Noonan Syndrome - Symptoms, Causes, Treatment NORD

Noonan Syndrome - Symptoms, Causes, Treatment | NORD 12/12/23, 21:52
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Noonan Syndrome
Last updated: August 21, 2019

Years published: 1987, 1990, 1996, 1998, 2000, 2009, 2011, 2012,
2016, 2019
Acknowledgment
NORD gratefully acknowledges Amy E. Roberts, MD, Associate
Professor of Medicine, Harvard Medical School and Cardiovascular
Genetics, Department of Cardiology and Division of Genetics,
Department of Pediatrics, Boston Children’s Hospital and Judith
Allanson, MD, Chief of Department of Genetics, Children’s Hospital
of Eastern Ontario, Ottawa and Professor of Pediatrics, University of
Ottawa, for assistance in the preparation of this report.
DISEASE OVERVIEW
Noonan syndrome is a genetic disorder that is typically evident at
birth (congenital). The disorder is characterized by a wide spectrum
of symptoms and physical features that vary greatly in range and
severity. In many affected individuals, associated abnormalities
include a distinctive facial appearance; a broad or webbed neck; a
low posterior hairline; a typical chest deformity and short stature.
Characteristic features of the head and facial (craniofacial) area may
include widely set eyes (ocular hypertelorism); skin folds that may
cover the eyes’ inner corners (epicanthal folds); drooping of the
upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal
root; a short nose with broad base; and low-set, posteriorly rotated
ears (pinnae). Distinctive skeletal malformations are also typically
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present, such as abnormalities of the breastbone (sternum),

curvature of the spine (kyphosis and/or scoliosis), and outward
deviation of the elbows (cubitus valgus). Many infants with Noonan
syndrome also have heart (cardiac) defects, such as obstruction of
proper blood flow from the lower right chamber of the heart to the
lungs (pulmonary valvular stenosis) and thickening of the ventricular
heart muscle (hypertrophic cardiomyopathy). Additional
abnormalities may include malformations of certain blood and lymph
vessels, blood clotting and platelet deficiencies, learning difficulties
or mild intellectual disability, failure of the testes to descend into the
scrotum (cryptorchidism) by the first year of life in affected males,
and/or other symptoms and findings.
In the majority of cases Noonan syndrome is an autosomal dominant

genetic disorder caused by abnormalities (mutations) in more than
eight genes. The five most commonly involved genes are: PTPN11
(50%), SOS1 (10-13%), RAF1 (5%), RIT1 (5%), and KRAS (less than
5%). Fewer individuals have a mutation in NRAS, BRAF, MEK2, RRAS,
RASA2, A2ML1, and SOS2. Noonan-like disorders are found in
association with mutations in SHOC2 and CBL. Noonan syndrome
caused by pathogenic variants in LZTR1 can be inherited in either an
autosomal dominant or an autosomal recessive manner.
SYNONYMS
female pseudo-Turner syndrome
male Turner syndrome
NS
Turner phenotype with normal chromosomes (karyotype)
SIGNS & SYMPTOMS

Individuals with Noonan syndrome have associated symptoms and
physical findings that vary greatly in range and severity from person
to person. Some affected individuals have only minor facial
abnormalities; others may have the majority of symptoms and
findings associated with the disorder, such as distinctive features of

the head and facial (craniofacial) area, a broad or webbed neck, short
stature, skeletal malformations, congenital heart defects,
malformations of certain blood and lymph vessels, blood clotting and
platelet deficiencies, attention issues, mild intellectual disability,
and/or other abnormalities.
Most infants with Noonan syndrome have characteristic craniofacial

features. In many cases, the head appears relatively large. Affected
infants may have several findings affecting the eyes including widely
set eyes (ocular hypertelorism) that are unusually prominent;
drooping of the upper eyelids (ptosis) and/or unusually thick,
“hooded” eyelids; an eye that turns in or turns out (strabismus);
downwardly slanting eyelids (palpebral fissures); skin folds
(epicanthal folds) that may cover the eyes’ inner corners; and/or
strikingly blue or bluish green colored portions of the eyes (irides).
Many infants with Noonan syndrome also have additional

craniofacial features. These may include an unusually deep vertical
groove in the middle of the upper lip (philtrum); and/or a small chin.
Affected infants may also have a small jaw (micrognathia); crowding
of the lower teeth, low-set, posteriorly rotated external ears (pinnae);
and/or distinctive abnormalities of the nose including a depressed
nasal root, a wide base, and a rounded (bulbous) tip. Affected infants
also often have excessive skin in the neck area (nuchal skin) and a
low hairline at the back of the neck (low posterior hairline).
The facial features of individuals with Noonan syndrome tend to

change in a predictable manner with age. During later childhood, the
face may appear relatively coarse and begin to appear more
triangular in shape; in addition, the neck lengthens, causing the
webbing of the neck (pterygium colli) to appear more pronounced
and/or the large, triangular muscles of the upper back and shoulders
(trapezius) to appear more prominent. During adolescence, the nasal
bridge is thinner and higher, with a “pinched” root and wide base, and
the eyes appear less prominent. During older adulthood,
characteristic features may include an abnormally high hairline on
the forehead; wrinkled, unusually transparent skin; and unusually
prominent folds between the nose and the lips (nasolabial folds). In
addition, individuals with Noonan syndrome may have wispy scalp

hair during infancy that typically becomes more wooly or curly
during later childhood or adolescence. Many affected individuals also
have distinctive eyebrows that appear highly arched and/or
“diamond shaped.”
Many newborns with Noonan syndrome attain normal birth weight.

