CLINICAL OVERVIEW  

Noonan Syndrome 
Elsevier Point of Care  (ver detalles)
Actualizado June 21, 2022. Copyright Elsevier BV. All rights reserved.

Synopsis

Key Points
Noonan syndrome is a congenital syndrome characterized by variable phenotype that may include:

Dysmorphic facial features

Most prominent in infants and become less dramatic with age; distinctive features may include down-
slanting palpebral fissures; ptosis; hypertelorism; and low-set, posteriorly rotated ears

Sternal deformity and webbed neck

Congenital heart disease (eg, pulmonary valve stenosis, hypertrophic cardiomyopathy)

 Cryptorchidism, lymphatic abnormalities, and bleeding disorders

Postnatal short stature and pubertal delay

Prenatal diagnosis may be suspected mainly based on abnormalities seen on prenatal ultrasonography; targeted
prenatal molecular testing may confirm diagnosis

Postnatal diagnosis is largely clinical; genetic testing may play a role in certain patients

Baseline screening for associated congenital anomalies at the time of diagnosis includes echocardiography and
ECG with cardiology consultation, CBC with differential, prothrombin time/partial thromboplastin time, renal
ultrasonography, hearing and ophthalmologic assessments, and multidisciplinary developmental evaluation

Treatment mainly involves promoting growth, managing associated congenital anomalies, and monitoring for
acquired diseases that frequently are associated with Noonan syndrome

Cardiovascular disease (eg, pulmonic stenosis, hypertrophic cardiomyopathy) is managed in standard fashion
according to established guidelines for general population

Feeding difficulties, gastrointestinal reflux, and failure to thrive in infancy may require multidisciplinary care
(eg, nutrition specialist, gastroenterologist, feeding team)

Treatment of bleeding diathesis is driven by presence of specific factor deficiency and/or platelet abnormality

Short stature may be managed with hGH treatment in consultation with endocrinologist

Pubertal delay is managed with sex hormone induction in consultation with endocrinologist

Developmental delay often requires multidisciplinary care (eg, occupational and physical therapy, speech
therapy, early intervention program)
 Lifelong monitoring for cardiac manifestations (eg, development of hypertrophic cardiomyopathy, pulmonary
valve dysfunction) requires consultation with cardiologist

Prognosis is good for most patients; among patients who develop cardiomyopathy, up to 25% die in the first year
from heart failure 1

Pitfalls
Abnormalities in coagulation cascade and platelet count are not uncommon and may result in excessive bleeding
with invasive surgical procedures

Screen for and define precise hemostatic abnormality before elective surgery so that abnormalities can be
appropriately managed 2

Terminology

Clinical Clarification
Noonan syndrome is a congenital syndrome characterized by a variable phenotype that may include: 2 3

Distinctive facial dysmorphology, sternal deformity, and webbed neck

Congenital heart disease (eg, pulmonary valve stenosis, hypertrophic cardiomyopathy)

Cryptorchidism

Lymphatic abnormalities and bleeding disorders

 Postnatal short stature and pubertal delay

Developmental delay and mild learning disabilities

Diagnosis

Clinical Presentation

History
Timing of diagnosis varies. Some patients are diagnosed in infancy, but in
others the condition does not become evident until childhood or adolescence

Common presentations include a variety of manifestations, either alone or in Two children with Noonan
combination syndrome. - These 2 children with
Noonan syndrome show similar
facial features (broad forehead, wide
Dysmorphic facial or other characteristic features (eg, webbed neck, sternal
spaced down-slanted eyes, low-set
deformity) posteriorly rotated ears) with
proportionate short stature, wide set
Congenital heart disease or hypertrophic cardiomyopathy nipples, hypertrophic
cardiomyopathy (left) and atrial
Failure to thrive with feeding difficulties in infants septal defect with pulmonic stenosis
(right). Both had feeding problems,
with mildly delayed development
Lymphedema, excess nuchal folds, or cryptorchidism in newborns
later.

Easy bruising or excessive bleeding with surgical procedures

 Slowed linear growth or short stature in children

Findings from prenatal screenings may suggest Noonan syndrome

Nonspecific abnormalities that may be found on ultrasonography include:

Increased nuchal translucency and polyhydramnios

Noonan syndrome. - A, An 18-year-
old man with Noonan syndrome
Congenital cardiac defects, cystic hygroma, pleural effusion, edema, or (Turner phenotype with normal
renal abnormalities genotype). There is typical webbing
of the neck. Long hair obscures low
Results of targeted genetic testing of fetal samples may confirm specific anterior and posterior hair lines. B,
pathogenic variants known to cause Noonan syndrome A 24-year-old man with Noonan
syndrome and a dissecting
aneurysm of the ascending aorta.
Karyotype is within reference range 3
There is a low posterior hairline,
webbing of the neck, low-set
Family history auricles, and micrognathia.

Parent may have Noonan syndrome, whether diagnosed or not

If family history is negative, carefully assess parents; this may uncover subtle findings consistent with Noonan
syndrome that were not previously recognized

Physical examination
Findings are variable

Neonates: birth weight, length, and head circumference are usually within reference range because intrauterine
growth generally is typical 2 4

Dysmorphic features characteristically evolve considerably with age 3 5

Neonates

Facial dysmorphology

Large head compared with face 3

High forehead with narrow temples 1

Wide-set eyes (ie, ocular hypertelorism) 1

Downward slant of palpebral fissures 1

Epicanthal folds 1

Short, broad nose with depressed root and full tip 1

Deeply grooved philtrum 1

Full lips with high, wide peaks to the vermilion border of upper lip 1

Small chin (micrognathia) 1

Oval, low-set, posteriorly rotated ears with thick helixes 3

Low posterior hairline 1

General dysmorphology

Short neck 3

Excess nuchal skin 1

3
 Swelling of the dorsal aspect of hands and feet 3

Infants

Large head 1

Wispy hair

Tall and prominent forehead 1

Thickly hooded, prominent eyes and ptosis

Hypertelorism 1

Wide-based, depressed nose with bulbous, upturned tip

Cupid bow appearance of upper lip 3

Children and adolescents

Facial dysmorphology

Inverted triangle–shaped head (ie, wide forehead tapering to pointed chin)

Thick, curly or woolly hair is common; thin, sparse hair has also been reported 1

Face often lacks expression (ie, myopic facies) 6

Coarse facial features 1

General dysmorphology
 Broad, webbed neck and prominent trapezius musculature 3 6

