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Noonan Syndrome

Author: Margaret M McGovern, MD, PhD; Chief Editor: Luis O Rohena, MD

BACKGROUND

Noonan syndrome was first recognized as a unique entity in 1963 when


Noonan and Ehmke described a series of patients with unusual facies
and multiple malformations, including congenital heart disease. These
patients were previously thought to have a form of Turner syndrome,
with which Noonan syndrome shares numerous clinical features. The
observation that patients with Noonan syndrome have normal
karyotypes was important in allowing the distinction to be made
between the Turner and Noonan syndromes.
The cardinal features of Noonan syndrome include unusual facies (ie,
hypertelorism, down-slanting eyes, webbed neck), congenital heart
disease, short stature, and chest deformity. Approximately 25% of
individuals with Noonan syndrome have mental retardation. Bleeding
diathesis is present in as many as half of all patients with Noonan
syndrome. Skeletal, neurologic, genitourinary, lymphatic, eye, and skin
findings may be present to varying degrees.[1]
PATOPHYSIOLOGY

The pathophysiology of Noonan syndrome is not fully understood but is


associated with mutations in genes that are part of the
RAS/RAF/MEK/ERK signal transduction pathway, an important
regulator of cell growth. Approximately 50% of patients have gene
mutations in PTPN11, with SOS1 and RAF1 mutations identified in
another 13% and 5-17% of patients, respectively. Mutations in KRAS,
NRAS, BRAF, and MAP2K1 also have been identified, but in smaller
numbers of patients.
EPIDEMIOLOGY
Frequency
United States
The incidence of Noonan syndrome is estimated to be 1 case per 1000
to 1 case per 2500 live births.
International
The incidence of Noonan syndrome appears to be consistent
worldwide.
Mortality/Morbidity
The primary source of morbidity and mortality in patients with Noonan
syndrome depends on the presence and type of congenital heart
disease.
Noonan syndrome is also characterized by a slight increase in the risk
for certain cancers. In a literature review spanning 1937-2010, Kratz et

al found the most commonly reported cancers in Noonan syndrome, as


diagnosed in a total of 1051 patients, to be neuroblastoma (8 cases),
acute lymphoblastic leukemia (8 cases), low-grade glioma (6 cases),
and rhabdomyosarcoma (6 cases); like Noonan syndrome, all of these
cancers are associated with RAS signaling pathway mutations.[2]
Juvenile myelomonocytic leukemia and myeloproliferative disorder have
also been associated with Noonan syndrome.
A study by Jongmans et al also demonstrated an elevated cancer risk in
patients with Noonan syndrome.[3] Twelve of 297 patients with a PTPN11
mutation developed a malignancya 3.5-fold increased risk compared
with that of healthy individuals. Hematologic malignancies occurred
most frequently, while 2 malignancies not previously observed in
Noonan syndrome were found: a malignant mastocytosis and malignant
epithelioid angiosarcoma.
Race
Noonan syndrome is panethnic.
Sex
Noonan syndrome occurs in either a sporadic or autosomal dominant
fashion. In either case, males and females are equally affected.
Age
The disorder is present from birth, but age impacts the facial phenotype.
Infants with Noonan syndrome can be difficult to recognize by facial
appearance alone. The phenotype becomes more striking in early
childhood, but with advancing age, it may again become quite subtle.
Careful examination of an affected child's parents may in fact reveal that
they are mildly affected.
HISTORY (ANAMNESIS)
The prenatal history in Noonan syndrome is typically unremarkable;
however, some cases are complicated by polyhydramnios, fetal edema,
increased nuchal fold translucency, cystic hygroma, or congenital heart
disease (particularly pulmonary valvular dysplasia).
A careful family history should be obtained, paying particular attention to
the presence of congenital heart disease, mental retardation, short
stature, or unusual facies among the parents or siblings of an affected
child.
A child with mild expression of the facial phenotype may present only
with developmental delay and history of congenital heart disease. A
history of abnormal bleeding is present in as many as 50% of patients.
A study by Niemczyk et al suggested that incontinence affects a
significant proportion of children with Noonan syndrome. The study, of
19 children and 10 adults with Noonan syndrome, found that among the
younger children (aged 4-12 years), the incidence of daytime urinary
incontinence, nocturnal enuresis, and fecal incontinence was 36.4%,
27.3%, and 11.1%. However, only one adolescent and one adult