However, in some newborns, the birth weight may be increased due
to abnormal accumulations of fluid between layers of tissue under
the skin (subcutaneous edema). For example, swelling of the back of
the hands and top of the feet (peripheral lymphedema) is common in
newborns with Noonan syndrome; in such cases, edema affecting
the fingers may result in an increased number of whorls on the
fingertips (abnormal dermatoglyphics). Such edema may be due to
improper or late development of certain lymph vessels (congenital
lymphatic dysplasia).
Some infants with Noonan syndrome may experience feeding

problems and fail to grow and gain weight at the expected rate
(failure to thrive). In addition, children with the disorder tend to be
short for their age, and approximately 20 percent experience
delayed bone maturation. Most affected children have a relatively
normal growth rate (velocity) before puberty; however, the growth
spurt that is typically experienced during puberty may be reduced or
absent in some adolescents. Average adult height is approximately
five feet, four inches (162.5 cm) in males with Noonan syndrome and
approximately five feet (152.7 cm) in females with the disorder.
Individuals with the disorder typically reach their adult height by the
end of the second decade of life. Growth patterns are influenced by
the molecular genetic cause of NS. People with NS harboring
mutations in RAF1 and SHOC2 are shorter than other genotypes,
whereas those with SOS1 and BRAF mutations have more preserved
growth.
Some males and females with Noonan syndrome may also

experience abnormalities in the development of secondary sexual
characteristics. In approximately 60 to 75 percent of males with
Noonan syndrome, one or both testes fail to descend into the
scrotum (unilateral or bilateral cryptorchidism) before birth or during
the first year of life. If not corrected surgically, male reproductive

cells (spermatozoa) may fail to develop properly within the testes
(deficient spermatogenesis), and some affected males may
experience infertility (sterility). Other males with Noonan syndrome
may experience a delayed yet normal acquisition of secondary sexual
characteristics (e.g., increased growth of the testes, scrotum, and
penis; appearance of facial and pubic hair; etc.). According to the
medical literature, puberty may be delayed an average of two years
in such cases. Other males with Noonan syndrome may experience
normal pubertal development. Even in the absence of a history of
cryptorchidism, adult males appear to have decreased fertility. In
females with the disorder, the acquisition of secondary sexual
characteristics (e.g., the appearance of pubic hair, breast
development, and menstruation) may be mildly delayed but is more
often normal. Most females with Noonan syndrome have normal
fertility.
Many individuals with Noonan syndrome also have skeletal

abnormalities. Approximately 70 percent of affected children have a
distinctive chest malformation characterized by abnormal protrusion
of the upper (superior) portion of the breastbone (sternum) and/or
abnormal depression of the lower (inferior) portion of the breastbone
(pectus carinatum and/or pectus excavatum, respectively). In
addition, the chest may be unusually broad, and the nipples may
appear low set. Some affected individuals may have additional
skeletal malformations including rounded shoulders; outward
deviation of the elbows (cubitus valgus); abnormally short fingers
(brachydactyly) with blunt fingertips; and/or front-to-back and/or
sideways curvature of the spine (kyphoscoliosis and/or scoliosis
respectively). Children with NS have a significantly lower total body
bone mineral density when evaluated by DEXA scan putting them at
risk for fractures. There is also an increased incidence of serious
cervical spine disorders, including cervical stenosis, Arnold-Chiari
malformation, and syringomyelia.
Approximately two thirds of infants with Noonan syndrome also

have heart (cardiac) abnormalities at birth (congenital heart defects).
In about half of such cases, affected infants have obstruction of the
normal flow of blood from the lower right chamber (ventricle) of the
heart to the lungs (pulmonary stenosis). In those with pulmonary
stenosis, the heart must work harder to send blood to the lungs for
oxygenation. The symptoms resulting from pulmonary stenosis will
vary, depending on the severity of the stenosis and any other
associated findings. In some severe cases, an affected infant’s heart
may begin to enlarge immediately after birth (i.e., upon initiation of
breathing in the newborn). In such cases, the heart may be unable to
pump blood effectively (heart failure) to the lungs and throughout
the body. Associated symptoms and findings may include bluish
discoloration of the skin and mucous membranes (cyanosis) due to
abnormally low levels of circulating oxygen (hypoxia),
breathlessness, swelling of the abdomen, feeding difficulties, and/or
other abnormalities. Potentially life-threatening complications may
result without appropriate treatment. In less severe cases of
pulmonary stenosis, symptoms may not become apparent until later
childhood. Such symptoms may include breathlessness, easy
fatigability, and/or other abnormalities. In other cases, pulmonary
stenosis may be mild and symptoms may not occur (asymptomatic).
In approximately 30 percent of infants with Noonan syndrome, there

may be an abnormal opening in the fibrous partition (septum) that
divides the two upper chambers (atria) of the heart (atrial septal
defects). Another 20 percent of those with congenital heart defects
may have enlargement (hypertrophy) of the partition that separates
the left and right ventricles (interventricular septum) and, in some
patients, of the left ventricular wall (hypertrophic cardiomyopathy).
Less often, other congenital heart defects may be present (e.g.,
ventricular septal defects, patent ductus arteriosus, atrioventricular
canal defect). According to the medical literature, most individuals
with Noonan syndrome have a single heart defect. However, some
affected individuals may have pulmonary stenosis in combination
with either an atrial septal defect or hypertrophic cardiomyopathy,
for example.
Atrial septal defects occur in approximately 30 percent of those with