Pectus sternal deformity with prominent superior sternum (pectus carinatum) and depressed inferior
sternum (pectus excavatum) 1

Widely spaced nipples

Cubitus valgus deformity of upper extremity (ie, increased carrying angle at elbow joint)

Adults

Facial dysmorphology

Inverted triangle–shaped head

High anterior hairline

Prominent nasolabial folds

General dysmorphology

Transparent, wrinkled skin 1

Features that persist in most age groups include:

Arched and diamond-shaped eyebrows 1

Vivid blue or blue-green irises 1 6

Ptosis, hypertelorism, epicanthal folds, and downward slant of palpebral fissures 3 6

3
 High-arched palate 3

Low-set, posteriorly rotated ears with thick helixes 1 6

Low posterior hairline 7

Associated congenital anomalies

Cardiac anomalies

Occur in 50% to 80% of patients with Noonan syndrome and may include: 6

Pulmonary valve stenosis (20%-50%) 6

Often occurs with dysplastic pulmonary valve 3

May be isolated or may occur with other cardiac defects 6

Hypertrophic cardiomyopathy (20%-30%) 2

May be congenital or develop in childhood 2

May be mild or severe

Atrial septal defect (6%-10%) 1

Less common anomalies include ventricular septal defect, peripheral pulmonary stenosis, atrioventricular
canal, aortic stenosis, mitral valve abnormalities, aortic coarctation, tetralogy of Fallot, and coronary artery
anomalies 4

Gastrointestinal abnormalities
 Feeding difficulties (eg, poor suck, prolonged feeding time) and recurrent vomiting and reflux 3

Very common in neonates and infants

May result in failure to thrive

Self-limited, although poor weight gain may persist up to 18 months 1 6

Intestinal malrotation, immature gut motility, and delayed gastrointestinal motor development are reported

Renal and genitourinary anomalies

Renal anomalies (10%-11%) 2

Usually minor and include solitary kidney, renal pelvis dilation, and duplicated collecting system 2

Structural anomalies may increase risk for development of urinary tract infection 2

Cryptorchidism (80% of boys) 2 (Related: Undescended Testis)

May be unilateral or bilateral 1

May require surgical orchiopexy if testes fail to descend by age 1 year 2

Musculoskeletal deformities

Sternal deformity

Characteristically with pectus carinatum superiorly and pectus excavatum inferiorly 3

Cubitus valgus (increased carrying angle) and talipes equinovarus (club foot) 3
4
 Scoliosis 4

Dermatologic signs 3

Thick, curly hair or thin, sparse hair

Dystrophic nails

Extra prominence on finger and toe pads

Hyperelastic skin

Multiple moles and pigmented nevi 1

Multiple lentigines

Keratosis pilaris

Central nervous system malformations

Arnold-Chiari malformation (extension of cerebellar tonsils into spinal canal)

Cerebrovascular anomalies (eg, arteriovenous malformations, aneurysms, hypoplasia of the posterior vessels,
moyamoya) (Related: Moyamoya)

Lymphatic abnormalities

Lymphedema involving dorsal foot and hand 3

Cystic hygroma (ie, congenital lymphatic collection, usually in the neck or axilla)
 Chylothorax

Pulmonary lymphangiectasis

Chylous ascites

Genital edema

Hydrops fetalis (rare) 1

Hematologic anomalies

Increased bleeding tendency

Potential hematologic abnormalities include thrombocytopenia, platelet dysfunction, and coagulation factor
deficiencies 2

Manifestations are usually mild 2

Most common include easy bruising, epistaxis, and menorrhagia 2

May result in significant bleeding with surgical procedures 2

Myeloproliferative disorder

May develop in infants, often during first few months of life 4

Characterized by hepatosplenomegaly, leukocytosis with monocytosis, and thrombocytopenia 4

Endocrinologic
 Short stature (50%-70%) 2

Postnatal growth failure is usually observable from approximately the first year of life 6

During childhood, mean height usually follows along third percentile on standard growth chart 2

During adolescence, delayed puberty and attenuated pubertal growth spurt often result in a sharp,
progressive decline in growth 2

Some catch-up growth is achieved owing to delayed bone maturity; patients may continue slow growth until
around age 20 years 6

Delayed puberty

May occur in both boys and girls

Developmental and behavioral

Developmental delay

Early motor milestones are delayed, often owing to hypotonia and joint hyperextensibility 3

Poor coordination and clumsiness

Learning difficulties

Behavioral manifestations

Risk for attention-deficit/hyperactivity disorder symptoms is increased 8

3
 Stubbornness and irritability have been reported but association is not well established 3

Causes and Risk Factors

Causes
Genetic variants that encode various products involved in the RAS-MAPK (mitogen-activated protein kinase)
signal transduction pathway are responsible for disease

RAS-MAPK signal transduction pathway is vital for cell differentiation, growth, and senescence 3

Expression may vary markedly among people with the same pathogenic variant for syndrome 3

Known pathogenic variants may involve the following genes; some general genotype-phenotype correlations
are noted:

PTPN11 (OMIM #163950) 9

Gain-of-function mutations are responsible for approximately 50% of cases 10

Short stature is more prevalent in patients with PTPN11 mutation; pulmonic stenosis is common 2

Hypertrophic cardiomyopathy is relatively less prevalent in patients with PTPN11 mutation 1

Germline pathogenic variants at certain specific codons—61, 71, 72, and 76—are significantly associated
with leukemogenesis and identify a group of patients at increased risk for juvenile myelomonocytic
leukemia 6

SOS1 (OMIM #610733) 10

 Missense mutations at locus 2p22.1 are present in from 10% to 28% of patients 1 10

Pulmonic stenosis is more frequent in SOS1 mutation–positive patients than in those without SOS1 or
PTPN11 mutations; ectodermal manifestations are common 6 10

Developmental delay and short stature is much less prevalent in patients with SOS1 mutation than in the
general Noonan population 10

RAF1 (OMIM #611553) 11

Mutations in RAF1 cause Noonan syndrome in 5% to 15% of people 1

Hypertrophic cardiomyopathy is much more frequent in RAF1 mutation–positive patients (80%-95%) 4

than in general Noonan syndrome population; multiple nevi, lentigines, and café au lait spots are
common 6

RIT1 (OMIM #615355) 12

Heterozygous mutations at locus 1q22 are responsible for up to 5% of cases 12

Cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems occur

more frequently in RIT1 mutation–positive patients than in general Noonan syndrome population 12

KRAS (OMIM #609942) 13

Heterozygous mutations at locus 12p12.1 are responsible for less than 2% to 5% of cases 1 10

Severe phenotypic effects are typical; majority have cardiac involvement, and profound intellectual
disability may occur 1
 Unusual association of Noonan syndrome with craniosynostosis is noted in families with KRAS
mutation–positive patients 6

Rarely, pathogenic variants responsible for disease occur in other known loci (eg, NRAS, SHOC2, CBL,
BRAF, MAP2K1) 1 6 14

Genotype-phenotype correlations in Noonan syndrome.

