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Cancer Prone Disease Section
Review
Noonan syndrome
Marco Tartaglia, Bruce D Gelb
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy (MT, BDG)
Published in Atlas Database: June 2005
Online updated version: http://AtlasGeneticsOncology.org/Kprones/NoonanID10085.html
DOI: 10.4267/2042/38259
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology
multiple skeletal defects (spine and chest), webbed
neck, mental retardation, cryptorchidism and bleeding
diathesis.
Identity
Alias
Male Turner syndrome
Pseudo-Turner syndrome
Inheritance
Noonan syndrome is an autosomal dominant disorder.
Rare cases with parental consanguinity have been
described, but it is not clear that these represent true
instances of autosomal recessive
inheritance. Like many autosomal dominant disorders,
a significant, but not precisely determined, percentage
of cases represent de novo mutagenesis. The prevalence
of Noonan syndrome has not been determined
accurately to date. Most authors cite the figure of 1 in
1,000-2,500 live births. However, that estimate was not
based on a population study. Fetal loss occurs for
Noonan syndrome so disease incidence is higher than
prevalence, but no estimate of the magnitude of this
discrepancy is available.
Neoplastic risk
Children with Noonan syndrome are predisposed to
malignancies, juvenile myelomonocytic leukemia
(JMML) most commonly. JMML, formerly termed
juvenile chronic myeloid leukemia or chronic
myelomonocytic leukemia, is a myeloproliferative/
myelodysplastic disorder of childhood characterized by
excessive proliferation of immature and mature
myelomonocytic cells that originate from a pluripotent
stem cell. In childhood, JMML accounts for
approximately 30% of cases of myelodysplastic and
myeloproliferative syndromes and 2% of leukemias. It
typically presents in infancy and early childhood, and is
often lethal. Recent studies have provided strong
evidence that hypersensitivity to granulocytemacrophage colony-stimulating factor (GM-CSF), due
to a selective inability to down-regulate the
RAS/MAPK cascade, plays a central role in the clonal
cell growth characteristic of JMML. In approximately
15-30% of JMML cases, the pathological activation of
the RAS/MAPK cascade results from oncogenic NRAS
or KRAS2 mutations that specifically affect GTP
hydrolysis, leading to the accumulation of RAS in the
GTP-bound active conformation. JMML has been
reported in children with neurofibromatosis type 1
(NF1), an autosomal dominant disorder resulting from
germline loss-of-function mutations of the NF1 tumor
suppressor gene. In children with NF1 and JMML, the
proliferative advantage of the leukemic cells results
from a second hit, the somatic loss or inactivation of
the normal NF1 allele.
Clinics
Phenotype and clinics
Noonan syndrome is a clinically variable
developmental disorder defined by short stature, facial
dysmorphism and a wide spectrum of congenital heart
defects. The distinctive facial features consist of a
broad forehead, hypertelorism, down-slanting palpebral
fissures, ptosis, high-arched palate and low-set,
posteriorly rotated ears. Cardiovascular abnormalities,
primarily pulmonic stenosis and hypertrophic
cardiomyopathy, are present in up to 85% of affected
individuals. Additional relatively frequent features are
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
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Noonan syndrome
Tartaglia M, Gelb BD
Clinical features in Noonan syndrome. (A) Prenatal echography showing nuchal cystic hygroma; (B) dysmorphic facial features; (C)
pectus deformities and cubitus valgus; (D) webbed neck; (E) schematic representation of major cardiac defects: 1, pulmonic stenosis; 2,
hypertrophic cardiomyopathy; 3, atrial septal defects; 4, ventricular septal defects; 5, patent ductus arteriosus. (Figures kindly provided by
G. Zampino, MD, Università Cattolica del Sacro Cuore, Rome, Italy).
Since the NF1 gene product, neurofibromin, is a
negative modulator of RAS function, this loss is
associated with RAS hyperactivity. Remarkably,
deregulated RAS function appears to be restricted to
GM-CSF signaling in hematopoietic cells. More
recently, somatic activating mutations in the PTPN11
gene, which encodes the protein tyrosine phosphatase
(PTP) SHP-2, have been documented in approximately
35% of cases with JMML.
prognosis
without
transplantation.
stem
cell
Other findings
Note
A significant percentage of Noonan syndrome cases
arise from de novo PTPN11 mutations. Among
fourteen informative families, each consisting of an
affected individual heterozygous for a PTPN11
mutation and unaffected parents, the paternal origin of
mutation has been demonstrated in all cases.
