Subscribe to RSS
Co-occurrence of Noonan and Cardiofaciocutaneous Syndrome Features in a Patient with KRAS VariantFunding This work was supported by Fondecyt Grant 1140450 to F.R.
15 January 2018
09 April 2018
16 May 2018 (online)
We report the case of a 3-year-old girl, who is the third child of nonconsanguineous parents, with short stature, hypertrophic cardiomyopathy, and mild dysmorphic features; all suggestive of Noonan syndrome. In addition, the patient presents with feeding difficulties, deep palmar and plantar creases, sparse hair, and delayed psychomotor and language development, all characteristics frequently observed in cardiofaciocutaneous syndrome. Molecular analysis of the Ras/ MAPK pathway genes using high-resolution melting curve analysis and gene sequencing revealed a de novo KRAS amino acid substitution of leucine to tryptophan at codon 53 (p.L53W). This substitution was recently described in an Iranian patient with Noonan syndrome. The findings described in this report expand the phenotypic heterogeneity observed in RASopathy patients harboring a KRAS substitution, and advocate for the inclusion of genes with low mutational frequency in genetic screening protocols for Noonan syndrome and other RASopathies.
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
- 1 Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 2009; 19 (03) 230-236
- 2 Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet 2013; 14: 355-369
- 3 Romano AA, Allanson JE, Dahlgren J. , et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010; 126 (04) 746-759
- 4 Aoki Y, Niihori T, Inoue S, Matsubara Y. Recent advances in RASopathies. J Hum Genet 2016; 61 (01) 33-39
- 5 Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science 2001; 294 (5545): 1299-1304
- 6 Brasil AS, Malaquias AC, Kim CA. , et al. KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis. Am J Med Genet A 2012; 158A (05) 1178-1184
- 7 Tafazoli A, Eshraghi P, Pantaleoni F. , et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci 2018; 63 (01) 87-93
- 8 Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10 (06) 845-858
- 9 Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010; 66 (Pt 4): 486-501
- 10 Adzhubei IA, Schmidt S, Peshkin L. , et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
- 11 Carta C, Pantaleoni F, Bocchinfuso G. , et al. Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet 2006; 79 (01) 129-135
- 12 Zenker M, Lehmann K, Schulz AL. , et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 2007; 44 (02) 131-135
- 13 Razzaque MA, Komoike Y, Nishizawa T. , et al. Characterization of a novel KRAS mutation identified in Noonan syndrome. Am J Med Genet A 2012; 158A (03) 524-532
- 14 Cavé H, Caye A, Ghedira N. , et al. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. Eur J Hum Genet 2016; 24 (08) 1124-1131
- 15 Richards S, Aziz N, Bale S. , et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
- 16 Runtuwene V, van Eekelen M, Overvoorde J. , et al. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. Dis Model Mech 2011; 4 (03) 393-399