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Mini Review
Horm Res 2009;71:185–193
DOI: 10.1159/000201106
Noonan Syndrome and Related Disorders:
A Review of Clinical Features and Mutations
in Genes of the RAS/MAPK Pathway
Alexander A.L. Jorge Alexsandra C. Malaquias Ivo J.P. Arnhold
Berenice B. Mendonca
Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42,
Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo , Brazil
Introduction
Noonan syndrome (NS; OMIM 163950) is one of the
most common syndromes transmitted by a mendelian
mode. The incidence of affected individuals is estimated
to be between 1:
1,000 and 1: 2,500 [1, 2] . NS is a clinically
heterogeneous disorder predominantly characterized by
dysmorphic facial features ( fig. 1 ), congenital heart dis-
ease (most commonly pulmonary valve stenosis, hyper-
trophic cardiomyopathy and atrial septal defects), pro-
portionate post-natal short stature, neck abnormalities
and chest deformities
[1, 3 , 4] ( table 1 ). Mild mental retar-
dation, bleeding diathesis, lymphedema, hearing difficul-
ty and cryptorchidism are also occasionally observed in
affected individuals. NS has an equal ma le to female ratio
[5, 6] . Familial cases correspond to approximately 20% of
the cases
[1] and presented mostly an autosomal domi-
nant inheritance with a near complete penetrance
[7] .
In recent years, germline mutations that affect compo-
nents of the RAS-MAPK (mitogen-activated protein ki-
nase) pathway were shown to be involved in the patho-
genesis of NS and of four rare syndromes with NS over-
lapping features: Leopard syndrome (OMIM 151100),
cardio-facio-cutaneous syndrome (CFC; OMIM 115150),
Costello syndrome (OMIM 218040) and neurofibroma-
tosis type 1 (NF1; OMIM 162200)
[8] .
Key Words
Noonan syndrome ⴢ Genetics ⴢ MAPK ⴢ PTPN11 ⴢ SOS1 ⴢ
RAF1 ⴢ Short stature ⴢ Genetics
Abstract
Noonan syndrome (NS) is one of the most common syn-
dromes transmitted by a mendelian mode. In recent years,
germline mutations that affect components of the RAS-
MAPK (mitogen-activated protein kinase) pathway were
sh ow n t o b e in vo lv ed i n t he pa tho ge ne si s o f NS an d f ou r r are
syndromes with clinical features overlapping with NS: Leop-
ard syndrome, cardio-facio-cutaneous syndrome, Costello
syndrome and neurofibromatosis type 1. Several hormones
act through receptors that stimulate the RAS-MAPK path-
way, and therefore, NS and related disorders represent a re-
markable opportunity to study the implication of the RAS-
MAPK pathway in different endocrine systems. Additionally,
children with NS frequently are referred to the endocrinolo-
gist because of short stature, delayed puberty and/or unde-
scended testes in males. In this paper, we review the diag-
nostic, clinical and molecular aspects of NS and NS-related
disorders. Copyr ight © 2009 S. Karger AG, B asel
Received: August 13, 2008
Accepted : October 30, 2008
Published online: March 4, 2009
H
O
RM
O
NE
RESEARCH
Alexander A .L. Jorge
Hospital das Clínic as, Laboratorio de Hormonios e G enetica Molecular
Av Dr Eneas d e Carvalho Aguiar 155 PAMB, 2 andar Bloc o 6
São Pau lo 05403-00 0 (Brazil)
Tel. +55 11 3069 7512, Fax +55 11 3069 7519, E-Mail a lexj@usp.br or beremen@usp.br
© 200 9 S. Karger AG, Basel
0301– 0163/09/0 714–0185 $26.0 0/0
Accessible online at:
www.karger.com/hre
Jorge/Malaquias/Arnhold/Mendonca
Horm Res 2009;71:185–193
186
Several hormones, including growth hormone (GH)
and insulin-like growth factor 1 (IGF-1), act through re-
ceptors that stimulate the RAS-MAPK pathway, and
therefore NS and related disorders represent a remarkable
opportunity to study the implication of the RAS-MAPK
pathway in different endocrine systems. Additionally,
children with NS are frequently referred to endocrinolo-
gists because of short stature, delayed puberty and/or un-
descended testes in males. Therefore, NS is important in
the differential diagnosis of short stature and has impor-
tant implications in GH therapy
[9–11] .
