Noonan Syndrome

VIKAS BHAMBHANI, MD, and MAXIMILIAN MUENKE, MD

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of
potential health conditions. Most affected individuals have characteristic facial features that evolve with age; a broad,
webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short
stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental
or behavioral problems, vision problems, hearing loss, and lymphedema. Familial recurrence is consistent with an
autosomal dominant mode of inheritance, but most cases are due to de novo mutations. Diagnosis can be made on
the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm
diagnosis in 70% of cases and has important implications for genetic counseling and management. Most patients with
Noonan syndrome are intellectually normal as adults, but some may require multidisciplinary evaluation and regular
follow-up care. Age-based Noonan syndrome–specific growth charts and treatment guidelines are available. (Am Fam
Physician. 2014;89(1):37-43. Copyright © 2014 American Academy of Family Physicians.)

N
This article is one in a oonan syndrome is a common Clinical Presentation
series coordinated by the
genetic disorder with multiple The diagnosis of Noonan syndrome depends
National Human Genome
Research Institute, congenital abnormalities. It primarily on the identification of character-
National Institutes of is characterized by congenital istic clinical features (Table 11-11). The clini-
Health, Bethesda, Md. A heart disease, short stature, a broad and cal spectrum in children is well described,
glossry of genomics terms
is available at http://www.
webbed neck, sternal deformity, variable but few studies have examined medical com-
aafp.org/afp/genglossary. degree of developmental delay, cryptor- plications in adults.3 Figures 1 through 4 show
chidism, increased bleeding tendency, and the cardinal phenotypic features of Noonan
CME This clinical content
conforms to AAFP criteria characteristic facial features that evolve syndrome based on patient age.6-8
for continuing medical with age. Molecular genetic testing can con- Nonspecific prenatal anomalies common
education (CME). See CME firm the diagnosis in most cases, which has among patients with Noonan syndrome
Quiz Questions on page 6. important implications for genetic coun- include increased nuchal translucency, poly-
Author disclosure: No rel- seling and management. Physicians should hydramnios, and abnormal maternal serum
evant financial affiliations. know how to diagnose Noonan syndrome triple screen (α-fetoprotein, human chorionic
Patient information: because patients who have it require moni- gonadotropin, and unconjugated estriol). The
▲

A handout on this topic, toring for a large number of potential health most common morphologic fetal anomaly is
written by the authors of conditions. Age-appropriate guidelines for hydrothorax. Diagnosis of cardiac anoma-
this article, is available
the management of Noonan syndrome are lies is rarely made prenatally. The diagnosis
at http://www.aafp.org/
afp/2014/0101/p37-s1. available.1 of Noonan syndrome should be considered
html. Access to this hand- in all fetuses with a normal karyotype and
out is free and unrestricted. Epidemiology increased nuchal translucency, especially
Noonan syndrome is characterized by when cardiac anomaly, polyhydramnios,
marked variable expressivity, which makes and/or multiple effusions are observed.12
it difficult to identify mildly affected indi- Patients who have Noonan syndrome dis-
viduals. The incidence is one in 1,000 to play clinical similarities to patients who have
2,500 live births for severe phenotype, but Turner syndrome (editor’s note : see http://
mild cases may be as common as one in www.aafp.org/afp/2007/0801/p405.html).
100 live births.2 Familial recurrence is con- However, patients can be easily differentiated
sistent with an autosomal dominant mode because with Turner syndrome, only females
of inheritance, but de novo mutations are are affected (because of the loss of the X chro-
more common, accounting for 60% of mosome), left-side heart defects are common,
cases.3 There is no known predilection by developmental delay occurs less often, renal
race or sex. anomalies are more common, and primary