Consistent with this finding, advanced paternal age was
noted among fathers of sporadic Noonan syndrome
cases, compared with fathers of the reference
population.
Moreover, when a parent is affected with Noonan
syndrome and harbors a PTPN11 mutation, a sex-ratio
bias is operative for offspring who inherit the defect.
This bias favors males by a factor of 2:1. The available
data point to this bias being attributable to sex-specific
developmental effects of PTPN11 mutations that favor
survival of affected male embryos compared to female
ones.
Mutations in the PTPN11, RAS and NF1 genes are
largely mutually exclusive in JMML, and their
combined prevalence accounts for approximately 85%
of cases. Acute lymphoblastic leukemia and solid
tumors,
particularly
neuroblastoma
and
rhabdomyosarcoma, have also been documented with a
relatively higher prevalence respect to the general
population.
Evolution
In children with Noonan syndrome JMML may regress
without treatment or follow an aggressive clinical
course. By contrast, cases of JMML that arise in
children without Noonan syndrome have a poor
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
hematopoietic
346
Noonan syndrome
Tartaglia M, Gelb BD
domain also interacts with the PTP domain using a
separate site. As these subdomains show negative
cooperativity, the N-SH2 domain functions as an
intramolecular switch controlling SHP-2 catalytic
activation. Specifically, the N-SH2 domain interacts
with the PTP domain basally, blocking the catalytic
site. Binding of the N-SH2 phosphopeptide-binding site
to
the
phosphotyrosyl
ligand
promotes
a
conformational change of the domain that weakens the
auto-inhibiting intramolecular interaction, making the
catalytic site available to substrate, thereby activating
the phosphatase.
Expression: Widely expressed in both embryonic and
adult tissues.
Localisation: Cytoplasmic. It binds to activated cell
surface receptors, cell adhesion molecules and
scaffolding adapters. Phosphorylation of two tyrosine
residues at the C-terminus by activated tyrosine kinase
receptors creates binding sites for other SH2 domaincontaining signal transducers.
Function: SHP-2 functions as a intracellular signal
transducer. It positively modulates signal flow in most
circumstances, but can also function as negative
regulator depending upon its binding partner and
interactions with downstream signaling networks. SHP2 positively controls the activation of the RAS/MAPK
cascade induced by several growth factors, and
negatively regulates JAK/STAT signaling. In most
cases, SHP-2's function in intracellular signaling
appears to be immediately proximal to activated
receptors and upstream to RAS. The mechanisms of
SHP-2's action and its physiological substrates are still
poorly defined. However, both membrane translocation
and PTPase activity are required for SHP-2 function.
SHP-2 is required during development. Embryos
nullizygous for Shp-2 have defects in gastrulation and
mesodermal
patterning
resulting
in
severe
abnormalities in axial and paraxial mesodermal
structures. Shp-2 function is also required for
development of terminal and skeletal structures,
semilunar valvulogenesis in the heart, and
hematopoiesis.
Genes involved and proteins
PTPN11 (Protein tyrosine phosphatase,
non-receptor type, 11)
Location
12q24.1
Centromere - FLJ34154 - RPL6 - PTPN11 - RPH3A OAS1 – telomere.
DNA/RNA
Description: The PTPN11 gene counts 16 exons. Exon
1 contains the 5'-UTR and the translation initiation
ATG, and a few additional codons. Exon 15 contains
the stop codon and exon 16 contains a major portion of
the 3'-UTR. Other features of the PTPN11 gene, such
as the promoter region and enhancer elements have not
been delineated.
Transcription: A 7.0-kb transcript is detected in several
tissues (heart, brain, lung, liver, skeletal muscle,
kidney, and pancreas) with highest steady-state levels
in heart and skeletal muscle. The predominant human
PTPN11 mRNA contains an open reading frame of
1,779 bases, resulting in a predicted protein of 593
amino acid residues.
Pseudogene: A number of speudogenes, sharing more
than 92% nucleotide identity with PTPN11 cDNA
(including the untranslated regions), have been
documented in the human genome. All the pseudogenes
harbour frameshift mutations and multiple stop codons.
Three of the five pseudogenes are likely to be
expressed but with distinct tissue distribution and
expression level.