Noonan syndrome who have congenital heart defects. In the normal
heart, a small opening is present between the two atria (foramen
ovale) at birth. Shortly after birth, the atrial septum gradually closes
and covers this opening. In infants with atrial septal defects,
however, the atrial septum may not close properly or may be
malformed during fetal development. As a result, the opening
between the atria persists long after it should be closed, causing an
increase in the workload on the right side of the heart and associated
enlargement of the right ventricle, the right atrium, and the main
pulmonary artery. The size, location, and nature of an atrial septal
defect and any associated abnormalities determine the severity of
symptoms.
Many children with atrial septal defects have no symptoms.

However, in some cases, associated symptoms may include poor
weight gain, mild growth delays, and an increased susceptibility to
repeated respiratory infections (e.g., pneumonia) and bacterial
infections of the lining of the heart (endocarditis) and the heart
valves. In rare cases, severely affected children may also experience
breathlessness, easy fatigability with exercise, heart failure, and/or
irregular heartbeats (arrhythmias).
Approximately 20 percent of affected infants with heart defects

experience hypertrophic cardiomyopathy. In most cases, such
abnormal enlargement (hypertrophy) affects a localized area of the
fibrous partition separating the left and right ventricles (anterior
interventricular septal hypertrophy); in other cases, the entire
septum and the wall of the left ventricle may be affected.
Hypertrophic cardiomyopathy may cause reduced cardiac output.
Associated symptoms and findings may include fatigue, brief
fainting episodes (syncope) during exertion or exercise, and heart
failure. Without appropriate treatment, life-threatening
complications may result in some cases. Patients with NS with HCM
have a worse risk profile at presentation compared with other
children with HCM, resulting in significant early mortality (22% at 1
year). Rarely, hypertrophic cardiomyopathy can also develop later in
life.
Some infants with Noonan syndrome may also have malformations

of certain blood vessels, such as the presence of abnormal passages
(fistulas) involving the arteries that supply blood to heart muscle
(coronary arteries). The coronary arteries may also be dilated

(ectatic) and/or curved (tortuous) in contour. In addition, some
affected infants may have malformations of certain lymph vessels
(congenital lymphatic dysplasia). Lymph, a bodily fluid that contains
white blood cells (lymphocytes), fats, and proteins, accumulates
outside blood vessels in spaces between cells in tissues and flows
back into the bloodstream via lymph vessels. In some infants with
Noonan syndrome, lymphatic system malformations may include
underdevelopment (hypoplasia) of certain channels within lymph
tissue through which lymph enters lymph vessels; abnormal
widening (dilatation) of lymph vessels within the lungs (pulmonary
lymphangiectasis); and/or widening (dilatation) of intestinal lymph
vessels (intestinal lymphangiectasis), particularly the vessels that
transport chyle, the milky fluid that is absorbed from food during
digestion. Intestinal lymphangiectasis may result in loss of protein
during intestinal absorption (protein-losing enteropathy), abnormally
low levels of certain circulating white blood cells (lymphopenia), and
loose, foul smelling stools that contain an excessive amount of fat
(steatorrhea). During the teenage years, some individuals with
Noonan syndrome develop swelling of the lower extremities
(lymphedema).
In utero, some affected infants may have an abnormal cystic swelling

beneath the skin in the neck area (cystic hygroma). There may, in
addition, may more amniotic fluid around the baby than usual
(polyhydramnios). Due to lymphatic system malformations and
associated obstruction of normal lymph flow into the bloodstream,
affected infants may have an abnormal accumulation of lymph fluid
in certain tissues (lymphedema). In some cases, edema may affect
tissues and cavities throughout the body (hydrops fetalis).
Approximately 20 to 33 percent of individuals with Noonan

syndrome also have various blood clotting defects (coagulation
factor deficiencies), low levels of circulating platelets in the blood
(thrombocytopenia), and/or improper function of blood platelets.
Platelets are specialized blood cells that help prevent and stop
bleeding. Affected individuals may have low levels of certain
substances in the blood (coagulation factors) that are essential in
the normal blood clotting process, a complex process that is