Pathologic
Cardiovascular Growth Developmental Skin and hair Other
variant

↑ ↑ Pulmonic ↑ Bleeding
PTPN11 ↑ Short stature Little to none —
stenosis diathesis

↓ Insulinlike ↑ Juvenile
↓ Hypertrophic
growth factor 1 myelomonocytic
cardiomyopathy
concentrations leukemia

↓ Atrial septal
defect

↑ Cutaneous findings (eg,

↑ Pulmonic ↓ Intellectual keratosis pilaris) similar to
SOS1 ↓ Short stature ↑ Macrocephaly
stenosis disability cardiofaciocutaneous
syndrome

↓ Atrial septal ↓ Language

defect delays

↑ ↑ Hypertrophic
RAF1 — — ↑ Nevi —
cardiomyopathy

 ↑ Lentigines
 Pathologic
Cardiovascular Growth Developmental Skin and hair Other
variant

↑ Café au lait spots

↑ Cardiovascular ↓ Intellectual ↑ Lymphatic

RIT1 ↓ Short stature ↓ Cutaneous findings
manifestations disability manifestations

↑ Cutaneous findings similar

↑ Severe
KRAS — — to cardiofaciocutaneous —
cognitive delay
syndrome
Título: Findings noted are more prevalent in Noonan patients with specific pathologic variant compared to Noonan patients without specific
pathologic variant.
Citación: Data from Aarskog-Scott syndrome; AAS. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated April 24, 2013. Accessed
January 8, 2020, #305400; Cardiofaciocutaneous syndrome 1; CFC1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated June 13,
2019. Accessed January 8, 2020, OMIM #115150; Costello syndrome; CSTLO. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated
January 5, 2016. Accessed January 8, 2020, OMIM #218040; Leopard syndrome 1; LPRD1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University.
Updated August 9, 2019. Accessed January 8, 2020, OMIM #151100; Neurofibromatosis, type 1; NF1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins
University. Updated October 31, 2017. Accessed January 8, 2020, OMIM #162200; Noonan syndrome 1; NS1. Online Mendelian Inheritance in Man. OMIM website. Johns
Hopkins University. Updated October 15, 2019. Accessed January 8, 2020, OMIM #163950; Noonan syndrome 3; NS3. Online Mendelian Inheritance in Man. OMIM
website. Johns Hopkins University. Updated May 18, 2011. Accessed January 8, 2019, OMIM #609942; Noonan syndrome 4; NS4. Online Mendelian Inheritance in Man.
OMIM website. Johns Hopkins University. Updated December 4, 2014. Accessed January 8, 2020, OMIM #610733; Noonan syndrome 5; NS5. Online Mendelian
Inheritance in Man. OMIM website. Johns Hopkins University. Updated October 20, 2016. Accessed January 8, 2020, OMIM #611553; Noonan syndrome 8; NS8. Online
Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated November 22, 2019. Accessed January 8, 2020, OMIM #615355; Phenotypic series -
PS163950. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Accessed January 8, 2020, PS163950; Roberts AE et al: Noonan syndrome.
Lancet. 381(9863):333-42, 2013; and Romano AA et al: Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 126(4):746-59, 2010.

Risk factors and/or associations

Age
Estimated incidence for severe phenotype is 1 per 1000 to 2500 live births 2

Genetics
3
 Many pathogenic variants are a result of sporadic (de novo) mutation 3

Affected parent may be identified in up to 75% of families 6

Familial inheritance is autosomal dominant 3

Risk of sibling also having Noonan syndrome is dependent on genetic status of parents

50% chance when 1 parent is affected 3

Less than 1% chance if neither parent is affected 3

If a parent has Noonan syndrome, risk of children having the syndrome is 50% 6

Other risk factors/associations

Advanced paternal age may be a risk factor in patients without known genetic association of Noonan syndrome 6

Diagnostic Procedures

  Primary diagnostic tools

Prenatal diagnosis

Suspect diagnosis on the basis of a constellation of findings noted on screening prenatal studies: 3

Nonspecific ultrasonographic abnormalities (eg, increased nuchal translucency, cystic hygroma,

polyhydramnios, multiple effusions, cardiac anomaly) and fetal karyotype within reference range
 Results of targeted prenatal genetic testing may confirm diagnosis with samples obtained through
chorionic villus sampling or amniocentesis

Detailed fetal ultrasonography and fetal echocardiography are indicated to assess for additional
abnormalities (eg, cardiac, renal, hydrops fetalis) when diagnosis is suspected or confirmed 3

Postnatal diagnosis

Largely based on clinical features 6

Consider diagnosis in any patient who either presents personally with 2 or more of the following key
features or has a first-degree relative with Noonan syndrome or any of the following key features: 3

Characteristic facial features

Congenital heart defect (eg, pulmonic stenosis, atrial septal defect) and/or hypertrophic
cardiomyopathy

Characteristic chest deformity (eg, superior pectus carinatum, inferior pectus excavatum)

Undescended testes

Short stature

Delayed puberty (either sex) and/or male infertility

Developmental delay and/or learning disability

Diagnostic scoring system may assist in diagnosis 3 7

Results of genetic testing can aid in diagnosis, which is particularly useful:

 To establish diagnosis in mildly affected patients 3

To differentiate from other syndromes with similar presentation 1

To enable specific treatment, monitoring, and prognostic guidance given known genotype-phenotype
correlations 1

To allow for preimplantation, prenatal, and postnatal genetic testing with defined familial pathogenic
variant 1

Obtain baseline screening for associated congenital anomalies at the time of diagnosis, including: 6

Complete physical and neurologic examination

Growth parameter plotting

Cardiac evaluation (eg, echocardiography, ECG)

Auditory and ophthalmologic assessments

Coagulation studies (ie, CBC with differential, prothrombin time/partial thromboplastin time)

Renal ultrasonography and urinalysis, if needed

Clinical and radiographic spine and rib cage assessments

Multidisciplinary developmental evaluation

Consult with clinical geneticist or genetic counselor (or both)