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Noonan Syndrome

Table 1. Clinical Features of Noonan Syndrome

Cardiovascular 4,5 Genitourinary2,8 Neurologic1,8

Hypertrophic cardiomyopathy Cryptorchidism Behavioral conditions (stubbornness, irritability,
Pulmonary stenosis, often with Female fertility is normal body image problems, poor self-esteem)
a dysplastic valve Males can have fertility issues (e.g., defective Central nervous system malformation
Dental/oral1,2 spermatogenesis caused by cryptorchidism, Early motor milestones delay (hypotonia and
Articulation difficulty gonadal dysfunction due to impaired joint laxity)
Sertoli cell function) Learning difficulties
High arched palate
Malformations (renal pelvis dilation, solitary Mild intellectual disability (33% of patients
Malocclusion
kidney, duplex collecting system) with Noonan syndrome )
Micrognathia
Puberty can be delayed in both sexes Most individuals have normal intelligence
Dysmorphic facial features 6,7
Growth2,4,8 Speech disorders
See Figures 1 through 4
Birth weight and length are normal Skeletal2,4
Ears 8
Failure to thrive and short stature (50% to Cubitus valgus
Hearing loss 70% of patients with Noonan syndrome)
Spinal abnormality (scoliosis, talipes
Eyes 2,9
Mean final adult height is 63 to 66 inches equinovarus)
Anterior segment problems (160 to 168 cm) in males and 59 to 61
Sternal deformities (pectus carinatum
(prominent corneal nerves, cataract, inches (150 to 155 cm) in females
superiorly, pectus excavatum inferiorly)
anterior stromal dystrophy) Hematologic1,3,4,10,11
Skin conditions2,4
Nystagmus Increased bleeding tendency (due to factor
Dystrophic nails
Ptosis, hypertelorism, and epicanthal deficiency, quantitative or qualitative
folds platelet defect) Extra prominence on pads of fingers and toes
Refractive error Leukemia Follicular keratosis
Strabismus Myeloproliferative disorder Hyperelastic skin
Gastrointestinal3,4 Lymphatic 8 Moles
Feeding difficulties (poor sucking Lymphedema Multiple lentigines
function, prolonged feeding time, Nevi
recurrent vomiting and reflux) Thick curly hair or thin sparse hair

Information from references 1 through 11.

Oval-shaped, low-
set, posteriorly
rotated ears with
Large head compared to face thick helix
Excess
Tall forehead with narrow temples nuchal skin

Wide-spaced eyes (hypertelorism)

Downward slant of palpebral fissures

Epicanthal folds

Short, broad nose with

depressed root and full tip Swollen
Deeply grooved philtrum edematous
dorsum of
Full lips with high, wide peaks to
hands and feet
the vermilion border of upper lip
Small chin and short neck

Figure 1. Newborn with Noonan syndrome.

38  American Family Physician www.aafp.org/afp Volume 89, Number 1 ◆ January 1, 2014
 Noonan Syndrome

hypogonadism causes amenorrhea and steril-

ity.8,13 A number of other partially overlapping Wispy hair
syndromes, such as cardio-facio-cutaneous
syndrome, Watson syndrome, Costello syn-
drome, neurofibromatosis 1, and LEOPARD
syndrome (lentigines, electrocardiogram con- Thickly hooded,
duction abnormalities, ocular hypertelorism, prominent eyes

pulmonary stenosis, abnormal genitalia,

retardation of growth, and sensorineural deaf-
Wide-based, depressed
ness), also can be differentiated from Noonan nose with bulbous,
syndrome based on clinical features.8,14 upturned tip

Diagnosis Cupid bow

Early, accurate diagnosis of Noonan syndrome appearance of
is important because each patient requires an upper lip