Differential Diagnosis of Noonan Syndrome
A lthough NS gi rls ca n be misdiagnosed as Turner syn-
drome (TS) because of clinical feature similarities be-
tween these two syndromes, the presence of hypergonad-
otrophic hypogonadism and abnormal karyotype in TS
girls facilitates the distinction between these two syn-
dromes. Several other disorders, with normal gonadal
function and normal karyotype, resemble NS phenotypi-
cally and constitute the true differential diagnosis of NS.
Leopard syndrome is an autosomal dominant disor-
der that shares some clinical characteristics with NS. The
acronym refers to the major features: Lentigines, ECG
conduction abnormalities, Ocular hypertelorism, Pul-
monic stenosis, Abnormal genitalia, Retardation of
growth and sensorineural Deafness
[12, 13] . The pres-
ence of café-au-lait spots in early infancy and generalized
multiple lentigines after 5–6 years of age are the main
characteristics of Leopard syndrome ( fig. 2 ).
In addition to Leopard syndrome, two other rare syn-
dromes, Costello syndrome and CFC syndrome, present
facial features and cardiac malformations that resemble
Fig. 1. NS features: ( a ) eye abnormalities: ptosis, hypertelorism,
epicanthal folds; (
b ) webbed neck, and ( c ) ear abnormalities: low-
set posteriorly rotated ears and thick helix.
Fig. 2. Generalized multiple lentigines in a patient with Leopard
syndrome.
Noonan Syndrome and Related Disorders Horm Res 2009;71:185–193
187
NS. In comparison with NS, Costello and CFC syndromes
present a coarser face and both syndromes are associated
with more frequent and severe developmental delay. Cos
-
tello syndrome patients usually have macrocephaly, cutis
laxa, nasal and perioral papillomata, deep palmar and
plantar creases, diffuse skin hyperpigmentation and nail
dy smorpholog y, as wel l as an inc rea sed risk of ma lig nanc y,
especia lly rhabdomysarcoma . CFC syndrome patients ty p-
ically have ectodermal abnormalities such as sparse hair
and eyebrows, follicular hyperkeratosis, palmoplantar hy-
perkeratosis and an ichthyosis-like condition
[14, 15] .
Clinical Diagnosis of Noonan Syndrome
Diagnosis of NS is primarily based on clinical find-
ings. Generally, classical facial features or a typical car-
diac malformation trigger suspicions of NS. In the new-
born, facial features can be less apparent, but generalized
edema, exce ss nu ch al fo ld an d c ong en it al he ar t d ef ec t c an
suggest the diagnosis.
Widely variable facial appearance is observed among
NS patients, even among patients from the same family
[16] or with the same molecular defect [17] . Furthermore,
a marked change of phenotype with age from newborn
period, infancy, childhood and adolescence to adulthood
was classically documented, resulting in a mild pheno-
type in adult patients
[3] . All these facts can contribute to
misdiagnosis, especially in patients without congenital
heart disease, with mild forms and/or at an older age.
In 1981, Duncan et a l. [4] proposed a scoring system for
NS diagnosis with 26 items devised on the basis of fre-
quency and severity of NS features in 23 typical patients.
This complex first scoring system was difficult for routine
use by non-geneticist specialists. In 1993, Sharland et al.
[18] proposed that the diagnosis should be based on the
pres ence of typical fa cia l feat ures in a pat ient wit h norma l
chromosomes plus short stature (height ! 10th centile for
sex and age) and/or cardiac defect and/or undescended
testicles in males. These new criteria did not allow the di-
agnosis in patients with mild facial features. Finally, in
1994, van der Burgt et al.
[16] proposed a simple and ac-
curate scoring system for the diagnosis of NS based on the
variable clinical NS presentation in one family ( table 2 ).
