Abnormal growth in Noonan syndrome: correlation between growth parameters and genotype

Background: Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, dysmorphic features, congenital heart defects and other anomalies. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS are detected in 60-75% of cases. Objective and hypotheses: The aim of this study was to find out a possible correlation between the linear growth, the GH secretion and the genotype in NS patients. Methods: A cohort of 34 patients affected by NS diagnosed by Van der Burgt criteria was studied: 13 had a PTPN11 mutation, 9 SOS1 (in one case associated with RAF1) and 12 were mutation negative. All of these patients underwent a clinical and auxological evaluation, GH secretion was evaluated in 29 patients. Results: Short stature was detected in 9/13 (69%) PTPN11+ patients, in 8/12 (67%) mutation negative and only in 2/9 (22%) of SOS1+ patients. The average H-SD was significantly higher in the SOS1+ group compared to PTPN11+ and to mutation negative groups, while no significant difference was found between the latter two groups. The average H-DS of PTPN11+ and of mutation negative groups was significantly lower (p<0,002) than their respective target height (TH) (-1,9±0,88 vs 0,43±1,26 and -2,18±1,4 vs -0,33±1,2, respectively) while it was close to TH in SOS1+ group (-0,63±0,49 vs -0,53±0,37). GH deficiency (GHD) was diagnosed in 4/9 (44%) PTPN11+, 2/8 (25%) SOS1+ and in 3/12 (25%) mutation negative. The final height reached from 5 patients SOS1+ was normal, while it was low in 2 cases PTPN11+. Conclusions: In this study short stature was more frequently seen in PTPN11+ and mutation negative patients than in those SOS1+. Short stature was rarely observed in SOS1+ patients, and when present, it was secondary to GHD. The SOS1+ patients reached a normal final height, suggesting that this mutation seems to preserve the linear growth in patients with NS.