necessary to stop bleeding (hemostatis). In individuals with Noonan
syndrome, such deficiencies may include low levels of coagulation
factor XI and/or, in some cases, factors XII and/or VIII. Some
affected individuals may have von Willebrand disease; an inherited
condition characterized by deficiency of coagulation factor VIII,
prolonged bleeding time, and impaired adhesion of platelets. In
addition, in rare cases, affected individuals’ urine may have an
abnormally “fishy” smell (trimethylaminuria), a finding that may be
associated with platelet dysfunction. Due to coagulation factor
deficiencies, platelet dysfunction, and/or thrombocytopenia,
affected individuals may have a history of abnormal and easy
bruising and bleeding. They should avoid aspirin-containing
medications.
Some individuals with Noonan syndrome may also abnormal skin

discolorations. In approximately one quarter of affected individuals,
pigmented moles (nevi) may be present. In rare cases, there may be
pale tan or light brown patches (café-au-lait spots) and/or black,
darkish tan or brown “freckle-like” spots (lentigines) on the skin.
Up to 35 percent of individuals with Noonan syndrome may also

have mild intellectual disability. However, many affected individuals
have a normal I.Q. (intelligence quotient). In addition, affected
individuals may experience abnormal delays in the acquisition of
skills requiring the coordination of mental and muscular activity
(psychomotor retardation), learning disabilities, and language delays
that may potentially be due to hypotonia, difficulties speaking
and/or, in some individuals, mild hearing loss. Inattention and
challenges with executive functioning have also been reported. A
lowered speed of information processing and relatively intact
functioning in other cognitive domains characterizes the cognitive
profile of many adults with NS.
CAUSES
Noonan syndrome is most often an autosomal dominant genetic

disorder caused by abnormalities (mutations) in several different
genes, the main ones being: PTPN11, KRAS, SOS1 RIT1 and RAF1.
PTPN11 mutations have been found in approximately 50% of
affected individuals; KRAS mutations have been found in fewer than
5% of those affected; SOS1 mutations have been seen in
approximately 13% of people with Noonan syndrome; RIT1 mutations
have been seen in approximately 5% of people with Noonan
syndrome, and RAF1 mutations are observed in 5% of those affected.
Additional genes associated with Noonan syndrome have been
identified in fewer cases: NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1,
and SOS2. Two conditions with overlap are newly described in
association with mutations in SHOC2 and CBL. Noonan syndrome
caused by pathogenic variants in LZTR1 can be inherited in either an
autosomal dominant or an autosomal recessive manner.
Dominant genetic disorders occur when only a single copy of an

abnormal gene is necessary to cause a particular disease. The
abnormal gene can be inherited from either parent or can be the
result of a new mutation (gene change) in the affected individual.
Approximately 50% of affected individuals have an affected parent.
The risk of passing the abnormal gene from affected parent to
offspring is 50% for each pregnancy. The risk is the same for males
and females.
Recessive genetic disorders occur when an individual inherits the

same abnormal gene for the same trait from each parent. If an
individual receives one normal gene and one gene for the disease,
the person will be a carrier for the disease, but usually will not show
symptoms. The risk for two carrier parents to both pass the
defective gene and, therefore, have an affected child is 25 percent
with each pregnancy. The risk to have a child who is a carrier like the
parents is 50 percent with each pregnancy. The chance for a child to
receive normal genes from both parents and be genetically normal
for that particular trait is 25 percent. The risk is the same for males
and females.
AFFECTED POPULATIONS
Noonan syndrome appears to affect more males than females and is

thought to affect approximately one in 1,000 to one in 2,500 people.
However, other reports indicate that the disorder may affect more
than one in 1,000 newborns in the general population. Since Noonan
syndrome was originally reported in 1883 (O. Kobylinski) and more
thoroughly described in 1963 (J.A. Noonan and D.A. Ehmke), more
than 500 patients shave been discussed in the medical literature.
Because Noonan syndrome is extremely variable and therefore may
be under- or misdiagnosed, it may be difficult to determine the true
frequency of the disorder in the general population.
DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders may be similar to those of
Noonan syndrome. Comparisons may be useful for a differential
diagnosis:
Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic

disorder, is characterized by a distinctive facial appearance similar to
that seen in children with Noonan syndrome. Additional primary
characteristics may include unusually sparse, brittle, curly hair; skin
abnormalities; heart malformations that are present at birth
(congenital heart defects); growth delays; and moderate to severe
intellectual disability. Individuals with cardiofaciocutaneous
syndrome typically have an unusually large head (macrocephaly), a
prominent forehead, and abnormal narrowing of both sides of the
forehead (bitemporal constriction); a short, upturned nose with a
depressed nasal root; eye findings including downwardly slanting
eyelids (palpebral fissures), widely spaced eyes (ocular
hypertelorism), and/or drooping of the upper eyelids (ptosis). In most
patients, congenital heart defects are also present, particularly
obstruction of the normal flow of blood from the lower right
chamber (ventricle) of the heart to the lungs (pulmonary valve
stenosis) and/or an abnormal opening in the fibrous partition
(septum) that divides the two upper chambers (atria) of the heart
(atrial septal defects). Thickening of the heart muscle (hypertrophic
cardiomyopathy) can also be found. In addition, most individuals
with the disorder experience growth delays, moderate to severe
intellectual disability, and abnormal delays in the acquisition of skills

