Coagulation-factor deficiencies and abnormal bleeding in Noonan’s syndrome

Background: Noonan syndrome (NS) is a congenital autosomal disorder, characterized by dysmorphic facies, congenital heart defects, short stature and other anomalies including coagulation abnormalities not fully studied so far. Objective and hypotheses: The aim of this study was to evaluate phenotypic features, gene mutations and coagulation parameters in a cohort of NS patients. Method: We studied 19 NS patients (10 M, 9 F), 12 probands and 7 first degree relatives, we found in 7/19 a mutation of PTPN11, in 8 of SOS1 and in 1 case of SOS1/RAF1, the remaining 3 cases were mutation-negative. Results: A positive history for abnormal bleeding was found in 9 patients (47%), a prolonged PTT in 5 cases (26%), coagulation factors deficiency in 9 patients (47%) and abnormal platelet aggregation in 8 cases (44%); the coagulation anomalies were found both in the 9 patients with a history of abnormal bleeding and in 6 cases (60%) without clinical evidence of bleeding disorders. The coagulation abnormalities were reported both in patients with or without a mutation and were not correlated with a mutation of a specific gene. Important differences in haemostatic status were found between probands and their relatives: the former showed coagulation abnormalities in the majority of the cases while the latter showed a history of bleeding diathesis, but normal laboratory hematological findings. The coagulation abnormalities were more frequent in patients with heart defects; however, a history of bleeding diathesis was detected in patients without cardiopathy. Conclusions: A high frequency of coagulation abnormalities was found in NS. These abnormalities do not seem to be related with the patients’ genotype. The heart defects should not to be the only cause of the haemostatic disorders. The bleeding disorders, as well as the other phenotypic NS features, tend to decrease with age. Our advice is to screen patients with NS for bleeding diathesis to avoid bleedings and post-operative complications.