LS may be sporadic or inherited as an autosomal dominant fully penetrant trait. In approximately 85% of the patients with a definite diagnosis of LS, a missense mutation is found in the
PTPN11 gene, located on chromosome 12q24.1 [
9,
19]. The
PTPN11 gene encodes for the SRC homology 2 (SH2) domain-containing PTPase (SHP2) protein, characterised by two tandemly arranged SH2 (N-SH2 and C-SH2) domains and one protein tyrosine phosphatase (PTP) domain. SHP2 functions as a cytoplasmic signalling transducer downstream of multiple receptors for growth factors, cytokines and hormones, with a particular role through the RAS-mitogen activated protein kinase (MAPK) pathway [
20,
21]. To the best of our knowledge, 11 different missense
PTPN11 mutations, in exon 7, 12 and 13 (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Gly), have been reported so far, two of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases [[
9,
10,
22‐
29], personal data]. Germinal mutations in the
PTPN11 gene are also responsible for about 40–50% of Noonan (NS) and Noonan-like/Multiple Giant Cell lesions syndrome cases [
30,
31]. Known changes appear to be exclusive for NS or LS, leading to specific genotype-phenotype correlations between these two disorders [
23,
31]. Among patients with
PTPN11 mutations, an association between exon 7 and 12 mutations and HCM, and between exon 8 mutations and PVS, has been established [
23]. LS patients without
PTPN11 mutations show a higher prevalence of ECG abnormalities and left ventricle hypertrophy [
8]. Analyses of the natural history of HCM in LS patients with different genotypes indicate that patients without
PTPN11 mutations show a higher frequency of family history of sudden death, increased left atrial dimensions, bradyarrhythmias and other adverse arrhythmic and nonarrhythmic events [
12]. Mutations affecting exon 13 in the
PTPN11 gene are often associated with an important cardiac phenotype, characterised by rapidly progressive severe biventricular obstructive HCM, often with prenatal onset, and with serious cardiac complications during follow-up (heart failure, septal myectomy, and sudden death) [
12,
28,
32]. Analysis of personal cohorts of LS patients indicate that mutation of the Thr468 residue is less frequently associated with short stature, compared to mutation of the Tyr279 residue (26%
vs. 47%), in which also deafness is more common (24%
vs. 9%) [personal data]. This data confirm a previous observation of less adverse effects of the Thr468Met mutation on body growth and cardiac development, with lower prevalence of PVS in these patients [
33].
Genetic heterogeneity was supported by linkage analysis [
36], and recently confirmed by the identification of
RAF1 gene mutations in two out of six
PTPN11 mutation negative LS patients [
37]. RAF1 protein is one of the three mammalian RAF isoforms (ARAF, BRAF and CRAF or RAF1), threonine-serine protein kinases with nonredundant developmental functions, acting downstream of RAS [
38].
RAF1 gene mutations are also responsible for a subset of NS, 75% of which develop HCM [
37,
39]. The two LS subjects carrying the Leu613Val and Ser257Leu changes disclosed a full blown LS phenotype, with multiple lentigines, CLS, HCM and delayed puberty [
37]. Pandit
et al. investigated the functional effect of different RAF1 mutants, including the Leu613Val change, and showed that those associated with HCM had increased kinase activity and enhanced ERK activation [
37]. These data reinforce the role of increased RAS signalling in cardiomyocyte hypertrophy pathogenesis and suggest that LS pathogenesis should not be simply related to a reduced RAS signal transduction [
37,
40].