requiring the coordination of mental and muscular activity
(psychomotor retardation). Cardiofaciocutaneous syndrome is
caused by mutations in several genes: BRAF, MEK1 and 2, and KRAS.
(For more information choose “CFC Syndrome” as your search term
in the Rare Disease Database.)
Turner syndrome is a chromosomal disorder that has some

similarities to Noonan syndrome. In fact, because some individuals
with Noonan syndrome may superficially resemble those with Turner
syndrome (due to certain findings that may be associated with both
disorders, such as short stature, webbed neck, etc.), Noonan
syndrome has in the past been referred to as “male Turner
syndrome,” “female pseudo-Turner syndrome,” or “Turner phenotype
with normal chromosomes”. However, there are many important
differences between the two disorders. Noonan syndrome affects
both males and females, and there is a normal chromosomal makeup
(karyotype). Only females are affected by Turner syndrome, which is
characterized by abnormalities affecting the X chromosome.
Females with Turner syndrome may have a short, webbed neck with
a low posterior hairline; short stature; drooping of the upper eyelids
(ptosis) and/or widely spaced eyes (ocular hypertelorism); widely
spaced, inverted, and/or underdeveloped (hypoplastic) nipples;
congenital heart defects, especially coarctation; and/or kidney
abnormalities. In almost all cases, immature (streak) ovaries are
present that cannot produce the female hormone estrogen. As a
result, normal secondary sexual characteristics, such as the
appearance of pubic hair, breast development, and menstruation
(primary amenorrhea) fail to develop during puberty. Almost all
affected females are infertile. Although intellectual abilities are
usually normal, some individuals may experience difficulties with
visual-spatial relationships (e.g., right-left disorientation). (For more
information on Turner syndrome, please choose “Turner” as your
search term in the Rare Disease Database.)
Costello syndrome is a rare genetic disorder characterized by growth

delay after birth (postnatal), leading to short stature; a distinctive
facial appearance; excessive, loose skin on the neck, palms of the
hands, fingers, and soles of the feet; development of benign (non-

cancerous) growths (papillomata) around the mouth (perioral),
nostrils (nares) and anus; and mild to moderate intellectual disability.
Newborns with the disorder may have an abnormal accumulation of
lymph fluid in tissues throughout the body (generalized
lymphedema) and high birth weight. In addition, affected infants
often have severe feeding and swallowing difficulties and may fail to
grow and gain weight at the expected rate (failure to thrive).
Characteristic craniofacial abnormalities associated with the disorder
may include an unusually large head (macrocephaly) and wide
forehead; a large, depressed nasal root; abnormally wide nostrils; skin
folds (epicanthal folds) that may cover the eyes’ inner corners; low-
set ears with large, thick lobes; and/or unusually thick lips. Other
physical features may include the development of dry, hardened,
thickened skin on the palms of the hands and the soles of the feet
(palmoplantar hyperkeratosis) and/or abnormally deep creases on
the palms and soles. Many affected individuals may also have
congenital heart defects similar to those found in Noonan and CFC
syndromes. More distinctive is the presence of unusual and chaotic
rhythms in about a third. Most cases of Costello syndrome occur
sporadically, with no family history of the disorder, and are caused by
mutations in HRAS. (For more information on this disorder, choose
“Costello” as your search term in the Rare Disease Database.)
Multiple giant cell lesions are abnormal cysts (lesions) involving

certain large cells (giant cells) within bone and soft tissue of the jaw.
They are found in Noonan syndrome and other overlapping disorders
such as CFC syndrome and are usually diagnosed in the first two
decades.
Neurofibromatosis-Noonan syndrome is characterized by the

occurrence of neurofibromatosis type I in association with some
manifestations of Noonan syndrome. Associated symptoms and
findings may include multiple benign tumors of the nerves and skin,
short stature, webbing of the neck (pterygium colli), muscle
weakness, and/or learning disabilities. Affected individuals may also
have certain craniofacial abnormalities associated with Noonan
syndrome including drooping of the upper eyelids (ptosis), low-set
ears, and/or unusually prominent folds between the nose and the lips
(nasolabial folds). In addition, congenital heart defects often seen in
Noonan syndrome may be present, such as obstruction of the
normal outflow of blood from the lower right chamber (ventricle) of
the heart (pulmonary stenosis) and/or an abnormal opening in the
fibrous partition (septum) between the upper chambers (atria) of the
heart (atrial septal defect). Neurofibromatosis-Noonan syndrome
can be due to the chance occurrence of both disorders in the same
individuals, can be a phenotype of neurofibromatosis type I, or can
be a separate disease entity caused by mutations in the NF1 gene
but without some of the characteristic features of NF1.
Noonan syndrome with multiple lentigines (NSML, formerly known

as LEOPARD syndrome) is a rare inherited disorder characterized by
abnormalities of the skin, the structure and function of the heart, the
inner ear, the head and facial (craniofacial) area, and/or the genitals.
In individuals with the disorder, the range and severity of symptoms
and physical characteristics may vary from person to person.
Some of the most common features include lentigines (multiple

black or dark brown spots on the skin); electrocardiographic
conduction defects (abnormalities of the electrical activity and the
coordination of proper contractions of the heart); hypertrophic
cardiomyopathy, ocular hypertelorism (widely-spaced eyes);
pulmonary stenosis (obstruction of the normal outflow of blood from
the right ventricle of the heart); abnormalities of the genitals (in boys
usually undescended testes (cryptorchidism); slowed growth
resulting in short stature, delayed development; and deafness or
hearing loss due to malfunction of the inner ear (sensorineural
deafness). NSML is an autosomal dominant genetic disorder caused
by a mutation in one of two genes: PTPN11 or RAF1. (For more
information choose “LEOPARD Syndrome” as your search term in the
Rare Disease Database.)
DIAGNOSIS
In some cases, Noonan syndrome may be suspected before birth