The van der Burgt scoring system is the most used model
to select patients for molecular studies in recent studies
[19 –21] . In this scoring system, patients are first classified
ac cording to f aci al feature s as hav ing ty pical or sugg est ive
NS characteristics. Typical face and any other major sign
or two minor signs establishes the diagnosis of NS, where-
as patients with suggestive NS face need two major or
three minor criteria to confirm the NS diagnosis. Analy-
ses of clinical features in NS patients, who had their diag-
nosis confirmed by molecular study, demonstrated that
Tab le 1. Phenotypic abnormalities associated to NS [1, 3, 4]
Charac-
teristics
Sign
Inheritance Autosomal dominant
Growth Short stature (postnatal onset) (50–80%)
Failure to thrive in infancy (40%)
Head and
neck
Triangular face
Ear abnormalities (44–90%): low-set posteriorly ro-
tated ears and thick helix
Eye abnormalities (95%): ptosis, hypertelorism,
epicanthal folds, down-slanting palpebral fissures,
strabismus, proptosis, myopia and nystagmus
Deeply grooved philtrum with high peaks of upper lip
vermilion border (95%)
Neck abnormalities (95%): short or webbed neck
High-arched palate (45–34%)
Dental malocclusion (35%)
Low posterior hairline (32%)
Micrognathia (22%)
Cardio-
vascular
Congenital heart defect (50–75%): pulmonary valve
stenosis (50%), hypertrophic cardiomyopathy (10%),
atrial septal defects (10%) and other (aortic stenosis,
ventricular septal defects and mitral insufficiency)
Electrocardiogram with left axis deviation and a neg-
ative pattern in the left precordial leads
Chest Thoraxic abnormalities (53–70%): flat, funnel, shield
or deformed chest, pectus carinatum superiorly and/
or pectus excavatum inferiorly
Genito-
urinary
Cryptorchidism (60–69%)
Puberty delay
Skeletal Cubitus valgus (47%)
Hand abnormalities: clinodactyly and brachydactyly
and blunt fingertips (30%)
Vertebral abnormalities (25%)
Neurologic Motor developmental delay (26%), language delay
(20%) and learning disability (15%)
Mental retardation, generally mild (25–35%)
Hema-
tology
Bleeding anomalies (20%), including factor XI or XII
deficiencies, von Willebrand’s disease, platelet dys-
function and leukemia (in especial juvenile myelo-
monocytic leukemia – JMML)
Other Peripheral lymphedema, splenomegaly, deafness
Values in parentheses show percent frequency.
Jorge/Malaquias/Arnhold/Mendonca
Horm Res 2009;71:185–193
188
no is ol ate d cl in ic al ch ar ac te ri st ic ca n e ns ur e t he d ia gn osis
of NS; however, t he van der Burg t et al. criteria, which take
in account the facial features, growth pattern, chest defor-
mity and cardiac defects, have been shown to be an accu-
rate tool for NS diagnosis
[22] . For these reasons, we rec-
ommend the use of this scoring system by endocrinolo-
gists during the evaluation of short stature children to
facilitate the recognition of patients with NS.
Genetic Heterogeneity of Noonan Syndrome
In 1994, Jamieson et al. [23] performed a genome-wide
scan in a large Dutch NS family and demonstrated a link-
age with several markers located at chromosome 12q22-
qter. In parallel, they demonstrated the existence of
genetic heterogeneity in NS by haplotype analysis of
another NS family. Subsequent studies reduced the chro-
mosome 12 interval which contains the NS candidate
gene region
[24, 25] and several positional candidate ap-
proaches were taken to identify the NS disease gene.
Finally, in 2001, Tartaglia et al.
[26] demonstrated the
presence of heterozygous missense mutations in PTPN11
(protein tyrosine phosphatase, non-receptor type 11;
OMIM 176876), a gene mapped to chromosome 12q24.1,
in patients with NS. Several further studies confirmed
PTPN11 as the most affected gene in NS patients and
demonstrated a mutation frequency of 38–100 and 37–
52% in individuals with familial and sporadic NS, respec-
tively
[7, 19, 27, 28] .
