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Am Fam Physician. 2014;89(1):37-43

Patient information: See related handout on Noonan syndrome, written by the authors of this article.

Author disclosure: No relevant financial affiliations.

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.

Noonan syndrome is a common genetic disorder with multiple congenital abnormalities. It is characterized by congenital heart disease, short stature, a broad and webbed neck, sternal deformity, variable degree of developmental delay, cryptorchidism, increased bleeding tendency, and characteristic facial features that evolve with age. Molecular genetic testing can confirm the diagnosis in most cases, which has important implications for genetic counseling and management. Physicians should know how to diagnose Noonan syndrome because patients who have it require monitoring for a large number of potential health conditions. Age-appropriate guidelines for the management of Noonan syndrome are available.1

Epidemiology

Noonan syndrome is characterized by marked variable expressivity, which makes it difficult to identify mildly affected individuals. The incidence is one in 1,000 to 2,500 live births for severe phenotype, but mild cases may be as common as one in 100 live births.2 Familial recurrence is consistent with an autosomal dominant mode of inheritance, but de novo mutations are more common, accounting for 60% of cases.3 There is no known predilection by race or sex.

Clinical recommendationEvidence ratingReferencesComments
The diagnosis of Noonan syndrome should be considered in all fetuses with a normal karyotype and increased nuchal translucency, especially when cardiac anomaly, polyhydramnios, and/or multiple effusions are observed.C12
Management of patients with Noonan syndrome is optimized by adherence to age-specific guidelines that emphasize screening and testing for common health issues.C1, 17 U.S. and United Kingdom age-specific guidelines are available.
Referral to a clinical geneticist for assistance in diagnosis and management of Noonan syndrome may be helpful.C1
The appropriateness and sequence of genetic testing should be determined by a clinical geneticist.C8 Mutation testing will prove a diagnosis in approximately 70% of cases. Mutation testing may benefit a family if reproductive decisions depend on this information.

Clinical Presentation

The diagnosis of Noonan syndrome depends primarily on the identification of characteristic clinical features (Table 1111 ). The clinical spectrum in children is well described, but few studies have examined medical complications in adults.3 Figures 1 through 4 show the cardinal phenotypic features of Noonan syndrome based on patient age.68

Cardiovascular4,5
Hypertrophic cardiomyopathy
Pulmonary stenosis, often with a dysplastic valve
Dental/oral1,2
Articulation difficulty
High arched palate
Malocclusion
Micrognathia
Dysmorphic facial features6,7
See Figures 1 through 4
Ears8
Hearing loss
Eyes2,9
Anterior segment problems (prominent corneal nerves, cataract, anterior stromal dystrophy)
Nystagmus
Ptosis, hypertelorism, and epicanthal folds
Refractive error
Strabismus
Gastrointestinal3,4
Feeding difficulties (poor sucking function, prolonged feeding time, recurrent vomiting and reflux)
Genitourinary2,8
Cryptorchidism
Female fertility is normal
Males can have fertility issues (e.g., defective spermatogenesis caused by cryptorchidism, gonadal dysfunction due to impaired
Sertoli cell function)
Malformations (renal pelvis dilation, solitary kidney, duplex collecting system)
Puberty can be delayed in both sexes
Growth2,4,8
Birth weight and length are normal
Failure to thrive and short stature (50% to 70% of patients with Noonan syndrome)
Mean final adult height is 63 to 66 inches (160 to 168 cm) in males and 59 to 61 inches (150 to 155 cm) in females
Hematologic1,3,4,10,11
Increased bleeding tendency (due to factor deficiency, quantitative or qualitative platelet defect)
Leukemia
Myeloproliferative disorder
Lymphatic8
Lymphedema
Neurologic1,8
Behavioral conditions (stubbornness, irritability, body image problems, poor self-esteem)
Central nervous system malformation
Early motor milestones delay (hypotonia and joint laxity)
Learning difficulties
Mild intellectual disability (33% of patients with Noonan syndrome)
Most individuals have normal intelligence
Speech disorders
Skeletal2,4
Cubitus valgus
Spinal abnormality (scoliosis, talipes equinovarus)
Sternal deformities (pectus carinatum superiorly, pectus excavatum inferiorly)
Skin conditions2,4
Dystrophic nails
Extra prominence on pads of fingers and toes
Follicular keratosis
Hyperelastic skin
Moles
Multiple lentigines
Nevi
Thick curly hair or thin sparse hair

