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.