Genotypic and phenotypic characterization of Noonan syndrome: New data and review of the literature

Marjolijn Jongmans, Erik A. Sistermans, Alwin Rikken, Willy M. Nillesen, Rienk Tamminga, Michael Patton, Esther M. Maier, Marco Tartaglia, Kees Noordam, Ineke Van Der Burgt

Research output: Contribution to journalArticlepeer-review


Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, minor facial anomalies, and congenital heart defects. In approximately 50% of cases the condition is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the protein SHP-2. In this study, PTPN11 mutation analysis was performed in 170 NS patients. In 76 (45%) of them a mutation was identified. We report on the distribution of these mutations, as well as on genotype-phenotype relationships. The benefit of the NS scoring system developed by van der Burgt et al. [(1994); Am J Med Genet 53:187-191] is shown, among physicians who consequently based their diagnosis on the NS scoring system the percentage mutation positive subjects was 54%, whereas this percentage was only 39% among physicians who made less use of the scoring system. In two patients with some uncommon manifestations mutations were found in the C-SH2 domain, a region in which defects are not often identified in NS. A trend was observed in patients carrying the 922A → G change (Asn308Asp) receiving normal education. In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C → T (Thr73Ile) was found. This confirms previous findings indicating that individuals with NS with specific mutations in PTPN11 are at risk of developing JMML.

Original languageEnglish
Pages (from-to)165-170
Number of pages6
JournalAmerican Journal of Medical Genetics
Volume134 A
Issue number2
Publication statusPublished - Apr 15 2005


  • C-SH2 domain
  • Juvenile myelomonocytic leukemia (JMML)
  • Noonan syndrome
  • PTPN11

ASJC Scopus subject areas

  • Genetics(clinical)


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