experienced incontinence, indicating that the condition tends not to


persist into adulthood.[4]
PHYSICAL EXAMINATION

Growth parameters
Size at birth is usually within the reference range in Noonan syndrome.
Short stature is present in as many as 80% of patients. Average adult
height for is 5 feet 5 inches in males and 5 feet in females.
A study by Cessans et al comparing growth patterns in patients with
Noonan syndrome based on genotype found that at birth, patients with
PTPN11 mutations tended to be shorter and thinner than were those
with mutations in SOS1, KRAS, or Noonan syndrome with multiple
lentiginesassociated PTPN11 (NSML-PTPN11). Additionally, at age 2
years, growth retardation was more severe and frequent in patients with
PTPN11 mutations than in those with mutations in SOS1 or NSMLPTPN11. At age 10 years, although patients with Noonan syndrome had
lower body mass indexes in general, no growth differences were found
between the different genotypes.[5]
Facial features
These include the following:
Triangular-shaped face
Hypertelorism
Down-slanting palpebral fissures
Ptosis
Strabismus (48%)
Amblyopia (33%)
Refractive errors (61%)
Low-set ears with thickened helices: In a study of 97 patients with
Noonan syndrome, van Trier et al found that 75 of them (77%) had
external ear anomalies, including 69 patients whose ears were low set,
28 whose ears were posteriorly rotated, 14 whose ears protruded, and
18 who had thickened helices [6]
High nasal bridge
Short, webbed neck
A subgroup of patients have Noonan-like/multiple giant cell lesion
syndrome (NS/MGCLS), which is characterized by benign, tumorlike
lesions, usually occurring in the jaws. This condition was once thought
to be separate from Noonan syndrome but is now considered to be a
variant of it. NS/MGCLS is associated with PTPN11 and SOS1 gene
mutations.[7]
A study by Allanson et al, however, indicated that facial phenotype by
itself is not sufficient to predict the presence of specific Noonan
syndrome mutations. In an examination of facial photos of 81 persons
with Noonan syndrome, the investigators determined that even though
mutations in PTPN11 are associated with the cardinal physical

characteristics of the disorder, some individuals with these mutations


have facial features that are atypical for the syndrome. On the other
hand, although a correlation can be seen between KRAS mutations and
an intellectual and physical phenotype that is somewhat atypical for
Noonan syndrome, some patients with these mutations have the
characteristic facial features of the disorder.[8]
Chest/back features
These include p ectus carinatum and/or excavatum. Scoliosis is another
feature.
Cardiovascular findings
Cardiac defects occur in up to 80% of patients. The characteristic lesion
is dysplastic/stenotic pulmonic valve, but virtually all types of congenital
heart defects have been described in patients with Noonan syndrome.
Hypertrophic cardiomyopathy (obstructive or nonobstructive type) is
present in up to 30% of patients and can present at birth or in infancy or
childhood. Other cardiac defects frequently include atrial and ventricular
septal defects, branch pulmonary artery stenosis, tetralogy of Fallot,
and coarctation of the aorta.[1]
Abdominal features
Hepatosplenomegaly unrelated to cardiac status is present in
approximately 25% of patients.
Genitourinary features
Renal anomalies are present in 10% of patients but are not clinically
significant. However, more than half of male patients have undescended
testes.
Skeletal features
Joint laxity is present in more than half of patients. Talipes equinovarus,
radioulnar synostosis, cervical spine fusion, and joint contractures are
less common findings.[9]
Skin findings
These include the following:

Lymphedema (See the images below) Inline figure

Lymphedema of the feet in an infant is shown. The toes have the characteristic
sausagelike appearance. /Inline figure Inline figure

