola, Débora Romeo; Pereira, Alexandre C.; Brasil, Amanda Salem; Albano, Lilian Maria José; Kim, Chong; Krieger, José Eduardo

doi:10.1007/s10038-007-0146-1

Cited by 35 publications

(24 citation statements)

References 23 publications

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“…Our experience is that most patients with an NCFC syndrome, regardless of whether it is NS, CFC or CS, have a CFC index of >12, and usually around 15–17. Similar problems of distinguishing CS from NS and CFC have been reported recently 16 17 20 25 28. Owing to the clinical similarities between NS, CFC and CS, it is often complicated to ascertain the correct diagnosis.…”

Section: Discussionsupporting

confidence: 57%

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

Nyström

Ekvall

Berglund

et al. 2008

Journal of Medical Genetics

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Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

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Section: Discussionsupporting

confidence: 57%

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

Nyström

Ekvall

Berglund

et al. 2008

Journal of Medical Genetics

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“…Although there is significant overlap in their clinical manifestations, each syndrome is characterized by mutations in specific loci. Most CS patients carry mutations in H-RAS (5)(6)(7)(8), although some CS patients sharing features with NS and CFC syndrome have been shown to carry mutations in the k-RAS locus (9)(10)(11)(12). About half of NS patients have mutations in PTPN11 (13).…”

Section: Introductionmentioning

confidence: 99%

A mouse model for Costello syndrome reveals an Ang II–mediated hypertensive condition

Schuhmacher

Guerra²,

Sauzeau³

et al. 2008

J. Clin. Invest.

127

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Germline activation of H-RAS oncogenes is the primary cause of Costello syndrome (CS), a neuro-cardio-faciocutaneous developmental syndrome. Here we describe the generation of a mouse model of CS by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in ES cells. Germline expression of the endogenous H-Ras G12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-Ras G12V mutant mice closely phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. These mice also displayed alterations in the homeostasis of the cardiovascular system, including development of systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys. This phenotype was age dependent and was a consequence of the abnormal upregulation of the renin-Ang II system. Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies.

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“…Furthermore, we collected further published images of patients with confirmed genetic variants in genes of the RAS/MEK signaling pathways as well as in PACS1 (Rauen, 1993, 2006; Bertola et al, 2007; Gripp et al, 2007; Makita et al, 2007; Rauen, 2007; Zampino et al, 2007; Nystrom et al, 2008; Schulz et al, 2008; Tidyman and Rauen, 2008; Cordeddu et al, 2009; Kratz et al, 2009; Zenker, 2009; Allanson et al, 2010; Wright and Kerr, 2010; Kleefstra et al, 2011; Lepri et al, 2011; Siegel et al, 2011; Schuurs-Hoeijmakers et al, 2012; Hopper et al, 2013; Twigg et al, 2013). …”

Section: Methodsmentioning

confidence: 99%

Diagnostically relevant facial gestalt information from ordinary photos

Ferry

Steinberg

Webber

et al. 2014

eLife

145

166

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Craniofacial characteristics are highly informative for clinical geneticists when diagnosing genetic diseases. As a first step towards the high-throughput diagnosis of ultra-rare developmental diseases we introduce an automatic approach that implements recent developments in computer vision. This algorithm extracts phenotypic information from ordinary non-clinical photographs and, using machine learning, models human facial dysmorphisms in a multidimensional 'Clinical Face Phenotype Space'. The space locates patients in the context of known syndromes and thereby facilitates the generation of diagnostic hypotheses. Consequently, the approach will aid clinicians by greatly narrowing (by 27.6-fold) the search space of potential diagnoses for patients with suspected developmental disorders. Furthermore, this Clinical Face Phenotype Space allows the clustering of patients by phenotype even when no known syndrome diagnosis exists, thereby aiding disease identification. We demonstrate that this approach provides a novel method for inferring causative genetic variants from clinical sequencing data through functional genetic pathway comparisons.DOI:http://dx.doi.org/10.7554/eLife.02020.001

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Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

Cited by 35 publications

References 23 publications

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

A mouse model for Costello syndrome reveals an Ang II–mediated hypertensive condition

Diagnostically relevant facial gestalt information from ordinary photos

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