  Laboratory

  Imaging

  Functional testing

  Other diagnostic tools

Differential Diagnosis

Most common
Turner syndrome (Related: Turner Syndrome)

Turner syndrome is caused by loss of all or part of the X chromosome; occurs

only in females

Some phenotypic manifestations closely resemble Noonan phenotype,

including dysmorphic facial features, lymphedema, webbing of the neck, Turner syndrome. - A 4-year-old girl
wide-spaced nipples, and short stature with typical features of Turner
syndrome, including ptosis, down
Some subtle differences in clinical manifestations: slanting palpebral fissures,
retrognathia, broad chest with
widely spaced nipples, and
Left-sided heart anomalies are more common in Turner syndrome; right-
lymphedema of the hands and feet.
sided pulmonic stenosis is more common in Noonan syndrome 1
 Arrested pubertal development and gonadal dysgenesis are uncommon in
Turner syndrome; delayed onset of puberty is more common for Noonan
syndrome 1

Renal anomalies are more common in Turner syndrome 6

Diagnose Turner syndrome with karyotype analysis

Cardiofaciocutaneous syndrome (OMIM #115150) 20

Cardiofaciocutaneous syndrome. - A
child with cardiofaciocutaneous
Most commonly caused by heterozygous mutation involving the BRAF gene
syndrome due to a mutation in the
BRAF1 gene. Note the unusually
Also may be caused by gain-of-function mutations in KRAS, MEK1, or curly hair.
MEK2 genes 10

Some phenotypic manifestations closely resemble Noonan phenotype, such

as dysmorphic facial features, cardiac defects (pulmonic stenosis, septal
defects, hypertrophic cardiomyopathy), and intellectual disability 20 21

Some subtle phenotypic differences in manifestations:

Blue eyes are more common in patients with Noonan syndrome; broader,
longer face; coarser facial features; rounder, more bulbous nasal tip; and
wider nasal base are more suggestive of cardiofaciocutaneous syndrome 6 Costello syndrome. - Neonate with
21 Costello syndrome due to a
mutation in HRAS gene.

Florid, severe cutaneous findings (eg, follicular keratosis; sparse eyebrows

and lashes; ichthyosis) are more suggestive of cardiofaciocutaneous
syndrome 1 6
 Most infants with cardiofaciocutaneous syndrome have severe and often
long-lasting feeding difficulties, whereas infants who have Noonan
syndrome have self-limited feeding difficulties 1

Central nervous system structural abnormalities are much more common

in patients with cardiofaciocutaneous syndrome 6

Bleeding diathesis is rare in patients with cardiofaciocutaneous syndrome,

but common in patients with Noonan syndrome 6 Costello syndrome. - Unusually
deep palmar creases in a neonate.

Most patients with cardiofaciocutaneous syndrome develop moderate

intellectual disability as opposed to mild or minimal intellectual disability
noted in patients with Noonan syndrome 1

Differentiate by clinical presentation, clinical diagnostic criteria, and lack of

pathogenic genetic variant associated with Noonan syndrome

Diagnosis is largely based on clinical criteria; 3 mutation analysis identifying

distinct pathogenic variants associated with cardiofaciocutaneous syndrome
may assist in definitive diagnosis Noonan syndrome with multiple
lentigines (formerly LEOPARD
Costello syndrome (OMIM #218040) 22 syndrome). - Lentigo. Multiple
lentigines persisted all year round
on the face, upper trunk, and
Caused by de novo heterozygous mutation in the HRAS gene; autosomal
extremities of this 13-year-old boy
dominant inheritance may occur 1
with LEOPARD syndrome. The
mucous membranes were spared,
Some phenotypic manifestations include similar coarse facial dysmorphology but he had lip involvement, axillary
as noted in patients with Noonan syndrome, short stature, ulnar deviation at freckling, and multiple café-au-lait
wrist, developmental delay, cardiac abnormalities (eg, pulmonic stenosis, spots. His sister, father, and
grandfather had similar cutaneous
hypertrophic cardiomyopathy), and intellectual disability 1
findings.
 Although significant phenotypic overlap occurs with Noonan syndrome,
some subtle differences may occur

Several more suggestive features of Costello syndrome: 1

Facial or perineal papillomata are common

Supraventricular arrhythmias are common Aarskog syndrome. - This child with

Aarskog syndrome has
proportionate short stature, ocular
Premature aging and hair loss, and increased skin pigmentation over
hypertelorism, anteverted nostrils,
time broad upper lip, with shawl
scrotum, hyperextensible fingers,
Deep palmar and plantar creases and flexion or ulnar deviation of wrist wide flat feet, ovoid periumbilical
and fingers depression and attention-
deficit/hyperactivity disorder.
Moderate deficits in intellectual ability (as opposed to mild deficits in
most Noonan patients)

Prenatal overgrowth is a common finding in Costello syndrome and

uncommon in Noonan syndrome 23

Differentiate by clinical presentation and lack of pathogenic genetic variant

associated with Noonan syndrome
Café-au-lait spots, commonly seen
Diagnosis is largely based on clinical criteria; 3 mutation analysis identifying in neurofibromatosis. - Café-au-lait
distinct pathogenic variants in HRAS associated with Costello syndrome may spots. (a-c) This 16-year-old girl with
neurofibromatosis had multiple
assist in definitive diagnosis 22
café-au-lait spots since early
childhood. (a) Her axilla
Noonan syndrome with multiple lentigines (formerly called LEOPARD demonstrates a 4 cm diameter café-
syndrome, an acronym for lentigines, ECG conduction abnormalities, ocular au-lait spot and diffuse freckling. (b)
At puberty she began to develop
hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, widespread neurofibromas. Note the
variable size of the dermal tumors
and sensorineural deafness) (OMIM #151100) 24
on her abdomen. (c) Cutaneous
neurofibromas also erupted on her
Syndrome is usually caused by specific PTPN11 mutations and less nipples. Note the extensive freckling
commonly by BRAF and RAF1 mutations 24 on her breasts. (d) In the center of a
large café-au-lait spot, which was
present at birth, this 6-year-old girl
Characteristics of syndrome include lentigines, ocular hypertelorism, cardiac
developed a spongy tumor. Skin
conduction abnormalities, pulmonary stenosis, abnormal genitalia, growth biopsy of the mass demonstrated a
retardation, and sensorineural deafness 1 neurofibroma. Note the dark-brown,
pigmented nevus within the café-
Many also develop hypertrophic cardiomyopathy au-lait spot. (e) A large, unilateral
café-au-lait spot was noted at birth
Phenotypic manifestations may closely resemble those of Noonan syndrome; on this infant's abdomen. She
subsequently developed other
however, a characteristic of these patients is that lentigines begin to appear at
findings typical of Albright
approximately age 4 to 5 years and increase to thousands by puberty 1 23 syndrome. (f ) This healthy 8-year-
old boy had a large segmental café-
Patients with Noonan syndrome with multiple lentigines may be au-lait macule which was
diagnosed with Noonan syndrome early in life until characteristic unchanged from birth.
cutaneous manifestations evolve 1

