Progress in Pediatric Cardiology 20 (2005) 177 – 185

www.elsevier.com/locate/ppedcard

Noonan syndrome and related disorders

Jacqueline A. Noonan*
Division of Cardiology, Department of Pediatrics, University of Kentucky, College of Medicine,
800 Rose Street, Room MN470, Lexington, KY 40536-0298, United States
Available online 13 June 2005

Abstract

Noonan syndrome is a common multiple malformation syndrome seen in children with congenital heart disease. Recently, a mutation
in the PTPN11 gene was found to be present in about 50% of individuals with Noonan syndrome. Over 80% of these patients have
some form of congenital heart disease with pulmonary stenosis often associated with a dysplastic valve being, by far, the most common
lesion. Hypertrophic cardiomyopathy occurs in 20 – 30%. Characteristic facies, chest deformity, short stature, undescended testes in the
male and learning disabilities comprise the Noonan phenotype but there is wide phenotypic variation and a changing phenotype with
age. This phenotype is noted in several other syndromes which share similar cardiac defects. These include LEOPARD,
neurofibromatosis, Noonan syndrome, cardio-facio-cutaneous syndrome and Costello syndrome. A definitive diagnosis is particularly
difficult in infancy.
D 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Noonan syndrome; Dysplastic pulmonary valve; Hypertrophic cardiomyopathy; Cardio-facio-cutaneous syndrome; Costello syndrome

1. Introduction 2. Noonan syndrome

Noonan syndrome is one of the most common non-
chromosomal syndromes seen in children with congenital
heart disease [1]. Affected individuals have characteristic
facies, are usually short, often have a chest deformity and
the majority have some structural cardiac abnormality.
Autosomal dominant inheritance has been well documented
but many cases are sporadic. Until recently, the diagnosis
rested solely on clinical findings but Tartaglia et al. in 2001
[2] found a mutation in the PTPN11 gene to be present in
about 50% of individuals with Noonan syndrome. There are
a number of syndromes which may be difficult to
distinguish from Noonan syndrome, especially in infancy,
and these will also be discussed. All these syndromes have a
high incidence of some form of congenital heart disease.
Pediatric cardiologists should be aware of the variable
clinical picture and the characteristic cardiac findings.
* Corresponding author. Tel.: +1 859 323 5494; fax: +1 859 323 3499.
E-mail address: jnoonan@uky.edu.
1058-9813/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ppedcard.2005.04.008
There is wide phenotypic variation in Noonan syndrome
and the phenotype also changes with time. Distinctive facial
features include hypertelorism, down-slanting palpebral
fissures, a high arched palate, low set posteriorly rotated
ears, malar hypoplasia, ptosis and often a short neck. In the
newborn, Noonan syndrome is difficult to diagnose by
facial appearance alone. The forehead is often sloping and
broad and the ears may be thick and posteriorly angulated.
A helpful sign, if present in the newborn, is the presence of
excessive nuchal skin which is the result of prenatal cystic
hygroma. In infancy, from neonatal to about age two, the
head often appears relatively large. The malar eminences
are flat and the eyes are often prominent and round. There is
a high nasal bridge which may appear flat. The neck is short
but no longer webbed (Figs. 1 and 2). At 2 to 3 years of
age, the body appears more stocky and the chest becomes
more prominent. In later childhood, the facial appearance
shows coarse features but becomes more triangular as the
chin lengthens, the eyes become less prominent and ptosis
may be more apparent. As the neck lengthens, the webbing
may become more obvious. In the teenager and young
178 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
Fig. 1. One-year-old female with Noonan syndrome.
adult, the facial features are more triangular and become
sharper (Fig. 3). The nose has a pinched root and a thin high
bridge. An older adult has prominent nasal labial folds, a
high anterior hairline and the skin often appears rather
transparent and wrinkled. Allanson et al. [3] pointed out the
changing phenotype and suggested that it is important to
ask parents to bring in pictures of them taken at the same
age as the affected child to help determine whether one of
the parents is also affected. The phenotype is variable and
many cases of Noonan syndrome go undiagnosed.
Although most patients with Noonan syndrome have an
unremarkable prenatal history, polyhydramnios is frequent.
Fig. 2. Two-year-old male with Noonan syndrome.
Fig. 3. Eighteen-year-old young lady with Noonan syndrome.
As fetal ultrasound has become more common, cystic
hygroma and fetal edema have been noted in a number of
fetuses who subsequently show signs of Noonan syndrome.
