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Review
. 2015 Oct 14:16:95.
doi: 10.1186/s12881-015-0239-1.

Mutation in NRAS in familial Noonan syndrome--case report and review of the literature

Sara Ekvall  1 , Maria Wilbe  2 , Jovanna Dahlgren  3 , Eric Legius  4 , Arie van Haeringen  5 , Otto Westphal  6 , Göran Annerén  7 , Marie-Louise Bondeson  8
Affiliations
Review

Mutation in NRAS in familial Noonan syndrome--case report and review of the literature

Sara Ekvall et al. BMC Med Genet. .

Abstract

Background: Noonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway.

Case presentation: Here, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS.

Conclusions: We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50% of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

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Figures

Fig. 1
Fig. 1
Photograph of the index patient affected by NS with a mutation in NRAS, p.G60E. a Facial features. b The back with multiple lentigines. c The left arm with multiple lentigines
Fig. 2
Fig. 2
Photograph of the affected father with the same NRAS mutation, p.G60E. a Frontal facial features. b Additional facial features. c The back with multiple lentigines
See this image and copyright information in PMC

References

    1. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333–342. doi: 10.1016/S0140-6736(12)61023-X. - DOI - PMC - PubMed
    1. Tartaglia M, Gelb BD. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann N Y Acad Sci. 2010;1214:99–121. doi: 10.1111/j.1749-6632.2010.05790.x. - DOI - PMC - PubMed
    1. Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–74. doi: 10.1038/ng1926. - DOI - PubMed
    1. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–79. doi: 10.1038/ng1939. - DOI - PubMed
    1. Martinelli S, Checquolo S, Consoli F, Stellacci E, Rossi C, Silvano M, Franciosa G, Flex E, Cossu C, De Luca A, et al. Loss of CBL E3-ligase activity in B-lineage childhood acute lymphoblastic leukaemia. Br J Haematol. 2012;159(1):115–119. doi: 10.1111/j.1365-2141.2012.09245.x. - DOI - PubMed