title: Mutation in NRAS in familial Noonan syndrome--case report and review of the literature.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. sara.ekvall@igp.uu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Ekvall
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. maria.wilbe@igp.uu.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Wilbe
authors.affiliation: Department of Paediatrics, the Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. jovanna.dahlgren@gu.se.
authors.forename: Jovanna
authors.initials: J
authors.lastname: Dahlgren
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium. Eric.Legius@uzleuven.be.
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. A.van_Haeringen@lumc.nl.
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.affiliation: Department of Paediatrics, the Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. otto.westphal@gu.se.
authors.forename: Otto
authors.initials: O
authors.lastname: Westphal
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. goran.anneren@igp.uu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. marielouise.bondeson@igp.uu.se.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bondeson
mesh_terms: D000328:Adult; D019080:Cafe-au-Lait Spots / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D011905:Genes, ras; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007911:Lentigo; D054429:Leukemia, Myelomonocytic, Juvenile / Q000453:epidemiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human