Cystic hygromas often are noted in the second trimester and,
interestingly, many resolve spontaneously by the third
trimester. Fetal edema is frequent which may be demon-
strated by excessive weight loss in the first week following
delivery. Although height and weight are within the normal
limits at birth, height tends to drop off within a few months
of age and over 70% of patients with Noonan syndrome
have significantly short stature [4]. Although many patients
with Noonan syndrome have an uneventful infancy and
early childhood, more than half have some mild feeding
difficulty, especially vomiting. Almost one-quarter will have
severe failure-to-thrive and require tube feedings. Important
other findings include a chest deformity which may be in the
form of a pectus carinatum or pectus excavatum as well as
apparent widely spaced nipples and a relatively broad chest.
Other skeletal findings are frequent and include scoliosis
and kyphosis which occur in about 15% of patients. Muscle
hypotonia is frequent and may account for some of the
motor delay. Although significant mental retardation is
uncommon, some degree of learning disability is frequent
and may require some special help particularly in the lower
grades but most are able to graduate from high school and
many graduate from college and a few have advanced
degrees. Conductive hearing loss is fairly frequent and all
children should have a hearing evaluation. Eye findings are
frequent with strabismus and refractive errors common. An
occasional patient will have a coloboma. Light blue or light
green irides are quite frequent. All children with Noonan
syndrome should have a complete eye examination. About
half the males with Noonan syndrome have one or both
 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
testes undescended and delay in puberty is common for both
males and females. Renal anomalies are seen but they are
generally of little clinical consequence. Neurologic pro-
blems include hypotonia and unexplained peripheral neu-
ropathy. A number of patients with Arnold-Chiari
malformation have been reported. Poor coordination is
reported by some parents and may be attributed to a
combination of muscle hypotonia and visual problems. Skin
and hair findings are relatively frequent. This includes
prominent fetal pads on the fingers and toes. Patients often
have curly hair but, in some, both the hair and eyebrows are
sparse. Both freckles and nevi are relatively common and
café-au-lait spots occasionally occur. In my experience,
there is a tendency for these children to form extensive
keloids following surgical procedures.
Of particular interest to the pediatric cardiologist are the
hematology problems. Hepatosplenomegaly, usually unex-
plained, is present in about 25% of patients particularly in
infancy. Bleeding problems and easy bruising have been
noted fairly frequently. The variety of bleeding problems
includes deficiency of Factor-XI, Von Willebrand disease,
thrombocytopenia and platelet function defects. Deficiency
of factors VIII and XII have also been noted [5 –7]. If there
is any suspicion of a bleeding problem, a prothrombin time,
partial thromboplastin time, bleeding time and platelet count
should be obtained and aspirin or aspirin-containing
products avoided. Lymphatic abnormalities occur in less
than 20% of patients with Noonan syndrome but may
present serious problems. Lymphangiography [8,9] has
demonstrated hypoplasia or absence of superficial lymphatic
channels. As mentioned earlier, fetuses have been reported
with cystic hygroma and puffy hands and feet are relatively
common in severely affected newborns. This edema
generally subsides but, in some, lymphedema develops in
late childhood or as adults. Intestinal lymphangiectasia,
leading to protein losing enteropathy, has been reported
[10]. In 1975, Baltaxe et al. [11] reported pulmonary
lymphangiectasia. Smith et al. [12], in 1979, described a
patient with both chylothorax and protein losing enteropa-
thy. Since then, spontaneous chylothorax has been reported
and chylous effusion following surgery is a known risk in
patients with Noonan syndrome. Complications of these
abnormal lymphatic vessels may include chylothorax,
chyloperitoneum and may lead to malnutrition and lympho-
penia. A report by Goens et al. [13] discussed spontaneous
chylothorax in an 18-month-old child with Noonan syn-
drome who had severe pulmonary stenosis as well as an
atrial septal defect. Balloon valvuloplasty was only mildly
effective. Because the chylous effusion persisted after
thoracentesis, the patient was sent to the operating room
and had an outflow patch placed across the supravalvular
pulmonary stenosis and a partial pulmonary valvulectomy.