Generalized lymphedema is seen here in an infant. The loose skin folds around the
neck will form a webbed neck later in life. /Inline figure

Prominent pads of fingers and toes (67%)


Follicular keratosis of the face and extensor surfaces (14%)
Multiple lentigines (3%)

Neurologic findings
These include the following:
Hypotonia
Seizure disorder (13%)
Unexplained peripheral neuropathy (infrequent)
CAUSES
Sporadic and autosomal dominant cases have been identified. Female
patients with Noonan syndrome have normal pubertal development and
fertility, while fertility in males with undescended testes may be
decreased. For this reason, the mother is more frequently the
transmitting parent in familial cases.
Causative gene mutations in Noonan syndrome include the following[10,
11, 12, 13, 14]
:
PTPN11 mutations: Account for approximately 50% of clinically
recognized cases
SOS1 mutations: Account for approximately 13% of cases
RAF1 mutations: Account for 5-17% of cases
KRAS, NRAS, BRAF, and MAP2K1 mutations: Account for a smaller
number of cases
Cases due to SOS1 mutations are generally associated with better
cognitive function than those associated with PTPN11 mutations.[15]
Correlations have been demonstrated between patient phenotype in
Noonan syndrome and mutations in specific genes. A study by Lee et al
found that patients with Noonan syndrome who had SOS1 mutations
tended to have normal stature, while RAF1 mutations appeared to be
associated with hypertrophic cardiomyopathy and developmental delay.
[16]

DIFFERENTIAL DIAGNOSIS

Diagnostic Considerations

These include the following:


Costello syndrome
Craniofaciocutaneous syndrome
Fetal hydantoin syndrome
Lentigines, electrocardiographic (conduction abnormalities), ocular
(hypertelorism), pulmonary (stenosis), abnormal (genitalia), retardation
(of growth), and deafness (LEOPARD) syndrome
XO/XY mosaicism
Turner syndrome
Neurofibromatosis type 1
SPRED1 spectrum

Differential Diagnoses
Fetal Alcohol Syndrome

WORKUP

All patients with Noonan syndrome should be evaluated to determine


which disease manifestations they display. A complete physical and
neurologic examination should be performed, and a genetics
consultation should be sought. In addition, the following assessments
should be made at the time of diagnosis:
Cardiac evaluation: Including echocardiographic and
electrocardiographic assessment
Ophthalmologic and audiologic evaluation
Coagulation screen
Renal ultrasonographic examination
Developmental assessment
Before any patient with Noonan syndrome can undergo a surgical
procedure, a full hematologic workup must be performed.
Laboratory Studies
Bleeding diatheses are common among patients with Noonan
syndrome. The most frequent abnormality is factor XI deficiency, but
various disorders have been reported in patients with Noonan
syndrome. A complete blood count (CBC) with platelet count,
coagulation profile, and measurement of factor XI level should be
obtained at a minimum. Moreover, before any patient with Noonan
syndrome can undergo a surgical procedure, a full hematologic workup
must be performed.
If full phenotypic expression is not apparent, karyotyping may be
necessary. Mutation analysis may confirm the diagnosis of Noonan
syndrome, but failure to identify a germline mutation in any of the
associated genes does not rule out the disorder; this entity remains a
clinical diagnosis.
Many individuals with Noonan syndrome have reduced insulinlike
growth factor-1 (IGF-1) and IGF-binding protein 3, but these tests are
not diagnostic of the syndrome itself.
Imaging Studies

Appropriate imaging studies in Noonan syndrome include the following:


Echocardiography
Renal ultrasonography
Brain and cervical spine magnetic resonance imaging (MRI): If
neurologic symptoms are present
Radiography: To examine the chest and back if abnormalities are
present [1] and to evaluate the patient for Noonan-like/multiple giant cell
lesion syndrome (NS/MGCLS)