Nonspecific prenatal anomalies common among patients with Noonan syndrome include increased nuchal translucency, polyhydramnios, and abnormal maternal serum triple screen (α-fetoprotein, human chorionic gonadotropin, and unconjugated estriol). The most common morphologic fetal anomaly is hydrothorax. Diagnosis of cardiac anomalies is rarely made prenatally. The diagnosis of Noonan syndrome should be considered in all fetuses with a normal karyotype and increased nuchal translucency, especially when cardiac anomaly, polyhydramnios, and/or multiple effusions are observed.12

Patients who have Noonan syndrome display clinical similarities to patients who have Turner syndrome (EDITOR'S NOTE: see https://www.aafp.org/afp/2007/0801/p405.html). However, patients can be easily differentiated because with Turner syndrome, only females are affected (because of the loss of the X chromosome), left-side heart defects are common, developmental delay occurs less often, renal anomalies are more common, and primary hypogonadism causes amenorrhea and sterility.8,13 A number of other partially overlapping syndromes, such as cardio-facio-cutaneous syndrome, Watson syndrome, Costello syndrome, neurofibromatosis 1, and LEOPARD syndrome (lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness), also can be differentiated from Noonan syndrome based on clinical features.8,14

Diagnosis

Early, accurate diagnosis of Noonan syndrome is important because each patient requires an individual treatment regimen and has a different prognosis and recurrence risk. A scoring system has been devised to help diagnose patients with the condition (Table 215 ).

FeatureA = MajorB = Minor
1. FacialTypical facial dysmorphology (facial features vary with age and are described in Figures 1 through 4)Suggestive facial dysmorphology
2. CardiacPulmonary valve stenosis, hypertrophic cardiomyopathy, and/or electrocardiographic results typical of Noonan syndromeOther defect
3. Height< 3rd percentile< 10th percentile
4. Chest wallPectus carinatum/excavatumBroad thorax
5. Family historyFirst-degree relative with definite Noonan syndromeFirst-degree relative with suggestive Noonan syndrome
6. Other featuresAll of the following: intellectual disability, cryptorchidism, and lymphatic vessel dysplasiaOne of the following: intellectual disability, cryptorchidism, or lymphatic vessel dysplasia

Until recently, diagnosis was made solely on the basis of clinical features, but molecular genetic testing can provide confirmation in 70% of cases.8 Noonan syndrome is caused by mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway, which is essential for cell cycle differentiation, growth, and senescence.14 Approximately one-half of the known mutations are in the protein tyrosine phosphatase non-receptor, type 11 (PTPN 11) gene.8

Genetic Counseling

Most cases are sporadic. In familial cases, autosomal dominant inheritance is confirmed. The risk of Noonan syndrome developing in the sibling of an affected person is 50% if the parent is affected, but is less than 1% if the parent is unaffected. Risk of transmission to the offspring of an affected individual is 50%.8 Preimplantation genetic diagnosis can be offered in familial cases with known mutations.8

Management

Intellectual and physical abilities are normal in most adults with Noonan syndrome, but some may require multidisciplinary evaluation and regular follow-up care.16 Recently, management guidelines were developed by American and European consortia, and management is optimized by adherence to age-specific guidelines that emphasize screening and testing for common health issues.1,17 Referral to a clinical geneticist for assistance in the diagnosis and management of Noonan syndrome, including determining the appropriateness and sequence of genetic testing, may be helpful.1,8 Clinical growth charts are also available via a European network at http://www.dyscerne.org. Table 3 lists system-based management guidelines to assist physicians caring for patients with Noonan syndrome and their families.1,8,17 Table 4 describes when Noonan syndrome should be suspected.