(prenatally) based upon results of fetal ultrasonography, a
specializing imaging technique in which sound waves are used to
create an image of the developing fetus. A diagnosis of Noonan
syndrome may be considered due to abnormal maternal serum triple
screen, detection of excessive amniotic fluid surrounding the fetus
within the amniotic sac (polyhydramnios), the presence of an
abnormal cystic swelling consisting of dilated lymph vessels in the
neck area (cystic hygroma), a structural heart difference, other fetal
anomalies, and confirmation of a normal chromosomal makeup
(karyotype). However, in many cases, Noonan syndrome is
diagnosed at birth or early infancy based upon a thorough clinical
evaluation, identification of characteristic physical findings, and a
variety of specialized tests. If Noonan syndrome is suspected
prenatally, molecular genetic testing is available by amniotic fluid or
cell free fetal DNA analysis.
It is important to note that, in some cases, individuals who have only

minor, subtle characteristics associated with Noonan syndrome may
not receive a diagnosis. Physicians who specialize in diagnosing and
treating heart abnormalities (cardiologists) should suspect the
possibility of Noonan syndrome in any individuals who have
congenital pulmonary valve stenosis. Because Noonan syndrome
may be difficult to confirm in such cases (particularly if there is no
family history of the disorder), Noonan syndrome should be strongly
considered as a possible diagnosis in any individuals with pulmonary
valve stenosis and certain eye abnormalities typically found even in
the more mild cases (e.g., ptosis, epicanthal folds, ocular
hypertelorism). In addition, in such cases, all immediate (first-degree)
relatives should be examined for mild facial abnormalities and cardiac
defects potentially occurring in association with Noonan syndrome.
In many individuals with the disorder, certain advanced imaging

techniques and laboratory tests may be used to detect, confirm,
and/or characterize specific abnormalities that may be associated
with Noonan syndrome.
Congenital heart defects that occur in association with Noonan

syndrome may be detected and/or confirmed by a thorough clinical
examination and specialized tests that allow physicians to evaluate
the structure and function of the heart. Clinical examination may
include a physician’s evaluation of heart and lung sounds through use
of a stethoscope. In mild asymptomatic cases of pulmonary stenosis,
the condition may initially be detected through an abnormal heart
murmur heard during such stethoscopic evaluation.
Specialized cardiac tests may include electrocardiography (EKG),

echocardiography, and/or cardiac catheterization. An EKG, which
records the electrical activities of the heart muscle, may reveal
abnormal electrical patterns (e.g., left axis deviation, left anterior
hemiblock, deep S wave). During an echocardiogram, sound waves
are directed toward the heart, enabling physicians to study cardiac
function and motion. During cardiac catheterization, a small hollow
tube (catheter) is inserted into a large vein and threaded through the
blood vessels leading to the heart.
This procedure allows physicians to determine the rate of blood flow

through the heart, measure the pressure within the heart, and/or
thoroughly identify anatomical abnormalities. In addition, physicians
may also closely evaluate respiratory (ventilatory) capabilities since
associated heart defects may result in inadequate blood supply to
the lungs and breathlessness.
Specialized blood tests may be performed to detect potential

coagulation factor deficiencies and/or platelet dysfunction.
Molecular genetic testing for mutations in the associated genes is

available to confirm the diagnosis and for prenatal diagnosis.
STANDARD THERAPIES
Treatment
The treatment of Noonan syndrome is directed toward the specific

complications that are apparent in each individual. Treatment may
require the coordinated efforts of a team of specialists. Pediatricians,
physicians who diagnose and treat heart abnormalities

(cardiologists), physicians who diagnose and treat disorders of the
blood and blood-forming tissues (hematologists), physicians who
diagnose and treat disorders of growth (endocrinologists) and/or
other health care professionals may need to systematically and
comprehensively plan an affected child’s treatment.
In some individuals with congenital heart defects, treatment with

certain medications, surgical intervention, and/or other techniques
may be necessary. In such cases, any surgical procedures performed
will depend upon the location, severity, and/or combination of
anatomical abnormalities and their associated symptoms. Cardiac,
arteriovenous, and/or lymphatic malformations that may be present
must be taken into consideration during decisions concerning
surgical procedures. For example, during certain types of surgery
performed on lymphangiomas, there is an increased risk that chyle
may escape from the largest lymph channel in the body (thoracic
duct) into the cavity between the neck and the diaphragm (thoracic
cavity), potentially causing life-threatening complications
(chylothorax).
For those who also have thrombocytopenia, platelet dysfunction,

and/or coagulation factor deficiencies, physicians, dentists, and/or
other health care workers may recommend certain preventive
measures before or take certain supportive measures during surgery
to prevent, lower the risk of, or control abnormal bleeding.
Respiratory infections should be treated promptly and vigorously.

