Linear growth according to the genotype of patients with Noonan syndrome

Introduction: Noonan syndrome (NS) is a heterogeneous syndrome which is frequently associated with short stature. In addition to the PTPN11 and KRAS mutations, other 2 mutated genes SOS1 and RAF1 belonging to the conserved Ras-MAPK signaling pathway have been identified two years ago. The causative influences of these gene mutations on the linear growth are not currently well known. The aim of this study was to investigate the linear growth of NS according to their molecular characterization. Methods and Results: The cohort of this study included 34 subjects (17F, 17M), age range:3 days - 30 years, 13 (38%) carrying a PTPN11 mutation (11 probands and 2 affected mothers), 9 (26%) cases with a SOS1 mutation (2 sporadic and 2 familial with 5 affected members in their pedigree), 1 of these patients carried also a RAF1 mutation, and the remaining 12 (35%) subjects negative for gene mutations. The diagnosis of NS was proposed according to the clinical criteria defined by van der Burgt. Short stature with the height < 3rd percentile was detected in 8 (61%) out of 13 cases carrying the PTPN11 mutations. The mean H-SDS was lower than target height (TH) (-1,9±0,88 vs 0,43±1,26; p=0,0012). A growth hormone deficiency (GHD) was found in 2 probands and in one mother PTPN11 mutation-positive. The height of all 9 the cases carrying a SOS1 mutation, one of these carrying also a RAF1 mutation, was > 3rd percentile. The mean H-SDS was close to the TH (-0,63±0,49 vs -0,53±0,37; p=ns). The affected mother of 1 proband had manifested a transient GHD secondary to the pubertal delay. Short stature with the height < 3rd percentile was detected in 6 (50%) out of the 12 cases mutation-negative, 2 of them showed a GHD. The H-SDS was lower than TH (-2,18±1,4 vs -0,33±1,2; p=0,0021). The H-SDS of patients with SOS1 mutations was significantly higher than that of subjects with PTPN11 mutations or mutation-negative (p=0,0005 and p=0,0051, respectively). No significant differences were found between H-SDS of PTPN11 and mutation-negative patients. Conclusions. In this cohort of NS patients a high frequency of short stature with or without GHD has been detected in PTPN11 positive and in mutationnegative subjects. In contrast, normal stature has been detected in all SOS1 cases and in the child carrying a double heterozygosis for SOS1 and RAF1 mutation. Therefore, these last 2 mutations do not seem to be associated with short stature in NS.