He continued to have a chylous leak post-operatively. He
was treated with parenteral alimentation and later a low fat
diet of medium chain triglycerides. The chylous effusion
failed to respond to treatments which included a thoracic
179
duct ligation, two tetracycline pleurodesis and a left
pleurodectomy. A posterior mediastinal lymph node biopsy
specimen showed numerous ectatic lymphatic channels. On
the 49th hospital day, treatment was begun with Prednisone
1 mg/kg twice daily. The effusion resolved over the next 2
days and did not recur. He reviewed the findings from eight
other publications including 10 patients with Noonan
syndrome with chylothorax. In five the chylothorax
occurred spontaneously and five occurred post-operatively.
The majority responded to a low fat diet. Two died, one
from sepsis following ligation of the thoracic duct and
another died after an unsuccessful surgical procedure to
locate the leak. There are a number of unreported cases with
adverse results from persistent chylous thorax particularly in
young infants. This is a poorly understood condition and the
appropriate treatment is still unclear.
2.1. Cardiac findings
The majority of patients with Noonan syndrome have
some cardiac abnormality. The most characteristic lesion is
a dysplastic pulmonary valve but virtually every type of
cardiac defect has been described. In several studies in
which echocardiograms were performed on all patients
suspected to have Noonan syndrome, over 80% [14 – 16]
had some abnormality noted on cardiac ultrasound. The
electrocardiogram is of particular interest. Left axis
deviation and a dominant S wave over the precordial
leads is frequent and may be present in patients with little
or no heart disease (Fig. 4). The cause of this ECG finding
is unknown. In addition, pulmonary stenosis is the most
frequent cardiac lesion noted in Noonan syndrome. The
pulmonary valve may be only mildly dysplastic with no
significant obstruction and the long-term prognosis in these
patients is usually excellent. The typical patient with non-
syndromic pulmonary stenosis, if mild or moderate,
usually does not progress after the age of 2 years.
However, some patients with Noonan syndrome show
rapid progression of valvular obstruction. One of my
patients had a right ventricular pressure of 65 mm Hg at 2
years of age and, by 6 years of age, it had progressed to
160 mm Hg. Although balloon valvuloplasty may reduce
the gradient in patients with dysplastic pulmonary valves
and significant obstruction, it is seldom successful in
abolishing the right ventricular outflow tract obstruction
completely if there is severe dysplasia of the pulmonary
valve. The majority of children with Noonan syndrome
who have significant obstruction will require surgical
treatment. Unfortunately, a simple valvotomy may not be
adequate to relieve the obstruction and it is often necessary
to excise the entire valve. In addition, resection of
anomalous muscle bundles and sometimes an outflow tract
patch will be required. There is a high association of atrial
septal defect as well as pulmonary artery branch stenosis
which may exist with valvar pulmonary stenosis and an
occasional patient will have supravalvular pulmonary
180 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
Fig. 4. EKG of 6-year-old with Noonan syndrome and mild pulmonary stenosis. Unusual axis and prominent S waves are characteristic findings.
stenosis. Fortunately, many children with Noonan syn-
drome have only mild pulmonary stenosis and will never
require any intervention.
Ostium primum atrial defects, ventricular septal defects,
tetralogy of Fallot, Ebstein’s malformation and anomalous
pulmonary venous return have also been reported. Although
right-sided lesions predominate, valvar aortic stenosis,
subaortic stenosis, supravalvular aortic stenosis, coarctation
of the aorta and patent ductus arteriosus have been noted.
So far, there have been no reports of transposition of the
great arteries with Noonan syndrome. All of the cardiac
valves may be dysplastic. Mitral valve prolapse, either
isolated or associated with additional cardiac lesions, has
been noted in a number of patients. Coronary artery
anomalies have been infrequently reported in Noonan
syndrome. These include a coronary fistula, a right coronary
artery aneurysm, a single coronary artery and a proximal
left coronary artery occlusion in a patient who also had
hypertrophic cardiomyopathy [17]. One of my patients had
anomalous origin of the right coronary artery in association
with a ventricular septal defect and pulmonary stenosis.
Primary pulmonary hypertension has been documented in
several patients. I know of one patient who has undergone
successful lung transplantation.
Some degree of hypertrophic cardiomyopathy is felt to
occur in 20 – 30% of patients with Noonan syndrome. The
course and prognosis of hypertrophic cardiomyopathy is
variable and not well understood. The infant presenting with
hypertrophic cardiomyopathy is a particular challenge.