G e r m l i n e PTPN11 mutations have also been detected
in Leopard syndrome (OMIM 151100)
[12, 13] , Noonan-
like/multiple giant cell lesion syndrome (OMIM 163955)
[29] and in p atients wit h is olate d congenit al h ear t dise ase
[30] showing that mutations in this gene exhibit a broad
phenotype spectrum. Furthermore, it is noteworthy that,
during the screening of mutations in parents and rela-
tives of NS patients with PTPN11 mutations, some indi-
viduals carried the same PTPN11 mutations found in the
index case, but exhibited mild NS phenotypes that did
not fulfill the NS diagnostic criteria
[17, 26, 31, 32] . For
these reasons, we investigated 50 children with idiopath-
ic short stature that presented some NS-associated signs,
without fulfilling the van der Burgt et al. criteria for NS
diagnosis. No mutations were found in this cohort, sug-
gesting that PTPN11 mutations are not involved in the
pathogenesis of idiopathic short stature
[22] .
Specific somatic PTPN11 mutations were also found in
leukemia patients, especially in juvenile myelomonocytic
leukemia
[33] . Additionally, somatic mutations are iden-
tified at low frequency in several human cancers
[34] .
T h e PTPN11 protein product, SHP-2 (Src homology re-
gion 2-domain phosphatase 2), is a ubiquitously expressed
cytoplasmic protein member of a subfamily of protein ty-
rosine phosphatases that contains two Src homology 2 (C-
SH2 and N-SH2) domains. Through SH2 domains, SHP-2
binds to activated receptors and adapter proteins that pres-
ent specific phosphorylated tyrosines. In addition to tyro-
sine phosphatase actions, SHP-2 may also act as an adapt-
er molecule through phosphorylation of a tyrosine residue
at the amino terminus region, thus working as a docking
site for other SH-2-containing molecules
[35] . Both func-
tions, tyrosine phosphatases and adapter molecules, are
obviously relevant to several intracellular signal pathways,
including signal transduction of growth factors and cyto-
kines
[36 , 37] . From the endocrinological point of view,
Tab le 2. Noonan syndrome diagnostic criteria (adapted from van der Burgt et al. [16])
Clinical characteristics Major Minor
1 Facial typical face suggestive face
2 Cardiac pulmonary valve stenosis and/or typical ECG other defects
3 Height <3rd centile <10th centile
4 Chest wall pectus carinatum/excavatum broad thorax
5 Family history first-degree relative with definite diagnosis first-degree relative with suggestive diagnosis
6 Other:
Mental retardation
Cryptorchidism
Lymphatic dysplasia
all 3 any of the 3
Definite NS: typical face + one major or two minor clinical characteristics or suggestive face + two major or three minor clinical
characteristics.
Noonan Syndrome and Related Disorders Horm Res 2009;71:185–193
189
SHP-2 is implicated in GH [38, 39] , IGF-1 [4 0] , insulin [41]
and leptin
[42] signaling. The effects of NS PTPN11 muta-
tion on these hormone actions are still to be evaluated.
The PTPN11 mutations identified in patients with NS
or leukemia are predicted to be gain-of-function changes
that augment the capacity of tyrosine dephosphorylation
[26] . The SHP-2 mutants positively regulate the signal f lux
through the RAS/MAPK pathway induced by EGF (epi-
derma l grow th f actor), FGF (fibroblas t grow th fac tor), IL-
1 (interleukin-1) and TNF-1 (tumor necrosis factor-1), but
negatively regulate JAK/STAT signaling
[7] . Interestingly,
somatic PTPN11 mutations associated with leukemia pre-
sented a higher phosphatase activity than germline muta-
tions identified in NS patients
[20, 36] . Additionally, so-
matic mutations commonly found in leukemias rarely oc-
cur as germline mutation in NS patients and vice versa
[20, 36] , suggesting that somatic PTPN11 mutations with
higher tyrosine phosphatase activity and consequently
with more leukemogenic properties could cause embry-
onic lethality if they occur as germline mu tations.