individual treatment regimen and has a dif-

Figure 2. Infant with Noonan syndrome.
ferent prognosis and recurrence risk. A scor-
ing system has been devised to help diagnose
patients with the condition (Table 215). Inverted triangle–shaped head Pectus sternal deformity
Until recently, diagnosis was made solely (prominent superior
Coarse facial features
on the basis of clinical features, but molec- sternum and depressed
inferior sternum)
ular genetic testing can provide confirma-
tion in 70% of cases.8 Noonan syndrome is Curly/wooly hair Cubitus valgus
Wide forehead deformity of upper
caused by mutations in the RAS/mitogen- extremity (increased
activated protein kinase (MAPK) pathway, carrying angle at
which is essential for cell cycle differen- elbow joint)
Neck skin
tiation, growth, and senescence.14 Approxi- webbing
Widely spaced
mately one-half of the known mutations are Small chin nipples
in the protein tyrosine phosphatase non-
receptor, type 11 (PTPN 11) gene.8
Figure 3. Child/adolescent with Noonan syndrome.
Genetic Counseling
Most cases are sporadic. In familial cases,
autosomal dominant inheritance is con-
firmed. The risk of Noonan syndrome devel-
oping in the sibling of an affected person High anterior hairline
is 50% if the parent is affected, but is less
than 1% if the parent is unaffected. Risk of Triangle-shaped head
transmission to the offspring of an affected
individual is 50%.8 Preimplantation genetic Transparent, wrinkled skin
diagnosis can be offered in familial cases
with known mutations.8
Prominent nasolabial folds

Management
Intellectual and physical abilities are normal
in most adults with Noonan syndrome, but
some may require multidisciplinary evalua-
tion and regular follow-up care.16 Recently,
management guidelines were developed
by American and European consortia, and
management is optimized by adherence Figure 4. Adult with Noonan syndrome.

January 1, 2014 ◆ Volume 89, Number 1 www.aafp.org/afp American Family Physician 39

Noonan Syndrome

Genomics Glossary

Cardio-facio-cutaneous syndrome: Characterized by cardiac RAS/mitogen-activated protein kinase (MAPK)

abnormalities, distinctive craniofacial appearance, and cutaneous pathway: Essential in the regulation of the cell cycle,
abnormalities. differentiation, growth, and cell senescence, all of
Costello syndrome: Characterized by growth problems, developmental which are critical to normal development. Mutations in
delay or intellectual disability, coarse facial features, curly or sparse fine the genes that encode for the pathway have profound
hair, soft skin with deep palmar and plantar creases, papillomata of effects on development.
the face and perianal region, diffuse hypotonia, joint laxity, and cardiac Turner syndrome: A chromosomal abnormality in
disease. which one X chromosome is absent; 45,X karyotype.
LEOPARD syndrome: An acronym for the cardinal features of lentigines, Variable expressivity: The range of signs and
electrocardiogram conduction abnormalities, ocular hypertelorism, symptoms that can occur in different persons with the
pulmonary stenosis, abnormal genitalia, retardation of growth, and same genetic condition.
sensorineural deafness. Watson syndrome: An autosomal dominant disorder
Neurofibromatosis 1: Characterized by multiple café au lait spots, characterized by pulmonary stenosis, café au lait spots,
axillary and inguinal freckling, neurofibromas, Lisch nodules, gliomas, decreased intellectual ability, and short stature. Most
and osseous lesions. affected individuals have a large head, Lisch nodules,
Preimplantation genetic diagnosis: A procedure used to decrease the and neurofibromas.
chance of a particular genetic condition for which the fetus is specifically
at risk by testing one cell removed from early embryos conceived by
in vitro fertilization and transferring to the mother’s uterus only those
embryos determined not to have inherited the mutation in question.