Transient hypertrophic cardiomyopathy has been well
documented in some infants born to diabetic mothers and
is probably one of the most commonly diagnosed causes of
asymmetric septal hypertrophy in the newborn. This
condition is transient and usually resolves without any
therapy. Metabolic diseases such as Pompe’s disease are
another cause of septal hypertrophy and there are a number
of other metabolic and mitochondrial diseases that must be
considered. Other conditions with a phenotype similar to
Noonan syndrome include LEOPARD syndrome, cardio-
facial-cutaneous syndrome and Costello syndrome. When
they present in infancy with hypertrophic cardiomyopathy it
may be particularly difficult to make a firm clinical
diagnosis at that time. Ehlers et al. [18] in 1972 reported
an infant with Noonan syndrome who died of congestive
heart failure at 5 months of age and Hirsch et al. in 1975
[19] reported two infants who had evidence of severe
pulmonary stenosis as well as hypertrophic cardiomyopathy.
One infant showed transient improvement with Propranolol
but because of syncope, underwent surgery at 22 months of
age and died. The second, also treated with Propranolol,
showed transient improvement but then presented with
congestive heart failure and died. In 1994, Sreeram et al.
[20] reported on four infants presenting in the first year of
life. One died at 7 months awaiting surgery for severe
pulmonary stenosis. Another died at 14 months during a
repeat valvuloplasty for a severely dysplastic obstructive
pulmonary valve. Two others died during surgery at 14
months and 5-1/2 years in an attempt to relieve the outflow
obstruction. At post-mortem examination, all four valves
were thickened and dysplastic in three patients while one
had a normal aortic valve. Bilateral hypertrophic cardiomy-
opathy was present in all four. The microscopic findings are
similar to those found in non-syndromic familial hypertro-
phic cardiomyopathy. Myocardial disarray and thick walled
intramural coronary arteries are characteristic findings in
both [21].
 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
In my experience, hypertrophic cardiomyopathy may
have a remarkably variable picture. One of my patients
showed mild asymmetric septal hypertrophy at 2 days of
age. By 9 days, there was a left ventricular outflow gradient
of 51 mm Hg and a thick pulmonary valve. She was first
diagnosed at age 6 weeks with severe Noonan syndrome.
The left ventricular outflow tract gradient had increased to
78 mm Hg and there was a right ventricular gradient of 36
mm Hg. In spite of treatment with Propranolol, the
hypertrophy progressed. By 3-1/2 months, the left ventric-
ular gradient had increased to 100 mm Hg and the right
ventricle to 105 mm Hg and the septum was 1 cm. Her
condition continued to worsen. She required oxygen, tube
feedings and, by 5 months, the gradient had increased to 162
mm Hg across the left ventricular outflow tract and 117 mm
Hg across the right ventricle and the septum measured 1.2
cm. She had gross cardiac enlargement and pulmonary
congestion. Surgical relief was attempted. Anomalous right
muscle bundles were resected. The pulmonary valve was
dysplastic but not obstructive. A septal myectomy was
carried out through the aortic valve. This procedure reduced
the left ventricular gradient to 41 mm Hg and the right
ventricular outflow tract gradient to 38 mm Hg. Unfortu-
nately, she developed renal failure and died 10 days
following surgery. Typical muscle disarray was present in
the surgical specimen. On the other hand, most patients with
Noonan syndrome with both obstructive and non-obstruc-
tive hypertrophic cardiomyopathy remain asymptomatic and
stable for many years. One patient followed by me from
infancy was stable but developed increasing symptoms of
shortness of breath by 12 years of age. Between 7-1/2 and
12 years of age, the right ventricular outflow tract gradient
increased from 20 mm Hg to 58 and the left ventricular
outflow tract from 50 to 100 mm Hg. This was in spite of
treatment with a calcium channel blocker. She underwent
surgical treatment which included resection of the anoma-
lous right ventricular muscle bundles and a left ventricular
myectomy. On follow-up, she continued to have biventri-
cular hypertrophy with systolic anterior motion of the mitral
valve but no gradient was present across the right
ventricular outflow tract and only a small gradient across
the left ventricle. She has continued on calcium channel
blockers and remains stable. At 30 years of age, she
continues to be on medication and has had one episode of
atrial fibrillation. Another patient was documented to
develop hypertrophic cardiomyopathy. At 12 months of
age, he had severe pulmonary stenosis. At cardiac catheter-
ization, his right ventricular pressure was 142/7 mm Hg and
the left ventricle 80/8 mm Hg. The left ventricle appeared
normal by angiography. At operation, a dysplastic pulmo-
nary valve and anomalous muscle bundles were resected
from the right ventricle and an outflow tract patch was
placed. He did well but, at 7 years of age, mild hypertrophic
cardiomyopathy without a significant gradient was noted.