Differentiate by clinical presentation and lack of pathogenic variant associated with Noonan syndrome

Mutation analysis identifying distinct pathogenic variants associated with Noonan syndrome with multiple
lentigines may assist in definitive diagnosis 24

Aarskog syndrome (OMIM #305400) 25

Most disease is caused by mutation in the FGD1 gene. Inheritance is X-linked recessive, and wide phenotypic
variability is common among people with the syndrome
 Some manifestations overlap with Noonan syndrome, including similar dysmorphic facial features, short
stature, chest deformity, cryptorchidism, delayed puberty, and possible mild cognitive deficiency 1

Other distinct features of Aarskog syndrome include widow's peak, short nose, cleft lip and palate, inguinal
hernia, dysmorphic hands and fingers, joint hyperextensibility, and possible neurobehavioral features 25

Aarskog syndrome is not associated with congenital heart disease, and affected boys have a characteristic shawl
(saddle bag) scrotum 1

Diagnosis largely is based on clinical criteria; mutation analysis identifying distinct pathogenic variants in
FGD1 associated with Aarskog syndrome may assist in definitive diagnosis

Neurofibromatosis 1 (OMIM #162200) 26

Autosomal dominant disorder caused by heterozygous loss of function mutation or deletion in NF1 gene 23

Disease is characterized by café au lait spots, axillary and/or inguinal freckling, Lisch nodules (hematomas of
iris), fibromatous skin tumors, short stature, and increased susceptibility to development of benign and
malignant tumors 23

Shared features with Noonan syndrome include short stature, learning difficulties, and café au lait spots 6

Diagnosis is based on clinical criteria; 23 presence of pathogenic variant in NF1 associated with
neurofibromatosis 1 may assist in definitive diagnosis
Treatment

Goals
Promote growth with goal of attaining height within reference range for age, puberty at a typical age, and
eventual adult height within reference range

hGH treatment to promote linear growth

Estrogen or testosterone treatment to induce puberty if delayed

Manage congenital abnormalities associated with disease

Monitor for commonly associated disease manifestations

Disposition

Recommendations for specialist referral

Refer patients with suspected Noonan syndrome to geneticist or developmental pediatrician for further
diagnostic, management, and genetic counseling recommendations 3

Refer patients with short stature and pubertal delay to an endocrinologist for further diagnostic and treatment
recommendations 3
Treatment Options
Monitor and manage acquired disease frequently associated with syndrome

Cardiac disease

Manage pulmonic valve stenosis, hypertrophic cardiomyopathy, and other cardiovascular anomalies according
to established guidelines for general population 6

Pulmonary valve stenosis is often treated with balloon valvuloplasty but carries a high reintervention rate 6
(Related: Pulmonic Stenosis)

Some require pulmonary valvectomy or pulmonary homograph repair 4

Hypertrophic cardiomyopathy may require long-term β-blocker therapy or surgical myomectomy to reduce
outflow obstruction 4

Approximately one-third of adult patients require long-term management with medications, defibrillator, or
pacemaker for heart failure or arrhythmia 1

Failure to thrive, feeding difficulties, and gastrointestinal reflux in infancy

May require consultation with gastroenterologist and/or feeding team for further diagnostic and treatment
recommendations 4

May require placement of temporary feeding tube

Consult nutrition specialist to optimize nutritional status 4

Gastrointestinal reflux may require antireflux medications 4

Bleeding diathesis

Treatment is driven by specific factor deficiency or platelet aggregation defect in consultation with
hematologist 6

Avoid aspirin and aspirin-containing medications owing to potential for exacerbating a bleeding diathesis 4 6

Endocrine disease

Short stature may require hGH treatment in consultation with endocrinologist 6 27

hGH is approved to treat slowed linear growth, when present, but its use is controversial 1

Improves short-term speed of height growth; however, effect on adult height is not definitely known 28

Some authorities have raised concerns about use in patients with hypertrophic cardiomyopathy, but there
is minimal evidence for adverse effect 1 19

Delayed puberty may need to be induced with sex hormone treatment (ie, estrogen for girls, testosterone for
boys) in consultation with endocrinologist

Induction of puberty is indicated for lack of secondary sex characteristics in girls aged 13 years and boys
aged 14 years 4

Developmental disabilities

Manage in consultation with multidisciplinary recommendations for early intervention programs and
individualized education strategies 6

Except for SOS1 cases, referral in infancy may be appropriate

 Speech, occupational, and/or physical therapy and other specialized care may be indicated based on
multidisciplinary recommendations 4

Drug therapy
Recombinant hGH 29 30

No standard dose is established 6

Somatropin (Recombinant rhGH) Solution for injection; Children: Up to 0.066 mg/kg/day subcutaneously is
recommended. Prior to initiating somatropin, ensure that the patient has short stature. Not all children with
Noonan syndrome have short stature.

Nondrug and supportive care

Genetic counseling

Recommended for affected patients in adolescence or young adulthood for preconception planning 1

May need familial evaluation to determine future offspring's risk for Noonan syndrome by identifying subtle
findings in a previously unidentified affected parent

Provide patients and families with resources regarding education and support 3

Support organizations include: 4

Noonan Syndrome Foundation 31

NORD Noonan Syndrome 32

 Magic Foundation 33

Monitoring
Lifelong monitoring for commonly acquired diseases and other conditions associated with Noonan syndrome
include:

Hearing

Annual hearing tests throughout early childhood 3

Refer to ear, nose, and throat specialist for recurrent otitis media or serous otitis 1

Ocular

Recommend detailed screening ophthalmology examination at least every 2 years for patients without
known ocular abnormality 3

Dental (malocclusion)

Refer to dentist between ages 1 and 2 years, with annual dental evaluations thereafter 3

Primary care physician should perform oral examination at each visit 3

Cardiovascular

Children and adults without known heart disease require cardiac reevaluation every 5 years with consulting
cardiologist 3 4