Several other molecules in the RAS/MAPK pathway
were involved in NS patients without PTPN11 mutations:
germline KRAS [43] , SOS1 [44, 45] , RAF1 [46, 47] and
MEK
[15] mutations were found in 2.3, 21, 10 and 4.3% of
NS patients who did not harbor mutations in PTPN11
gene, respectively. Furthermore, mutations in other RAS/
MAPK molecules were also found in patients with NS-
like syndromes ( table 3 ). All these mutations, except
those found in patients with Leopard syndrome
[12, 13] ,
are characterized by an increase of constitutive function
of each mutated protein and consequently increased sig-
nal transduction via RAS/MAPK pathway. Due to the
clinical and molecular disease mechanisms and similari-
ties between NS and NS-like disorders, it is possible to
categorize these sy ndromes as a group of disorders caused
by RAS/MAPK pathway dysregulation.
R A S - M A P K P a t h w a y
RAS proteins (HRAS, NRAS and KRAS) are small
guanosine-binding proteins which act as signal switch
molecules that integrate extracellular inputs and activate
downstream effectors ( fig. 3 ) [reviewed in
8, 48 ]. Cell
stimulation promotes cycling between inactive GDP-
bound to active GTP-bound conformations (RAS-GDP
and RAS-GTP). The counterbalancing activities of gua-
nosine nucleotide exchange factors (GNEFs), which fa-
cilitate RAS-GTP conformation, and GTPase-activat-
ing proteins (GAPs), which increase the RAS intrinsic
GTPase activity and act in favor of the RAS-GDP confor-
mation, control RAS activity in vivo.
SOS1 (son of sevenless, drosophila , homolog 1 – OMIM
182530), the major GNEF, is recruited to protein com-
plexes that assemble on activated growth receptors. SOS1
binds to either RAS-GTP or RAS-GDP and displaces
guanine nucleotide. Because GTP is much more abun-
dant than GDP in the cytosol, this nucleotide exchange
Tab le 3. Genetic causes and summary of major features of NS and related disorders
Disorder Causative gene Phenotype
Noonan syndrome PTPN11, SOS1, RAF1, MEK1, KRAS See table 1
Neurofibromatosis type 1 NF1 Familial cancer syndrome; hallmark features include hyperpig-
mented skin lesions and benign neurofibromas; learning disabili-
ties are common
Leopard syndrome PTPN11, RAF1 Multiple lentigines, electrocardiographic conduction abnormali-
ties, ocular hypertelorism, pulmonic stenosis, abnormal genitalia,
growth retardation and deafness
Costello syndrome HRAS, KRAS, BRAF, MEK1 Mental retardation, high birth weight, neonatal feeding problems,
curly hair, coarse face, thick lips, nasal papillomata, diffuse skin
hyperpigmentation, and nail dystrophy
Cardio-facio-cutaneous
syndrome
KRAS, BRAF, MEK1, MEK2 Coarse face, congenital heart defects, ectodermal anomalies (fol-
licular and palmar hyperkeratosis), short stature, variable degrees
of mental retardation (moderate to severe) and facial features rem-
iniscent of NS and Costello syndrome
Jorge/Malaquias/Arnhold/Mendonca
Horm Res 2009;71:185–193
190
increases intracel lular RAS- GTP levels. In its GTP-bound
form, RAS can activate several intracellular pathways, in-
cluding the MAPK pathway. The RAF-MEK-ERK cas-
cade is the best characterized RAS effector pathway.
There are three RAF serine/threonine kinases (ARAF,
BRAF and RAF1) that activate the MEK-ERK kinase cas-
cade. ERK kinase can phosphorylate both cytosolic and
nuclear substrates, which include transcription factors
that control the cell cycle
[8, 48] .