to age-specific guidelines that emphasize

Table 2. Diagnostic Criteria for Noonan Syndrome screening and testing for common health
issues.1,17 Referral to a clinical geneticist for
Feature A = Major B = Minor assistance in the diagnosis and manage-
ment of Noonan syndrome, including deter-
1. Facial Typical facial dysmorphology (facial Suggestive facial
features vary with age and are dysmorphology mining the appropriateness and sequence
described in Figures 1 through 4) of genetic testing, may be helpful.1,8 Clini-
cal growth charts are also available via a
2. Cardiac Pulmonary valve stenosis, Other defect
hypertrophic cardiomyopathy, European network at http://www.dyscerne.
and/or electrocardiographic results org. Table 3 lists system-based management
typical of Noonan syndrome guidelines to assist physicians caring for
3. Height < 3rd percentile < 10th percentile patients with Noonan syndrome and their
families.1,8,17 Table 4 describes when Noonan
4. Chest wall Pectus carinatum/excavatum Broad thorax
syndrome should be suspected.
5. Family First-degree relative with definite First-degree relative
history Noonan syndrome with suggestive Resources
Noonan syndrome
The following education, support, refer-
6. Other All of the following: intellectual One of the following: ral, and research websites are useful for
features disability, cryptorchidism, and intellectual disability,
lymphatic vessel dysplasia cryptorchidism, or
physicians and for their patients who have
lymphatic vessel Noonan syndrome:
dysplasia • GeneTests (www.genetests.org)
• Genetics Home Reference (http://ghr.
NOTE: Noonan syndrome is considered present if the patient has typical facial dysmor- nlm.nih.gov/condition/noonan-syndrome)
phology plus one feature from categories 2A through 6A or two categories from fea-
tures 2B through 6B, or has suggestive facial dysmorphology plus two features from The authors thank Judith E. Allanson, MD, and Darryl
categories 2A through 6A or three features from categories 2B through 6B. Leja for their assistance with the preparation of the
Adapted with permission from van der Burgt I, Berends E, Lommen E, van Beersum manuscript.
S, Hamel B, Mariman E. Clinical and molecular studies in a large Dutch family with Figures 1 through 4 provided by Darryl Leja, National
Noonan syndrome. Am J Med Genet. 1994;53(2):190. Human Genome Research Institute, National Institutes of
Health, Bethesda, Md.

40  American Family Physician www.aafp.org/afp Volume 89, Number 1 ◆ January 1, 2014
 Table 3. Guidelines for Management of Noonan Syndrome

System-based
intervention Clinical issue Timing of intervention Comments

Auditory Hearing loss Hearing tests in infancy and/or —

at diagnosis
Annual hearing test throughout
childhood

Cardiovascular Congenital heart defects At the time of diagnosis and Cardiac consultation, echocardiography, and
regular follow-up with electrocardiography
cardiologist
Children and adults without
heart disease on initial
evaluation should have cardiac
reevaluation every five years

Dental Dental malocclusion Oral examination by primary —

care physician at each visit
Dental referral between one and
two years of age, with annual
dentist visits thereafter

Dermatologic See Table 1 for common skin Referral as indicated —

findings

Developmental Behavioral disorders Development assessment If screening results are abnormal, consider
Developmental delay annually (beginning in second appropriate intervention
half of first year of the
Learning difficulties
patient’s life or at diagnosis)
Mild intellectual disability
Baseline neuropsychologic
Speech disorders assessment at primary school
entry

Endocrine Delayed puberty Referral as indicated Endocrine evaluation for growth hormone
Hypothyroidism therapy to treat short stature and hormone
therapy for delayed puberty
Short stature
Thyroid function tests if patient shows signs
and symptoms of hypothyroidism

Gastroenterologic Feeding difficulties Referral as indicated Appropriate therapeutic intervention as

needed (e.g., swallowing study, speech
therapy, reflux studies)

Genetic To confirm diagnosis, genetic Referral as indicated —

counseling and genotype–
phenotype correlation

Growth Failure to thrive At the time of diagnosis, three Monitor and plot growth on Noonan
Short stature times a year for the first three syndrome age-based growth charts
years, then annually
Slow growth

Hematologic Increased bleeding tendencies Baseline coagulation screen at If bleeding symptoms:

(factor deficiency, diagnosis or after six to 12 First-tier: Baseline coagulation screen
quantitative or qualitative months of age if screening (complete blood count, prothrombin time,
platelet defect) was initially performed during activated partial thromboplastin time)
infancy or whenever diagnosis
Second-tier (in consultation with
is made
hematologist): Specific factor assay and
platelet function studies

Lymphatic Lymphatic vessel dysplasia, Referral as indicated Refer patients with lymphedema to
hypoplasia, or aplasia lymphedema clinic (contact National
Lymphedema Network; www.lymphnet.org)

continued

January 1, 2014 ◆ Volume 89, Number 1 www.aafp.org/afp American Family Physician 41

Noonan Syndrome
Table 3. Guidelines for Management of Noonan Syndrome (continued)

System-based
intervention Clinical issue Timing of intervention Comments

Metabolic Failure to thrive Referral as indicated Dietary assessment and nutrition intervention
Inadequate weight gain