Patients with known heart disease require regular individualized follow-up as directed by consulting
cardiologist 4
 European guidelines recommend annual screening echocardiogram to assess for signs of hypertrophic
cardiomyopathy until age 3 years, at ages 5 and 10 years, and during adolescence 19

Feeding difficulties and failure to thrive (in infancy)

Monitor weight gain for failure to thrive, feeding difficulties (eg, poor suck, prolonged feeding time), and
recalcitrant gastrointestinal reflux

Refer patients with poor weight gain, failure to thrive, difficulty feeding, or recurrent reflux to pediatric
gastroenterologist and/or feeding team for further diagnostic and treatment recommendations 3

Renal and genitourinary

Repeat renal ultrasonography and other monitoring may be necessary in consultation with nephrologist,
depending on initial findings 4 19

Patients with underlying structural abnormalities may be at increased risk for urinary tract infection;
maintain low threshold for obtaining urinalysis and urine culture if urinary tract infection symptoms
develop

Monitor clinical examination findings in infants with undescended testes; refer to urologist by age 1 year
for possible orchiopexy if testes remain undescended 4

Skeletal

Monitor annually for deformities with clinical back examination for scoliosis and chest examination for
pectus deformity of sternum 3

hGH treatment may worsen scoliosis 19

Order radiographic evaluation of spine if scoliosis is significant on examination 3

 Refer to orthopedic surgeon if functionally restrictive chest deformity is suspected

Dermatologic

Perform cutaneous examination at each primary care physician visit

Refer to dermatologist as clinically indicated for concerning moles and nevi, or difficult-to-manage
keratosis pilaris 3

Central nervous system

Monitor clinically for manifestations of craniosynostosis (eg, abnormal cranial shape), cerebrovascular
anomalies, and Arnold-Chiari malformation (eg, signs of increased intracranial pressure or hydrocephalus,
headaches, increasing head circumference, seizures) 3

Maintain low threshold for investigation of clinical manifestations with appropriate ancillary studies (eg,
EEG, MRI of the brain)

Lymphatic

Monitor clinically for manifestations of lymphedema secondary to lymphatic vessel dysplasia, hypoplasia,
or aplasia 3

Refer to lymphedema clinic when clinically indicated 3

Hematologic and oncologic

Bleeding tendencies secondary to factor deficiency or qualitative or quantitative platelet defects

CBC and coagulation studies

 Repeat CBC and coagulation studies 6 to 12 months after initial screening if first screening is
performed in infancy 4

European guidelines recommend at least 1 screening examination during mid- to late childhood (ages
5-11 years) 19

Monitor for clinical symptoms of bleeding

If excessive, unusual, or persistent bleeding occurs, then obtain coagulation studies (eg, CBC,
prothrombin time/partial thromboplastin time) 3

Refer these patients for further evaluation (eg, specific factor assays, platelet function studies) and
treatment recommendations 1

Preoperative monitoring

Obtain screening CBC and coagulation studies (ie, prothrombin time/partial thromboplastin time) 1

Refer patients with screening test results outside reference range to a hematologist for second-tier
testing (eg, factor levels, platelet aggregation studies) 1

Monitor for splenomegaly

Obtain screening CBC with differential for patients with splenomegaly 1

Monitor for hepatosplenomegaly

Obtain screening CBC with differential and liver function test results for patients with
hepatosplenomegaly 1
 Malignancy

Aside from screening CBC and obtaining liver function test results in presence of hepatosplenomegaly,
no specific surveillance strategy is available

Endocrine

Growth delay and short stature

Monitor linear growth on Noonan syndrome age–based growth chart 19

Monitor closely at each patient visit, a minimum of 3 times a year until age 3 years, then annually
thereafter 1 3

Refer patients with growth delay (eg, growth deceleration, height less than −2 standard deviations) to
endocrinologist with experience managing patients requiring hGH treatment 3 4

Delayed puberty

Monitor clinically for pubertal development

Refer patients with pubertal delay to endocrinologist for further diagnostic and treatment
recommendations 3

Fertility issues in men

Fertility clinic evaluation may be required for men with inability to conceive 3

Developmental, cognitive, behavioral, and neuropsychiatric

Developmental delay and learning deficiencies

 Perform development screening assessment beginning in the second half of the first year of life and
annually until age 18 years 1 3

May require multidisciplinary evaluation if screening assessment is abnormal to assess need for early
developmental intervention and individualized educational plan

Speech deficits

Recommend formal speech evaluation if indicated clinically to assess for deficits and need for
individualized treatment plan

Behavioral and neuropsychiatric deficits

Obtain baseline neuropsychologic assessment at primary school entry with follow-up based on results of
initial testing 3 19

Monitoring during hGH therapy

Limited data do not show significantly increased risk of worsening cardiomyopathy or negative effects on the
heart; however, theoretical concerns exist regarding worsening cardiac status and increasing ventricular wall
thickness during treatment 2

Monitor cardiac function with periodic clinical examination and echocardiography 2

Increased risk of hematologic malignancy is an additional theoretical (as yet undetermined) concern during
treatment

No specific monitoring recommendations are available

Additional monitoring parameters are directed by consulting endocrinologist

 Preoperative monitoring

Evaluate for coagulation abnormalities before initiating any surgical procedures 19

Preoperative evaluation for malignant hyperthermia risk may be indicated for certain subgroups (eg,
hypertrophic cardiomyopathy with creatine phosphokinase levels within reference range to elevated) 4

Manage patients with hemodynamically significant cardiac disease in accordance with usual principles for
patients with cardiovascular risk factors 19

Complications and Prognosis

Complications
Acquired disease

Ocular findings occur in up to 95% of patients and may include: 1

Nystagmus

Refractive error

Strabismus

Amblyopia

Anterior segment problems (eg, prominent corneal nerves, cataract, anterior stromal dystrophy)
 Fundal changes (eg, optic head drusen, optic disk hypoplasia, coloboma)

Auditory deficits

Sensorineural hearing loss is relatively common 1

Dental/oral findings 3

Malocclusion

Articulation difficulty

Cardiac anomalies

Pulmonary stenosis 34

Often associated with dysplastic valve 3

Most require periodic monitoring only 4

Approximately one-third of patients require surgery or procedure for valve dysfunction 1

Pulmonary valve insufficiency and right ventricular dysfunction may develop after valve repair 4