Because of the potentially increased risk of bacterial infection of the
lining of the heart (endocarditis) and the heart valves, affected
individuals with certain heart defects may be given medication prior
to any surgical procedures, including dental procedures, such as
tooth extractions.
In affected males with cryptorchidism, surgery should be performed

to move undescended testes into the scrotum and attach them in a
fixed position (orchiopexy). Such surgery is typically performed
between 12 and 24 months of age to help prevent the risk of
associated infertility.
In addition, appropriate supportive measures may be used in

affected individuals with lymphedema.
Early intervention may be important in helping children with Noonan

syndrome reach their potential. Special services that may be
beneficial to affected children may include special remedial
education, speech therapy, physical therapy, and other medical,
social, and/or vocational services. The short stature in patients with
Noonan syndrome can be treated with growth hormone which has
been shown to improve final adult height.
Genetic counseling is recommended for affected individuals and

their families. As mentioned earlier, thorough clinical evaluations may
be important in family members of diagnosed individuals to detect
any symptoms and physical characteristics that may be associated
with Noonan syndrome. Other treatment for the disorder is
symptomatic and supportive.
CLINICAL TRIALS AND STUDIES

Information on current clinical trials is posted on the Internet at
www.clinicaltrials.gov. All studies receiving U.S. Government funding,
and some supported by private industry, are posted on this
government web site.
For information about clinical trials being conducted at the NIH

Clinical Center in Bethesda, MD, contact the NIH Patient
Recruitment Office:
Tollfree: (800) 411-1222

TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on
the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-
trials/
For information about clinical trials sponsored by private sources,

contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/
Contact for additional information about Noonan syndrome:

Amy E. Roberts, MD
Associate Professor of Medicine
Harvard Medical School
Department of Cardiology and Division of Genetics, Department of
Medicine
Boston Children’s Hospital
Tel: 617-355-8794
Fax: 617-739-6282
RESOURCES
Please note that some of these organizations may provide
information concerning certain conditions potentially associated
with this disorder.
REFERENCES
TEXTBOOKS
Allanson JE. Noonan Syndrome. In: The NORD Guide to Rare
Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:
722-723.
JOURNAL ARTICLES
Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT,
Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung
VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain
M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A,
Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze
D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH,
Zweier C, Zenker M, Lee B, Biesecker LG, et al. Autosomal recessive

Noonan syndrome associated with biallelic LZTR1 variants. Genet
Med. 2018;20:1175–85. PMID: 29469822.
Prendiville TW, Gauvreau K, Tworog-Dube E, Patkin L, Kucherlapati

RS, Roberts AE, Lacro RV. Cardiovascular disease in Noonan
syndrome. Arch Dis Child. 2014 Jul;99(7):629-34. Epub 2014;Feb 17.
PMID: 24534818
Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome.

Lancet. 2013 Jan 26;381(9863):333-42. doi: 10.1016/S0140-
6736(12)61023-X. Epub 2013;Jan 10. Review.PMID:23312968
Briggs BJ, Dickerman JD. Bleeding disorders in Noonan syndrome.

Pediatr Blood Cancer. 2012;58(2):167-72.
Malaquias AC, Brasil AS, Pereira AC, et al. Growth standards of
patients with Noonan and Noonan-like syndromes with mutations in
the RAS/MAPK pathway. Am J Med Genet. 2012;Nov;158A(11):2700-
6.
Smpokou P, Tworog-Dube E, Kucherlapati RS, Roberts AE. Medical

complications, clinical findings, and educational outcomes in adults
with Noonan syndrome. Am J Med Genet A. 2012
Dec;158A(12):3106-11. doi: 10.1002/ajmg.a.35639. Epub 2012 Nov 19.
PMID: 23165751
Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with
Noonan syndrome and hypertrophic cardiomyopathy: A study from
the Pediatric Cardiomyopathy Registry. Am Heart J.
2012;164(3):442-8.
Wingbermühle E, Roelofs RL, van der Burgt I, et al. Cognitive

functioning of adults with Noonan syndrome: a case-control study.
Genes Brain Behav. 2012;Oct;11(7):785-93.
Baldassarre G, Mussa A, Dotta A, et al. Prenatal features of Noonan

syndrome: prevalence and prognostic value. Prenat Diagn.
2011;31(10):949-54.
Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically

related disorders. Best Pract Res Clin Endocrinol Metab.
2011;Feb;25(1):161-79.
Romano AA, Allanson JE, Dahlgren J, et al. Noonan syndrome: clinical

features, diagnosis, and management guidelines. Pediatrics.
2010;126(4):746-59.
Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube

E, SeidenbergMS Genotype differences in cognitive functioning in
Noonan syndrome. Genes Brain Behav. 2009;8(3):275-82.
Noordam C, Peer PGM, Francois I, De Schepper J, van der Burgt I,