Other Test
Any child suspected of having Noonan syndrome requires a detailed
cardiac workup. This includes electrocardiography, echocardiography,
and consultation with a pediatric cardiologist.
Assessment of development is necessary to identify any delays and
allow for intervention. Full-scale intelligence quotient (IQ) ranges from
48-130, with a mean of 86.1 (approximately one standard deviation [SD]
below the general population mean). Approximately 25% of patients
with Noonan syndrome have mental retardation. A study by Roelofs et
al found that in persons with Noonan syndrome, full-scale and
performance IQs saw significant improvement in adult scores compared
with childhood values, with performance IQ reaching normal levels.
However, verbal IQ did not advance proportionately to performance IQ
by adulthood. The investigators suggested that the improvement in
performance IQ in individuals with Noonan syndrome points to a
developmental delay in executive functioning that is outgrown in
adulthood. However, maturation of motor skills was also suggested as a
reason for the improvement. The study included 16 patients, whose
intelligence was evaluated in childhood and adulthood.[17]
The incidence of progressive high-frequency sensorineural hearing loss
may be as high as 50%. Thus, audiologic evaluation is indicated.
DNA-based testing of the known causative genes, which can be
performed via next-generation sequencing, can be considered for
confirmation of diagnosis.[18] Unless a known mutation is present in a
family, negative (ie, normal) test findings do not rule out a diagnosis of
Noonan syndrome.
TREATMENT
Medical Treatment
Growth charts specific for Noonan syndrome are available and can be
used to plot an individual's height, weight, and head circumference.[19]
Growth hormone has been used to accelerate growth in some patients
with the disorder, and achievement of near-adult height has been
documented. Such therapy is well tolerated, with very few adverse
events reported.[20, 21]
Careful follow-up evaluation of patients with Noonan syndrome is
needed for early identification of bleeding diathesis, malignancy, and
hypertrophic cardiomyopathy.
Surgical Care
Certain types of congenital heart lesions are amenable to surgical
correction.

Consultations

The following consultations may be indicated in Noonan syndrome:


Geneticist
Cardiologist
Hematologist
Ophthalmologist
Neurologist
Audiologist
Diet
No special dietary restrictions apply.
Activities
Activity may be limited by cardiac status and the presence of
hematologic abnormalities.
Medication Summary
Growth hormone may be used to treat short stature associated
with Noonan syndrome. Physiologic replacement for conditions of
growth hormone deficiency :
Somatropin (Norditropin)
Human growth hormone produced by recombinant DNA technology
(mouse C127 cell line). Elicits anabolic and anticatabolic influence on
various cells including: myocytes, hepatocytes, adipocytes,
lymphocytes, and hematopoietic cells. Stimulates growth of linear bone,
skeletal muscle, and organs. Exerts activity on specific cell receptors
including insulinlike growth factor-1 (IGF-1). Indicated for short stature
associated with Noonan syndrome.
FOLLOW UP
Prevention
If a causative mutation is found in patients, parental studies should be
offered in order to distinguish familial cases from sporadic ones. If an
individual carries a germline mutation, prenatal diagnosis can be offered
in future pregnancies.[22] The presentation of Noonan syndrome can vary
widely within families.
Prenatal testing for Noonan syndrome can be considered in the
absence of a family history when cystic hygroma is seen on
ultrasonography and karyotyping of amniocytes is normal.
Recurrence risk for parents who do not appear to be affected or who

have only some facial features of Noonan syndrome is 5%. Gonadal


mosaicism may account for this increase over population risk. Affected
individuals have a 50% chance of passing on the disorder with each
pregnancy.
Patient Education
Once the pattern of inheritance has been identified, parents need to be
counseled regarding recurrence risk with each pregnancy. Sporadic
cases present minimal recurrence risk to the siblings of the affected
child; the exception is parental gonadal mosaicism. Offspring of an
affected individual have a 50% chance of developing Noonan
syndrome.
Patients with bleeding disorders must be advised against the use of
aspirin and aspirin-containing products or other medications that may
interfere with coagulation or platelet function.