By 9 years, he had developed a peak gradient of 30– 40 mm
Hg but was still completely asymptomatic. At age 10, he
181
died suddenly on the playground. Another patient followed
since childhood through adulthood has always had severe
concentric hypertrophy of both right and left ventricle
without any evidence of obstruction. Right ventricular
biopsy in this patient showed the typical findings of
hypertrophic cardiomyopathy in the right ventricular spec-
imen [22]. It is apparent that there is marked variability in
the natural history of hypertrophic cardiomyopathy. It may
become symptomatic and rapidly progressive in infancy. It
may remain stable for many years or it may develop or at
least become recognized late in childhood. It may resolve,
remain stable or progress. Symptomatic hypertrophic
cardiomyopathy in Noonan syndrome is associated with
significant mortality in infancy. The risk of sudden death in
Noonan syndrome in asymptomatic patients is not well
known. There, however, have been several reports of sudden
unexpected death [14,23]. Treatment for hypertrophic
cardiomyopathy in Noonan syndrome is similar to that in
non-syndromic children with a few children having under-
gone cardiac transplantation. Surgical relief of the symp-
tomatic patient with obstructive cardiomyopathy has been
quite successful in the older child but the risk is very high in
infancy.
An important study by Õstman-Smith et al. [24] reported
66 patients who developed hypertrophic cardiomyopathy
before 19 years of age. Twenty-five of these had Noonan
syndrome. These authors found that the only medical
therapy that significantly reduced the risk of death was
among those given high dose beta blocker treatment. The
authors suggested a starting dose of 1.5– 3 mg/kg/day of
Propranolol and increasing to a minimum of 6 mg/kg/day up
to 23 mg/kg. In infants, an attempt was made to maintain
little variability in the heart rate and to maintain an awake
heart rate between 90 and 110 bpm. Twenty-four hour EKG
recordings were sometimes used when increasingly high
doses of Propranolol. They found a significant reduction in
cardiac hypertrophy in a group of patients on high dose beta
blocker therapy. The older patients were able to adapt well
to quite profound beta blockade and able to manage
schooling and adults were able to continue full-time
employment. In patients with asthma, high dose Metoprolol
was used along with prophylactic inhalers. In addition to a
beta blocker, an antiarrhythmic such as Amiodarone and, in
some cases, Disopyramide were used when indicated. There
are no long-term control studies to guide the clinician in the
most appropriate effective treatment for hypertrophic
cardiomyopathy in childhood. Based on our present
knowledge, beta blockade sufficient to achieve a stable
slow heart rate at present seems to be the most prudent
course.
3. LEOPARD syndrome
In 1969, Gorlin et al. [25] introduced the acronym,
LEOPARD to describe the combination of multiple lenti-
182 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
gines (L), ECG abnormalities (E), ocular hypertelorism (O),
pulmonary stenosis (P), abnormalities of the genitalia (A),
retardation growth (R), and deafness (D). This rare
syndrome shares many features similar to Noonan syndrome
including autosomal dominant inheritance, similar facial
dysmorphism and similar cardiac defect including pulmo-
nary stenosis and hypertrophic cardiomyopathy. The char-
acteristic cutaneous finding of lentigines is the main
distinguishing characteristic. Skin manifestations reported
in Noonan syndrome include café-au-lait spots, pigmented
nevi and occasionally lentigines. Until recently, it was not
clear whether LEOPARD syndrome was a separate syn-
drome or Noonan syndrome with lentigines.
Recently, Sarkozy et al. [26] reported clinical and
molecular studies in a consecutive series of 30 patients
with LEOPARD syndrome which included patients from
Italy and Australia. Mutations in the PTPN11 gene were
found in 27 of the 30 patients studied. Seven different
mutations were found with only one mutation reported
previously in a Noonan syndrome patient. Structural heart
disease was present in 15 of the mutated cases. Hypertro-
phic cardiomyopathy was the most common abnormality
and was found in 12 of 15 with cardiac problems.