Neurologic Arnold-Chiari malformation Referral as indicated Physician should have a low threshold
Craniosynostosis for investigating neurologic symptoms
(electroencephalography, magnetic
Headaches
resonance imaging of the brain)
Hydrocephalus
Seizures

Ocular Dysmorphic findings Detailed eye examination in —

Vision problems infancy and/or at diagnosis
Eye reevaluation as indicated if
abnormal or every two years
thereafter

Pregnancy Congenital heart defects Per obstetrician’s Chorionic villus sampling or amniocentesis for
Effusion recommendation diagnosis if indicated
Hydrops fetalis Fetal ultrasonography and echocardiography
Increased nuchal translucency
Polyhydramnios
Renal anomalies

Renal Renal anomalies (e.g., Renal ultrasonography at the Increased risk of urinary tract infection
pyeloureteral stenosis, time of diagnosis if structural anomaly found, consider
hydronephrosis) antibiotic prophylaxis and evaluation by
nephrologist

Reproductive Female fertility normal8 Orchiopexy if testes Fertility clinic evaluation in males
Male fertility problems undescended by one year
related to defective of age
spermatogenesis caused by
cryptorchidism or gonadal
dysfunction due to impaired
Sertoli cell function

Skeletal Pectus deformity of sternum Annual examination of chest If screening abnormal, consider radiography
Spinal abnormality and back of the spine

Surgical and Increased risk of complications Referral as indicated See cardiovascular, hematology, and skeletal
anesthesia risk due to a cardiac disorder, management recommendations
increased bleeding tendency,
or craniofacial and/or
vertebral anomalies

Information from references 1, 8, and 17.

Table 4. When to Suspect Noonan Syndrome The Authors

VIKAS BHAMBHANI, MD, is a clinical genetic fellow at
Noonan syndrome should be considered in anyone who presents with the National Human Genome Research Institute, National
two or more of the following: Institutes of Health, Bethesda, Md.
Characteristic facial features Short stature MAXIMILIAN MUENKE, MD, is chief of the Medical Genet-
(Figures 1 through 4) Typical chest deformity ics Branch at the National Human Genome Research Insti-
Developmental delay and/or Undescended testes tute, and director of the Medical Genetics and Genomic
learning disability
First-degree relative who has Noonan
Medicine residency and fellowship training programs at
Heart defect syndrome or any of the above features
the National Institutes of Health.
Pubertal delay and/or infertility Address correspondence to Maximilian Muenke, MD,
Medical Genetics Branch, National Human Genome

42  American Family Physician www.aafp.org/afp Volume 89, Number 1 ◆ January 1, 2014
 SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References Comments

The diagnosis of Noonan syndrome should be considered C 12 —

in all fetuses with a normal karyotype and increased
nuchal translucency, especially when cardiac anomaly,
polyhydramnios, and/or multiple effusions are observed.
Management of patients with Noonan syndrome is optimized by C 1, 17 U.S. and United Kingdom age-specific
adherence to age-specific guidelines that emphasize screening guidelines are available.
and testing for common health issues.
Referral to a clinical geneticist for assistance in diagnosis and C 1 —
management of Noonan syndrome may be helpful.
The appropriateness and sequence of genetic testing should be C 8 Mutation testing will prove a diagnosis
determined by a clinical geneticist. in approximately 70% of cases.
Mutation testing may benefit a
family if reproductive decisions
depend on this information.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Research Institute, National Institutes of Health, 35 Con- mation. http://www.ncbi.nlm.nih.gov/books/NBK1124.

vent Dr., MSC 3717, Bldg. 35, Room 1B-203, Bethesda, Accessed May 23, 2013.
MD 20892-3717 (e-mail: [email protected]). 9. Lee NB, Kelly L, Sharland M. Ocular manifestations of
Reprints are not available from the authors. Noonan syndrome. Eye (Lond). 1992;6(pt 3):328-334.
10. Kratz CP, Niemeyer CM, Castleberry RP, et al. The muta-
tional spectrum of PTPN11 in juvenile myelomonocytic
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