Mutations in several molecules involved in this cas-
cade were identified in NS and other related syndromes
( table 3 ). It has been proposed that these disorders should
be classified together as neuro-cardio-facial-cutaneous
syndromes based on a constellation of similar pheno-
typic features and the central role of hyperactive RAS/
MAPK in their pathogenesis
[49] . Based on genotype-
phenotype correlation, three clusters of genes were pro-
posed
[15] :
The first group comprises genes outside the RAS-
RAF-MEK chain, which encompasses those upstream of
RAS. Most patients with PTPN11 or SOS1 mutation have
NS or Leopard syndrome. NF1 is caused by mutations in
neurofibromin, a GAP protein involved in RAS inactiva-
tion. Mutations in this group of genes usually lead to a NS
phenotype, with a low rate of mental impairment and a
low rate of keratinization disorders, but a tendency to
patchy skin hyperpigmentation, and, at least for NF1 and
PTPN11 , a slightly increased risk of leukemia
[15] .
The second group comprises KRAS and the cascading
genes downstream. Mutations in these genes usually af-
fect the cognitive functions, have more influence on so-
matic growth, skin redundancy, keratinization, and hair
development, and usually result in a CFC syndrome phe-
notype. Malignancy risk appears to be low, but could in-
clude leukemias
[15] .
The third group is restricted to HRAS. Diffuse hyper-
pigmentation, papillomata, chaotic atrial fibrillation and
a tendency for soft-tissue tumors are the most distin-
guishing phenotypic features in this group and usually
result in a Costello syndrome phenotype
[15] .
Germline Mutations in Genes of RAS/MAPK Pathway
and Risk of Neoplasia
Somatic activating RAS mutations occur in ⬃ 30% of
huma n cancers: mutations in KRAS are commo n in pan-
creatic, colorectal, endometrial, biliary tract, lung and
cervical cancer, KRAS and NRAS mutations are preva-
lent in myeloid malignancies, whereas NRAS and HRAS
mutations are found in melanoma and bladder cancer,
respectively
[8] . BR AF mutations are also frequently
Fig. 3. RAS/MAPK pathway. Tyrosine-
phosphorylated domains of activated ty-
rosine kinase receptors act as docki ng sites
for several intracellular proteins, which
contain SH2 domains such as SHC, SHP-2
and GRB2. These molecules recruit SOS1
which promotes cycling between inactive
RAS-GDP to active RAS-GTP. RAS-GTP
directly activates the MAPK pathway
(RAF-MEK-ERK cascade). ERK kinase
can phosphorylate both cytosolic and nu-
clear substrates, which include transcrip-
tion factors that control the cell cycle.
SHC = Signaling and transforming pro-
tein contai ning Src homology 2 and 3 (SH2
and SH3) domains; SHP-2 = Src homology
region 2-domain phosphatase 2; GRB2 =
growth factor receptor-bound protein 2;
SOS 1 = son of sevenless 1; NF1 = neurofi-
bromin; RAS = rat sarcoma v iral oncogene
homolog; RA F = muri ne sarcoma viral on-
cogene homolog; MEK = mitogen-activat-
ed kinase kinase; ERK = mitogen-activat-
ed kinase.
Noonan Syndrome and Related Disorders Horm Res 2009;71:185–193
191
found in thyroid, colorectal and ovarian cancers [8] and
somatic PTPN11 mutation is responsible for one third of
juvenile myelomonocytic leukemia (JMML) and is less
frequent in other leukemias or solid tumors
[34] .
In contrast with higher malignancy potential of so-
matic mutations in RAS/MAPK components, germline
mutations presented more variable effects and depend on
which specific genes are affected. Patients with Costello
syndrome are predisposed to rhabdomyosarcoma, gan-
glioneuroblastoma and bladder cancer due to germline
HRAS mutations, whereas patients with NF1 mutations
frequently presented neurofibromas and show an in-
creased risk of neurofibrosarcoma, astrocytoma, pheo-
chromocytoma and JMML
[8] .
NS patients principally present an increase in the
prevalence of JMML and multiple giant cell lesions
(MGCL), although both conditions affect only a small per-
centage of patients. It is postulated that PTPN11 mutations
associated with NS-JMML present a higher increase in ty-
rosine phosphatases activity than mutations only associ-
ated with NS and not found in leukemias
[20, 36, 50] .