Pulmonary stenosis occurred in two patients and a partial
AV canal in one who later developed hypertrophic
cardiomyopathy. Like Noonan syndrome, there is wide
phenotypic variation. The skin lesions are usually not
present in infancy and deafness is variable and may be
unilateral, bilateral or not present. This important study
suggests that hypertrophic cardiomyopathy in patients with
the Noonan syndrome phenotype is likely to be associated
with distinctive mutations in the PTPN-11 gene and have
associated cutaneous findings of café-au-lait spots and
lentigines. From my own perspective, I have and will
continue to consider LEOPARD syndrome as Noonan
syndrome ‘‘with a lot of freckles’’.
4. Neurofibromatosis-Noonan syndrome
In 1985, Allanson et al. [27] reported the association of
a Noonan phenotype with neurofibromatosis. Recently,
Cooley et al. [28] examined sequentially 94 patients with
neurofibromatosis and found phenotypic features of Noo-
nan syndrome in 12 patients. In a recent paper, Baralle et
al. [29] identified six patients with neurofibromatosis-
Noonan syndrome. He examined the neurofibromatosis
type 1 (NF1) gene in these six patients and found several
mutations. Four of these patients were studied for the
PTPN11 gene and no mutations were found. However, a
variety of cardiac lesions were noted. Three had normal
echoes while one had an atrial septal defect, another had
coarctation of the aorta and the third pulmonary stenosis. It
may be difficult to recognize this particular condition in
young children with a Noonan syndrome phenotype since
the café-au-lait spots may not be present in infancy. There
is clearly phenotypic overlap between Noonan syndrome,
LEOPARD syndrome and neurofibromatosis-Noonan syn-
drome. It is too early to know if specific mutations of the
NF1 gene share the Noonan phenotype or if some patients
will have a PTPN11 mutation in addition to NF1 mutation.
Since 50% of neurofibromatosis is sporadic, it will be
important to follow patients diagnosed in infancy with
Noonan syndrome to look for the later development of
café-au-lait spots which might suggest neurofibromatosis.
My own experience includes a mother with neurofibroma-
tosis and a Noonan phenotype with no apparent cardiac
disease. Her son had subaortic stenosis and a daughter
with an ostium primum defect. Another child diagnosed
with Noonan syndrome had aortic stenosis and pulmonary
stenosis. On follow-up, the child was noted to have café-
au-lait spots. Evaluation of the mother revealed that she
had café-au-lait spots and the grandfather had clearly
established neurofibromatosis. Another mother and daugh-
ter with neurofibromatosis with a Noonan phenotype had
mild pulmonary stenosis.
5. Cardio-facio-cutaneous syndrome
It is difficult to distinguish an infant with cardio-facio-
cutaneous syndrome from Noonan syndrome although,
with time, the phenotype becomes more distinctive
[30,31]. Patients with cardio-facio-cutaneous syndrome
have a high forehead, a relatively large head and
bitemporal constriction. They often have a downward slant
of the palpebral fissures, posteriorly rotated ears and a
nasal bridge similar to Noonan syndrome. The hair is
usually sparse, curly and friable. In addition, sparse or
absent eyebrows are relatively frequent. Skin changes are
variable and may include keratosis pilaris with patchy
hyperkeratosis to a severe generalized ichthyosis-like
condition. Skin findings, however, may not be present in
early infancy. In time, the phenotype for cardio-facio-
cutaneous syndrome becomes more distinctive and less
Noonan-like. These patients are usually significantly
delayed in both motor and mental skills. Seizures are
relatively common and autistic behavior well described.
Like Noonan syndrome, infants often have failure-to-
thrive, frequent gastrointestinal complaints and often
require tube feedings. Cardiovascular abnormalities are
present in about 70% and, like Noonan syndrome include
pulmonary stenosis, atrial septal defect and dysplasia of
other valves. Hypertrophic cardiomyopathy occurs in 20–
30%. This group of patients present in infancy with severe
hypertrophic cardiomyopathy that may be difficult to
distinguish from Noonan syndrome. Management of the
cardiac lesion in these patients is similar to that for
Noonan syndrome. Like Noonan syndrome many of the
patients have only mild pulmonary stenosis which will
require no intervention. No PTPN11 mutations have been
found in patients with the syndrome [32].