Protein
Description: SHP-2 is a member of a small subfamily
of cytoplasmic Src homology 2 (SH2) domaincontaining protein tyrosine phosphatases. The aminoterminal SH2 (N-SH2 and C-SH2) domains selectively
bind to short amino acid motifs containing a
phosphotyrosyl residue and promote SHP-2 association
with cell surface receptors, cell adhesion molecules and
scaffolding adapters. Crystallographic data indicate that
the N-SH2
The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains
of the protein, comprising two amino-terminal, tandemly arranged SH2 domains (N-SH2 and C-SH2) followed by a protein tyrosine
phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those
domains.
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Noonan syndrome
Tartaglia M, Gelb BD
Figure 3: Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof and co-workers. Residues
involved in catalysis are shown (space fill).
Figure 4: Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin;
N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including
juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic
myelomonocytic leukemia (somatic origin; N=97). The pictures show the Ca trace of SHP-2 in its catalytically inactive conformation.
Affected residues are indicated with their side chains as black sticks.
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Tartaglia M, Gelb BD
EGF. Cell culture and whole embryo studies reveal that
increased RAS/MAPK signaling is variably present,
appearing to be cell-context specific.
Somatic: Somatic activating mutations in PTPN11 have
been documented in a heterogeneous group of
hematologic malignancies and pre-leukemic disorders,
and rarely in certain solid tumors.
Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A
(E69K), 214G>A (A72T), 215C>T (A72V), 226G>A
(E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G
(E76G), 227A>C (E76A), 1471C>T (P491S),
1472C>T (P491L), 1504T>C (S502P), 1504T>G
(S502A), 1520C>A (T507K), 1528C>A (Q510K).
Homology: PTPN6 (protein tyrosine phosphatase, nonreceptor type, 6) previously known as SHP1 or SHP-1
(Src homology 2 domain-containing protein tyrosine
phosphatase, 1).
Mutations
Studies reported PTPN11 mutation detection rates
ranging between 33% to 60%. Differences in inclusion
criteria stringency and recruiting strategies are likely to
responsible for such variable mutation detection rate. It
should also be emphasized that the mutation prevalence
detected in any Noonan syndrome cohort is sensitive to
its composition in terms of relative abundance of
sporadic and familial cases, as PTPN11 mutations
appear to be more prevalent among families
transmitting the trait compared to sporadic cases. With
those issues stipulated, the contribution of PTPN11
mutations to the etiology of Noonan syndrome appears
to be approximately 50%.
A statistically significant association with pulmonary
valve stenosis and lower incidence of hypertrophic
cardiomyopathy was found among the group with
PTPN11 mutations. Overall, a large percentage of
PTPN11 mutation-negative individuals tended to
exhibit fewer or mild clinical features of NS, even
though approximately half of the Noonan syndrome
patients without a PTPN11 mutation appeared
clinically indistinguishable from typical PTPN11
mutation-positive patients.
Germinal: The vast majority of mutations affect
residues residing at or close to the interface between
the N-SH2 and PTP domains. Increasing evidence
supports that a number of Noonan syndrome-causative
mutations promote SHP-2 gain-of-function by
destabilizing the catalytically inactive conformation of
the protein, and prolong signal flux through the
RAS/MAPK pathway in a ligand-dependent manner.
Selection: 124A>G (T42A), 182A>G (D61G), 184T>G
(Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G
(A72G), 218C>T (T73I), 228G>T, C (E76D), 236A>G
(N79R), 317A>C (D106A), 922A>G (N308D).
Two specific missense mutations (836A>G, Y279C;
1403C>T, T468M) have been identified to recur in
LEOPARD syndrome, a developmental disorder
closely related to Noonan syndrome. A mouse model
bearing the NS-causative Asp61Gly mutation in the
Ptpn11 gene has been recently generated and
characterized. The Ptpn11D61G/ D61G genotype is
embryonic lethal. At day E13.5, these embryos are
grossly edematous and hemorrhagic, and have diffuse
liver necrosis. A number of severe cardiac defects are
also observed. Heterozygous embryos exhibit cardiac
defects, proportionate growth failure and perturbed
craniofacial development. Hematologic anomalies
include
a
mild
myeloproliferative
disease.
Ptpn11D61G/+ embryonic fibroblasts are characterized
by a three-fold increased Shp-2 activity and increased
association of Shp-2 with Gab1 after stimulation with
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
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Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
This article should be referenced as such:
Tartaglia M, Gelb BD. Noonan syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2005; 9(4):345-350.
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