MGCL are benign tumor-like lesions most frequently af-
fecting the jaws and are associated with PTPN11 , SOS1 ,
BRAF and MEK1 mutations [51] . It is postulated that dys-
regulation of the RAS/MAPK pathway represents the
common and basic molecular event which predisposes to
MGCL.
The finding that the same molecular defects can be
found in NS patients with or without concomitant JMML
or MGCL indicates that NS-related heterozygous muta-
tions in RAS/MAPK pathway components are not suf-
ficient to produce both conditions and an additional
unknown factor (modifier gene, epigenetic factors or so-
matic second hit) is necessary for JMML or MGCL devel-
opment
[51] .
RAS/MAPK Pathway Dysregulation and Its
Consequences for the Endocrine System
The consequences of NS and NS-related disorders
with molecular RAS/MAPK pathway defects for the en-
docrine system remain mostly unexplored. One of the
cardinal signs of NS is short stature
[3, 4] , although the
physiopathological cause of growth impairment remains
u nclea r. G H i s e ss ent ia l f or nor ma l pos t-n at al gr ow th a nd
exerts its action after binding to a specific receptor that
phosphorylates several tyrosine residues located in the
intracellular domain. Tyrosine dephosphorylation leads
to the physiological interruption of the GH pathway.
It has been consistently documented that SHP-2, the
PTPN11 gene-encoded protein, negatively regulates
GHR-JAK2-STAT5 signa ling
[39, 52] . Thus, t he increased
tyrosine phosphatase action of the SHP-2 protein, ob-
served in PTPN11 -mutated NS children, is expected to
cause decreased GH action and consequently negatively
influence individual stature. We demonstrated that NS
children with PTPN11 gain-of-function mutations pre-
sented lower growth velocity and lesser height SDS gain
during GH therapy than patients with NS without PTPN11
mutations
[10] . These clinical f indings were also observed
in two other studies
[9–11] , suggesting that PTPN11 mu-
tations can cause partial GH insensitivity at post-recep-
tor level and appears to be a pharmacogenetic predictor
of GH responsiveness
[53] .
Add itiona lly, NS pat ient s with SOS1 mutations, a mol-
ecule that was not directly involved in the GHR-JAK2-
STAT5 pat hway, more f req uently have normal h eig ht
[44,
45] . These NS patients also presented a high frequency of
fetal macrosomia and macrocephaly, possibly due to the
increase in the RAS-MAPK pathway caused by NS-asso-
ciated SOS1 mutations and its positive inf luences on fetal
growth
[44, 45] .
Patients with NS often present delayed puberty and NS
boys frequently have cryptorchidism. Several cytokines,
tyrosine and G-protein-coupled receptors are involved in
the hypothalamic-pituitary-gonadal axis. Insulin acts
through a tyrosine kinase receptor, and thus, the repro-
ductive and metabolic effects of different NS-related mo-
lecular defects are still to be elucidated.
In summary, NS is a common condition and an im-
portant differential diagnosis in children with short stat-
ure, cryptorchidism and delayed puberty, conditions fre-
quently seen by endocrinologists. Germline mutations
that affect several components of RAS-MAPK pathway
are involved in the pathogenesis of NS and can be diag-
nosed by molecular studies. Genotype-phenotype corre-
lation studies are still necessary to better characterize the
effect of RAS/MAPK pathway dysregulation on endo-
crine and metabolic systems.
A c k n o w l e d g m e n t s
T h is wo rk w a s s up po rt ed by g ra nt s f ro m F un d ac ao de Am pa ro
a Pesquisa do Estado de São Paulo (FAPESP) (05/04726-0 and
07/59555-0 to A.C.M.) and from Conselho Nacional de Desen-
volvimento Cientifico e Tecnologico (CNPq) (301246/95-5 to
B.B.M., 300938/06-3 to I.J.P.A. and 307951/06-5 to A.A.L.J.). The
authors thank Prof. Martin O. Savage for his useful suggestions.
Jorge/Malaquias/Arnhold/Mendonca
Horm Res 2009;71:185–193
192
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