Hypertrophic cardiomyopathy 34

Develops in 20% to 30% of patients overall 2 4

May develop anywhere from prenatal period to late childhood

Mean age at diagnosis is 5 months, and more than 50% of patients are diagnosed by age 6 months 6
 May be mild or severe; natural history is variable and unpredictable

May resolve in some patients or become rapidly progressive in others 4

Up to 25% of patients with Noonan syndrome and hypertrophic cardiomyopathy die from heart failure
associated with cardiomyopathy within the first year of development 1

Dilated cardiomyopathy may evolve from hypertrophic cardiomyopathy; restrictive cardiomyopathy also
occurs 1

Left-sided obstructive lesions may develop in adulthood 4

Other less common complications in adult patients may include:

Mild aortic insufficiency 1

Substantial right ventricular outflow tract obstruction caused by subpulmonary or pulmonary valve
stenosis

Aortic root dilation

Aortic dissection

Giant aneurysm of the sinuses of Valsalva

Constrictive pericarditis

Idiopathic pulmonary hypertension

Arrhythmias are relatively uncommon 4

Gastrointestinal disorders

Feeding difficulties (eg, poor suck, prolonged feeding time) 3

Common in infancy

May lead to failure to thrive and may require temporary nasogastric feedings 1

Feeding difficulties often resolve by age 15 months 1

Gastrointestinal reflux and recurrent vomiting

Common in infancy 1

May compound feeding difficulties and lead to failure to thrive

Reflux and recurrent vomiting often resolve early in second year of life 1

Genitourinary complications

Cryptorchidism 3

Extremely common in male infants; may require orchiopexy if testes have not descended by age 1 year

Renal abnormalities are usually minor and include solitary kidney, renal pelvis dilation, and duplicated
collecting system 2

Structural anomalies may increase risk for development of urinary tract infection

Musculoskeletal anomalies
Sternal deformities

Characteristic deformity consists of pectus carinatum superiorly and pectus excavatum inferiorly 3

Hypotonia, joint laxity, and hyperextensibility are common 3 4

Poor coordination and clumsiness

Cubitus valgus (increased carrying angle at elbow) and talipes equinovarus (club foot) 3

Genu valgum (medial angulation of the knee) 1

Scoliosis

Develops in 15% to 30% of children, and approximately two-thirds require surgical correction 1 4

Pigmented villonodular synovitis

Proliferative synovial lesion involving joints, tendons, and bursae 1

Often polyarticular in distribution 1

Giant cell granulomatous lesions

Multiple giant cell granulomatous tumors may develop in bones, joints, and soft tissue

Characteristic jaw involvement presents with progressive, often bilateral, mandibular swelling, which
resembles cherubism and with lesions seen in neurofibromatosis type 1 and craniofaciocutaneous
syndrome 6 10
 Primarily occurs in patients with pathogenic variants involving PTPN11 and SOS1 1

Dermatologic characteristics 3

Thick, curly hair or thin, sparse hair

Keratosis pilaris involving extensor surfaces and face is relatively common 1

Dystrophic nails

Extra prominence on pads of fingers and toes

Hyperelastic skin

Multiple lentigines and café au lait spots

Moles and nevi

Lymphatic signs

Peripheral lymphedema occurs in up to 20% of patients 1

May occur in infants; typically resolves in the first few years of life 1

May develop later in adolescence or adulthood 1

Less common lymphatic abnormalities include: 1

Chylous effusions of the pleural space and peritoneum

Anomalous thoracic cage lymphatic vessels, aplasia, or absence of thoracic duct

 Pulmonary, testicular, or intestinal lymphangiectasia

Hypoplastic leg lymphatic vessels, hypoplastic inguinal and iliac lymphatic vessels

Localized lymphedema of scrotum or vulva

Hematologic and oncologic disorders

Bleeding diathesis

Most patients develop easy bruising or bleeding 1 5

An identifiable coagulation defect is identified in up to one-third of patients 5 and may include 1 or

more of the following: 6

Clotting factor deficiencies

Factor XI

Most common deficiency encountered in patients with Noonan syndrome 2

Approximately 25% of patients have partial factor XI deficiency 4

Factor XII and VIII

Represent the next most common factor deficiencies encountered 4

Platelet abnormalities

Thrombocytopenia
 Often secondary to decreased megakaryocyte numbers and/or splenomegaly 2

Qualitative platelet dysfunction 3

Screen for and define precise hemostatic abnormality before elective surgery so that abnormalities
can be appropriately managed 2

Malignancy and other hematologic complications

Transient monocytosis is reported 1

Overall risk of developing childhood malignancy is up to 8-fold higher than that of the general
population 6

Patients with PTPN11 mutation–positive disease may be at increased risk for unusual childhood
leukemia (ie, juvenile myelomonocytic leukemia) 6 23

Myeloproliferative disorder may occur in infants and is often a benign variant 3 6

Less commonly, infants develop fulminant disease progressing to aggressive leukemia 4

Acute lymphoblastic leukemia and acute myeloid leukemia develop more frequently than in general
population 6

Patients may be at increased risk for certain types of solid tumors (eg, neuroblastoma,
rhabdomyosarcoma) 2

Unknown whether or not hGH treatment further elevates increased baseline risk for neoplasia 2

Hepatosplenomegaly
 Common and may be related to subclinical myelodysplasia 6

Autoimmune disorders

Although development of thyroid antibodies is common, incidence of clinical hypothyroidism is similar to

general population 2

Systemic lupus erythematosus and celiac disease are uncommonly reported

Endocrine disorders

Short stature

Postnatal growth failure is usually observable from approximately the first year of life 6

Children usually track along the third percentile on standard growth chart 2

Delayed onset of puberty and attenuated pubertal growth spurt often contribute to a sharp and
progressive decline in growth during adolescence 2

Bone age is usually delayed (mean delay approximately 2 years); 4 therefore, some catch-up growth often
occurs, sometimes into the 20s 1 6

Growth hormone secretory dynamics vary among patients 2

Spontaneous growth hormone secretion may be normal or subnormal 2

Growth hormone resistance may occur 1

Mean final adult height is 161 to 167 cm in men and 150 to 155 cm in women 3 6
 Delayed puberty in boys and girls

Up to 35% of boys enter puberty after age 13.5 years 1

Up to 44% of girls enter puberty after age 13 years; 1 mean age of menarche is almost 15 years 6

Puberty may progress at a rapid pace (under 2 years) 4

By comparison, typical pubertal development occurs between ages 8 and 13.4 years in girls and ages 9 and
14 years in boys 35