 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
6. Costello syndrome
Costello syndrome is another rare syndrome which may
be difficult to distinguish from Noonan syndrome in infancy
[33]. These patients have a large head, sparse curly hair,
short wide nose, short neck, all similar to Noonan
syndrome. Unlike Noonan syndrome, Costello syndrome
patients usually have thick and relatively prominent lips and
tongue. They also have loose skin on the hands and feet and
deep palmer and plantar creases. In time, other findings
appear such as nasal papillomata. There is a significant risk
for malignancies in these patients. Costello syndrome
patients tend to be sporadic and have no known mutations
of the PTPN11 gene. Similar to Noonan syndrome and
cardio-facio-cutaneous syndrome, post-natal growth retar-
dation and poor feeding are frequent. There is usually
significant developmental delay. As children, they often
have an outgoing personality. Cardiovascular abnormalities
are found in about 60% [34] and are remarkably similar to
that found in Noonan and cardio-facio-cutaneous syn-
dromes. Pulmonary stenosis, atrial septal defect and
hypertrophic cardiomyopathy are the most prominent
lesions. Of interest is the relatively high incidence of
cardiac arrhythmias noted particularly in infancy. This is not
characteristic of either cardio-facio-cutaneous or Noonan
syndrome. My own limited experience with Costello
syndrome includes a patient who had fibromuscular
subaortic stenosis in addition to hypertrophic cardiomyop-
athy and another with hypertrophic cardiomyopathy who
had significant atrial as well as ventricular arrhythmia as a
young infant. The management of the cardiac lesions in this
syndrome is similar to that in Noonan syndrome.
7. Other conditions
Turner syndrome should be ruled out in female patients
with suspected Noonan syndrome, especially those with
left-sided lesions such as bicuspid aortic valve, aortic
stenosis or coarctation of the aorta. I have never seen a
patient with Turner syndrome who had valvar pulmonary
stenosis. Individual patients with Williams syndrome may
cause some confusion diagnostically but the phenotype is
quite distinctive. Fetal alcohol syndrome should also be
excluded as well as chromosomal abnormalities which may
share some of the phenotypic characteristics.
8. Genotype– phenotype correlations
In 1994, Jamison et al. [35] studied a large three-
generation family and 20 smaller two-generation families
and mapped the gene for Noonan syndrome to the distal part
of chromosome 12q (12q22-qter). Not all families with
Noonan syndrome studied showed this linkage suggesting
more than one gene was likely to be involved in the etiology
183
of Noonan syndrome. In 2002, Tartaglia et al. [2] found a
mutation in the PTPN11 gene to be present in about 50% of
patients with Noonan syndrome. This gene regulates
production of a protein called SHP-2 which is essential in
several intracellular signal transduction pathways and
controls a number of developmental processes including
cardiac semilunar valvulargenesis. The protein is expressed
throughout the body and it is an important player in cellular
response to growth factors, hormones, cytokines, and cell
adhesion molecules. So far, the PTPN11 mutations in
Noonan syndrome are clustered in interacting portions of
N-SH2 and PTP domains with evidence that the mutation
results in a gain of function for SHP-2 [36].
Literature review of six publications [36 –41] reporting
a series of patients with a diagnosis of Noonan syndrome
who underwent a screening for mutations in the PTPN11
gene, all show similar findings. The incidence of PTPN11
mutations ranged from 33% to 60%. A total of 393
patients were studied and 176 (45%) had a mutation. Over
20 different mutations have so far been identified with the
great majority occurring in exons 3, 8 and 13. Congenital
heart disease is present in over 80% of patients with a
mutation. Pulmonary stenosis, often with a dysplastic
pulmonary valve, occurred more frequently among patients
with Noonan syndrome who have a mutation than those
without and was present in 50– 80% of those with a
mutation. Atrial septal defects, ostium primum defects,
small ventricular septal defects, mitral valve abnormalities
and pulmonary artery branch stenosis have all been
reported among patients with a mutation but, so far,
coarctation of the aorta and tetralogy of Fallot have not
been found. In all studies, the incidence of hypertrophic
cardiomyopathy was lower among the patients showing a
mutation ranging from 0 to 10% compared to those
without a mutation of 20 –30%. Patients with LEOPARD
syndrome, which may be considered a variant of Noonan
syndrome, have a very high incidence of mutation.
Twenty-seven of thirty patients (90%) studied had muta-
tions of the PTP11 gene, all occurring in exons 7, 12 and
13 [26]. Seven different mutations have been identified so
far. Congenital heart disease was present in 18 (71%) with
hypertrophic cardiomyopathy present in 14 (57%). Pulmo-
nary stenosis was present in two patients and a partial AV
canal was seen in one individual who also developed
hypertrophic cardiomyopathy.