Otten BJ . Long-term GH treatment improves adult height in children
with Noonan syndrome with and without mutations in protein
tyrosine kinase phosphatase, non-receptor-type 11. Eur J Endocrinol.
2008;159: 203-6.
Osio D, Dahlgren J, Wikland KA, et al. Improved final height with

long-term growth hormone treatment in Noonan syndrome. Acta
Paediatr. 2005;94:1232-7.
INTERNET
Allanson JE, Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated

2019 Aug 8]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington,
Seattle; 1993-2019. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1124/ Accessed August 20,
2019.
Programs & Resources

RARECARE® ASSISTANCE PROGRAMS
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we don’t have a program for you now, please continue to check back
with us.
ADDITIONAL ASSISTANCE PROGRAMS
MedicAlert Assistance Program
NORD and MedicAlert Foundation have teamed up on a new

program to provide protection to rare disease patients in
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https://rarediseases.org/patient-assistance-
programs/medicalert-assistance-program/
Rare Disease Educational Support Program
Ensuring that patients and caregivers are armed with the tools
they need to live their best lives while managing their rare
condition is a vital part of NORD’s mission.
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disease-educational-support/
Rare Caregiver Respite Program
This first-of-its-kind assistance program is designed for

caregivers of a child or adult diagnosed with a rare disorder.
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PATIENT ORGANIZATIONS
RASopathies Network
NORD Member
https://rarediseases.org/organizations/rasopathies-network/
Human Growth Foundation

Phone: 516-671-4041 Email: [email protected]
Fax: 516-671-4055
https://rarediseases.org/organizations/human-growth-
foundation/
MAGIC Foundation
https://rarediseases.org/organizations/magic-foundation/
American Heart Association

Fax: 214-784-1307
https://rarediseases.org/organizations/american-heart-
association/
Restricted Growth Association

Fax: 300-111-2454
https://rarediseases.org/organizations/restricted-growth-
association/
NIH/National Heart, Lung and Blood Institute

Fax: 301-251-1223
https://rarediseases.org/organizations/nih-national-heart-lung-
and-blood-institute/
Noonan Syndrome Foundation

https://rarediseases.org/organizations/noonan-syndrome-
foundation/

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Home / Rare Diseases / Noonan Syndrome

Last updated: August 21, 2019

present, such as abnormalities of the breastbone (sternum),

In the majority of cases Noonan syndrome is an autosomal dominant

male Turner syndrome

Turner phenotype with normal chromosomes (karyotype)

SIGNS & SYMPTOMS

findings associated with the disorder, such as distinctive features of

Most infants with Noonan syndrome have characteristic craniofacial

Many infants with Noonan syndrome also have additional

The facial features of individuals with Noonan syndrome tend to

addition, individuals with Noonan syndrome may have wispy scalp

Many newborns with Noonan syndrome attain normal birth weight.

Some infants with Noonan syndrome may experience feeding

Some males and females with Noonan syndrome may also

the first year of life. If not corrected surgically, male reproductive

Many individuals with Noonan syndrome also have skeletal

Approximately two thirds of infants with Noonan syndrome also

In approximately 30 percent of infants with Noonan syndrome, there

Atrial septal defects occur in approximately 30 percent of those with

Many children with atrial septal defects have no symptoms.

Approximately 20 percent of affected infants with heart defects

Some infants with Noonan syndrome may also have malformations

(coronary arteries). The coronary arteries may also be dilated

In utero, some affected infants may have an abnormal cystic swelling

Approximately 20 to 33 percent of individuals with Noonan

the normal blood clotting process, a complex process that is

Some individuals with Noonan syndrome may also abnormal skin

Up to 35 percent of individuals with Noonan syndrome may also

Noonan syndrome is most often an autosomal dominant genetic

Dominant genetic disorders occur when only a single copy of an

Recessive genetic disorders occur when an individual inherits the

Noonan syndrome appears to affect more males than females and is

DISORDERS WITH SIMILAR SYMPTOMS

Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic

intellectual disability, and abnormal delays in the acquisition of skills

Turner syndrome is a chromosomal disorder that has some

Costello syndrome is a rare genetic disorder characterized by growth

hands, fingers, and soles of the feet; development of benign (non-

Multiple giant cell lesions are abnormal cysts (lesions) involving

Neurofibromatosis-Noonan syndrome is characterized by the

Noonan syndrome with multiple lentigines (NSML, formerly known

Some of the most common features include lentigines (multiple

In some cases, Noonan syndrome may be suspected before birth

It is important to note that, in some cases, individuals who have only

In many individuals with the disorder, certain advanced imaging

Congenital heart defects that occur in association with Noonan

Specialized cardiac tests may include electrocardiography (EKG),

This procedure allows physicians to determine the rate of blood flow

Specialized blood tests may be performed to detect potential

Molecular genetic testing for mutations in the associated genes is

The treatment of Noonan syndrome is directed toward the specific

physicians who diagnose and treat heart abnormalities

In some individuals with congenital heart defects, treatment with

For those who also have thrombocytopenia, platelet dysfunction,

Respiratory infections should be treated promptly and vigorously.

In affected males with cryptorchidism, surgery should be performed

In addition, appropriate supportive measures may be used in

Early intervention may be important in helping children with Noonan