System-based interventionClinical issueTiming of interventionComments
AuditoryHearing lossHearing tests in infancy and/or at diagnosis
Annual hearing test throughout childhood
CardiovascularCongenital heart defectsAt the time of diagnosis and regular follow-up with cardiologistCardiac consultation, echocardiography, and electrocardiography
Children and adults without heart disease on initial evaluation should have cardiac reevaluation every five years
DentalDental malocclusionOral examination by primary care physician at each visit
Dental referral between one and two years of age, with annual dentist visits thereafter
DermatologicSee Table 1 for common skin findingsReferral as indicated
DevelopmentalBehavioral disorders, developmental delay, learning difficulties, mild intellectual disability, speech disordersDevelopment assessment annually (beginning in second half of first year of the patient's life or at diagnosis)If screening results are abnormal, consider appropriate intervention
Baseline neuropsychologic assessment at primary school entry
EndocrineDelayed puberty, hypothyroidism, short statureReferral as indicatedEndocrine evaluation for growth hormone therapy to treat short stature and hormone therapy for delayed puberty
GastroenterologicFeeding difficultiesReferral as indicatedAppropriate therapeutic intervention as needed (e.g., swallowing study, speech therapy, reflux studies)
GeneticTo confirm diagnosis, genetic counseling and genotype–phenotype correlationReferral as indicated
GrowthFailure to thrive, short stature, slow growthAt the time of diagnosis, three times a year for the first three years, then annuallyMonitor and plot growth on Noonan syndrome age-based growth charts
HematologicIncreased bleeding tendencies (factor deficiency, quantitative or qualitative platelet defect)Baseline coagulation screen at diagnosis or after six to 12 months of age if screening was initially performed during infancy or whenever diagnosis is madeIf bleeding symptoms:
First-tier: Baseline coagulation screen (complete blood count, prothrombin time, activated partial thromboplastin time)
Second-tier (in consultation with hematologist): Specific factor assay and platelet function studies
LymphaticLymphatic vessel dysplasia, hypoplasia, or aplasiaReferral as indicatedRefer patients with lymphedema to lymphedema clinic (contact National Lymphedema Network; http://www.lymphnet.org/)
MetabolicFailure to thrive Inadequate weight gainReferral as indicatedDietary assessment and nutrition intervention
NeurologicArnold-Chiari malformation, craniosynostosis, headaches, hydrocephalus, seizuresReferral as indicatedPhysician should have a low threshold for investigating neurologic symptoms (electroencephalography, magnetic resonance imaging of the brain)
OcularDysmorphic findings, vision problemsDetailed eye examination in infancy and/or at diagnosis
Eye reevaluation as indicated if abnormal or every two years thereafter
PregnancyCongenital heart defects, effusion, hydrops fetalis, increased nuchal translucency, polyhydramnios, renal anomaliesPer obstetrician's recommendationChorionic villus sampling or amniocentesis for diagnosis if indicated
Fetal ultrasonography and echocardiography
RenalRenal anomalies (e.g., pyeloureteral stenosis, hydronephrosis)Renal ultrasonography at the time of diagnosisIncreased risk of urinary tract infection if structural anomaly found, consider antibiotic prophylaxis and evaluation by nephrologist
ReproductiveFemale fertility normal8; male fertility problems related to defective spermatogenesis caused by cryptorchidism or gonadal dysfunction due to impaired Sertoli cell functionOrchiopexy if testes undescended by one year of ageFertility clinic evaluation in males
SkeletalPectus deformity of sternum, spinal abnormalityAnnual examination of chest and backIf screening abnormal, consider radiography of the spine
Surgical and anesthesia riskIncreased risk of complications due to a cardiac disorder, increased bleeding tendency, or craniofacial and/or vertebral anomaliesReferral as indicatedSee cardiovascular, hematology, and skeletal management recommendations
Noonan syndrome should be considered in anyone who presents with two or more of the following:
Characteristic facial features (Figures 1 through 4)
Developmental delay and/or learning disability
Heart defect
Pubertal delay and/or infertility
Short stature
Typical chest deformity
Undescended testes
First-degree relative who has Noonan syndrome or any of the above features

Resources

The following education, support, referral, and research websites are useful for physicians and for their patients who have Noonan syndrome:

Cardio-facio-cutaneous syndrome: Characterized by cardiac abnormalities, distinctive craniofacial appearance, and cutaneous abnormalities.
Costello syndrome: Characterized by growth problems, developmental delay or intellectual disability, coarse facial features, curly or sparse fine hair, soft skin with deep palmar and plantar creases, papillomata of the face and perianal region, diffuse hypotonia, joint laxity, and cardiac disease.
LEOPARD syndrome: An acronym for the cardinal features of lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, andsensorineural deafness.
Neurofibromatosis 1: Characterized by multiple café au lait spots, axillary and inguinal freckling, neurofibromas, Lisch nodules, gliomas, and osseous lesions.
Preimplantation genetic diagnosis: A procedure used to decrease the 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.
RAS/mitogen-activated protein kinase (MAPK) pathway: Essential in the regulation of the cell cycle, differentiation, growth, and cell senescence, all of which are critical to normal development. Mutations in the genes that encode for the pathway have profound effects on development.
Turner syndrome: A chromosomal abnormality in which one X chromosome is absent; 45,X karyotype.
Variable expressivity: The range of signs and symptoms that can occur in different persons with the same genetic condition.
Watson syndrome: An autosomal dominant disorder characterized by pulmonary stenosis, café au lait spots, decreased intellectual ability, and short stature. Most affected individuals have a large head, Lisch nodules, and neurofibromas.

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