Male infertility

Sertoli cell dysfunction and cryptorchidism may play a role in impaired gonadal function and defective
spermatogenesis 3

Fertility does not appear to be affected in women 2

Developmental, behavioral, and social interaction

Developmental delay and learning difficulty

Approximately 25% of people with Noonan syndrome have learning disabilities 6

Approximately 10% to 15% of people with Noonan syndrome require special education 6

Delayed developmental milestones

Early motor milestones delay

Average age for sitting unsupported is around 10 months 6

6
 Average age for walking is approximately 21 months 6

Language delay

Average first words occur around age 15 months 6

Average simple 2-word phrases occur around age 31 to 32 months 6

May be secondary to hearing loss, perceptual motor disabilities, and articulation difficulties 6

Approximately 50% of school-aged children are diagnosed with developmental coordination disorder 6

Behavioral manifestations

May include stubbornness, irritability, body image problems, poor self-esteem, and social inadequacy 4

Other subtle deficits may include:

Social cognition impairments and alexithymia (difficulty identifying and expressing emotions) 1 5 6

Language impairments and communication difficulties 1

Delayed visual recognition memory 1

Speech disorders

Articulation difficulties are common and respond well to speech therapy 6

Neuropsychiatric disease

Attention and executive function tasks are challenging for many patients 6
 Prevalence of attention-deficit/hyperactivity disorder is increased 23

Limited information is available about the prevalence of psychiatric disease 2 6

Seizures

Recurrent seizures may develop in a minority of affected patients 4

Prognosis
Adult height

Final adult height

Approaches lower end of reference range for most patients 6

Below the third percentile in up to approximately 40% of males and 50% of females 4 6

Patients treated with hGH

Final effects depend on age at start of treatment, duration of treatment, age at onset of puberty, and
individual sensitivity to growth hormone 6

Increase in height varies from 0.6 to 1.8 standard deviation 6

Intelligence

Within reference range for most people with Noonan syndrome 2

Approximately 20% have some degree of intellectual impairment (IQ under 70) 1
2
 Impaired social and communication skills are noted in some 2

Hypertrophic cardiomyopathy

May resolve in some patients or become rapidly progressive in others 4

Early mortality is high

Among patients who develop cardiomyopathy, up to 25% die in the first year from heart failure 1

Rate of sudden death is less than that experienced by people with inherited hypertrophic cardiomyopathy 1

Myeloproliferative disorders

Most infants who develop myeloproliferative disorders have a favorable prognosis, improving by age 1 year
without specific treatment 4

Long-term mortality data are scarce 1

Screening and Prevention

Screening

At-risk populations
Parents of a proband
 30% to 75% of patients diagnosed have an affected parent 6

Siblings of a proband

Risk depends on genetic status of parents

Risk is low (less than 1%) but higher than in general population when parents are unaffected 6

Risk is 50% when a parent is affected or pathologic variant is identified in a parent 6

Children of a proband

Each child has a 50% risk of inheritance 6

Screening tests
Evaluation of parents, siblings (when parent is affected), and children of proband includes: 6

Careful physical examination to evaluate for specific features of Noonan syndrome

Review photographs of affected faces at all ages

Echocardiography and ECG

Coagulation screening

Genetic testing of parents if pathologic variant is known in proband

Screening for associated congenital anomalies

Hearing loss
 Refer to audiologist for age-appropriate evaluation in infancy or at time of initial diagnosis 3 4

Ocular abnormalities

Refer to ophthalmologist for detailed eye examination at time of diagnosis 3

Cardiac anomalies

Refer to cardiologist for cardiac evaluation, echocardiogram, and ECG 3

Patients without congenital heart defect on initial evaluation require cardiac reevaluation every 5 years 3

Feeding difficulties in infancy

Observe feeding to assess quality of suck and swallow coordination; determine need for lactation consultant
and early feeding team intervention

Additional testing (eg, swallow study, reflux studies) may be indicated based on findings and specific clinical
presentation 3

Renal anomalies

Obtain renal ultrasonography

Repeat imaging may be indicated depending on findings at time of diagnosis on initial screening examination
2

Scoliosis

Clinically assess spine and obtain imaging, if necessary 1

 Hematologic anomalies and disorders of hemostasis

CBC with differential and coagulation studies (prothrombin time/partial thromboplastin time) at time of
diagnosis; 1 consider measuring bleeding time 2 3

Repeat 6 to 12 months after initial screening if it was done in infancy 2 4

Other guidelines recommend obtaining baseline laboratory screening test results in children aged 5 years
or younger if major procedures are required 19

Refer patients with baseline coagulation study results outside reference range to hematologist for second-tier
studies (ie, specific factor assays and platelet function studies) 2

Growth

Plot on Noonan syndrome age-based growth chart and monitor growth at each primary care visit 3

Developmental delay and learning deficiencies

Obtain formal multidisciplinary developmental assessment in second half of first year of life or at time of
diagnosis 1 3 19

Obtain baseline neuropsychological assessment at the time of primary school entry 19

Prevention
Preimplantation genetic diagnosis may be available to families with known pathogenic gene variant 3
Referencias

1 Roberts AE et al: Noonan syndrome. Lancet. 381(9863):333-42, 2013

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2 Chacko E et al: Update on Turner and Noonan syndromes. Endocrinol Metab Clin North Am. 41(4):713-34, 2012
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3 Bhambhani V et al: Noonan syndrome. Am Fam Physician. 89(1):37-43, 2014

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4 Romano AA et al: Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 126(4):746-59, 2010
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6 Roberts AE et al: Noonan syndrome. In: Adam MP et al, eds: GeneReviews [internet]. University of Washington; 1993-2022
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29 Horikawa R et al: Long-term efficacy and safety of two doses of Norditropin® (somatropin) in Noonan syndrome: a 4-year
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30 Ozono K et al: Efficacy and safety of two doses of Norditropin (somatropin) in short stature due to Noonan syndrome: a 2-year
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31 Noonan Syndrome Foundation. Noonan Syndrome Foundation website. Accessed May 24, 2022. http://www-teamnoonan-
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32 National Organization for Rare Disorders: Noonan Syndrome. National Organization for Rare Disorders website. Published
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33 Magic Foundation: The Magic Foundation website. Accessed June 5, 2022. https://www-magicfoundation-
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34 Karnik R et al: Cardiac manifestations of Noonan syndrome. Pediatr Endocrinol Rev. 16(Suppl 2):471-6, 2019
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