title: A severe form of Noonan syndrome and autosomal dominant café-au-lait spots - evidence for different genetic origins.
abstract: OBJECTIVE
  The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype-phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed.
  
  
  METHODS
  Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing.
  
  
  RESULTS
  A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes.
  
  
  CONCLUSIONS
  We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Anna-Maja
authors.initials: AM
authors.lastname: Nyström
authors.forename: Sara
authors.initials: S
authors.lastname: Ekvall
authors.forename: Bo
authors.initials: B
authors.lastname: Strömberg
authors.forename: Gerd
authors.initials: G
authors.lastname: Holmström
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bondeson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D019080:Cafe-au-Lait Spots / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D016514:Genes, Neurofibromatosis 1; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C500760:SPRED2 protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11