ESPE Abstracts

Background: Noonan syndrome is autosomal dominantly inherited disease with an incidence of 1:1000 to 1:2500 newborns. It is caused by different gene mutations involved in the RAS/MAP kinase signaling pathway in the cells. Phenotype including expression of dysmorphic features and visceral organ affection is variable. Different gene mutations are found in approximately 60–70% of tested patients.

Objective and hypotheses: To report mutational analysis in 10 patients with clinical phenotype concordant with the Noonan syndrome.

Method: Clinical diagnosis was based upon the presence of majority of minor and/or major abnormalities characteristic for Noonan syndrome. All recommended analyses such as biochemical blood tests, ultrasound of heart and kidney, and evaluation of the growth were performed. Molecular analysis was performed by the NGS method including genes: NRAS, ROT1, SCHOC2, HRAS, CBL, KRAS, PTPN11, SPRED1, MAP2K1, NF1 and MAP2K2.

Results: Six patients (60%) had a relevant mutation: four patients had PTPN11 mutation (40%o), one had RAF1 and one had KRAS mutation. No mutation was detected in four patients(40%) two of whom had most of the characteristics of Noonan syndrome. Search for mutations of some other or regulatory gene mutation in this family is warranted. Patient with the RAF1 mutation had severe myocardiopathy as previously described, however similar finding appeared in a child with PTPN11. Three children had pulmonary stenosis that was treated surgically in three children. Short stature was detected in 4 (40%) children, three carrying heterozygous mutation in PTPN11 gene and treated with growth hormone with a modest response. One short child had a rare KRAS mutation accompanied with a significant developmental delay.

Conclusion:: This is the first report of the genetics of Noonan syndrome in a country from Balkan region. Clinical recognition of the syndrome was successful. Two rare mutations detected in a small number of patients require further genetic analysis in this region.