It will be important to study the specific mutations of the
PTPN11 gene to determine genotype –phenotype correla-
tions. So far, the numbers studied are not sufficient for such
a determination but, clearly, hypertrophic cardiomyopathy
with a Noonan phenotype is likely to be associated with
café-au-lait spots and lentigines and having a mutation in
exon 7, 12 or 13. As a general rule, these patients are less
likely to demonstrate very short stature in contrast to the
more typical Noonan syndrome patient. By physical
examination, it is not possible to diagnose which patient
with Noonan syndrome will have a mutation. Work is
184 J.A. Noonan / Progress in Pediatric Cardiology 20 (2005) 177 – 185
underway to search for other gene mutations which may be
involved in the etiology of Noonan syndrome.
So far, no genetic cause has been found for cardio-
facio-cutaneous syndrome but a mutation of the PTPN11
gene has been ruled-out. Costello syndrome is likely to be
an autosomal dominant genetic disorder involving a
spontaneous mutation. Elastin fiber formation has been
demonstrated to be abnormal in Costello syndrome. Hinek
et al. [42] found fibroblasts from Costello syndrome were
able to produce normal levels of tropoelastin and to
properly position the microfibrillar scaffold but they were
unable to assemble elastin fibers because of a deficiency in
the elastin binding protein. In addition, fibroblast cultures
from Costello syndrome patients showed an increased rate
of proliferation. It has been postulated that Costello
syndrome results in disturbed elastogenesis which would
help explain the interesting skin findings and the increased
proliferation of fibroblasts noted in tissue culture and
might explain the increased tumor rate in Costello
syndrome.
The genetic cause of neurofibromatosis with a Noonan
phenotype is unknown. Mutations of the NF1 gene would
clearly be diagnostic of neurofibromatosis. The possibility
of an additional mutation in the PTPN11 gene would
suggest that these two conditions may rarely occur
together in the same patient. It is also possible that a
particular mutation of the NF1 gene may result in a
phenotype similar to Noonan syndrome. This interesting
entity is poorly understood; however, there is clear
overlap between LEOPARD syndrome and neurofibroma-
tosis-Noonan syndrome.
9. Conclusion
Pediatric cardiologists are often the first to see children
with these syndromes. Referral to a geneticist is important
but a firm clinical diagnosis is often not possible unless there
is a specific diagnostic test available. Unfortunately, less
than 50% of Noonan syndrome patients will have a positive
test for the PTPN11 gene. No diagnostic test is yet available
for cardio-facio-cutaneous, Costello or neurofibromatosis-
Noonan syndromes. However, the cardiac diagnoses are
remarkably similar for all these syndromes and can be
managed in a similar manner. Since genetic mutations may
continue to exert an effect throughout the life of the patient,
it will be important for long-term follow-up through
adulthood. The first patient I reported [43] was found at
38 years of age to have congestive heart failure [44]. At age
six, he had severe pulmonary stenosis and underwent a
pulmonary valvotomy. He had no clinical evidence of a left-
sided lesion at that time. Danetz et al. reported in 1999 [44]
that this patient, at age 38, developed dyspnea, angina and
was found to have bilateral pleural effusions. Cardiac
catheterization revealed a thickened aortic valve with an
89 mm Hg gradient across the left ventricular outflow tract.
There was mild aortic insufficiency with a supravalvular
aortic web and a residual gradient across the right ventricular
outflow tract of 28 mm. A 90% stenotic lesion of the
posterior lateral branch of the left circumflex artery was also
noted. At surgery, there was a supravalvular fibrous ridge
that obscured both sinuses of Valsalva. This was resected
and it was noted that the entire left ventricular outflow tract
was grossly abnormal with diffuse endocardial fibrosis. This
resulted in diffuse fibrotic stenosis of the left ventricular
outflow tract. A fibrous shell, inferior to the right coronary
artery leaflet, was resected and a generous septal myomect-
omy was performed. The intraoperative gradient across the
left ventricular outflow tract was reduced to a peak of 50 and
a mean of 20. Post-operatively, his condition improved and
follow-up transthoracic echo showed no appreciable gradi-
ent across the aortic outflow tract but there was moderate
aortic insufficiency and some decreased left ventricular
function. I have followed other patients who had only mild
pulmonary stenosis but, as adults, demonstrate some
thickening of the aortic valve and mild aortic insufficiency.
It is clear that all patients with Noonan syndrome, as well as
those with these other syndromes should have long-term
cardiac follow-up.
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