Noonan Syndrome 

Updated: May 18, 2020
Author: Margaret M McGovern, MD, PhD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Practice Essentials

Noonan syndrome is a genetic disorder that prevents normal development of various parts of the body. The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, down-slanting eyes, webbed neck), congenital heart disease, short stature, and chest deformity. Approximately 25% of individuals with Noonan syndrome have mental retardation. Bleeding diathesis is present in as many as half of all patients with Noonan syndrome. Skeletal, neurologic, genitourinary, lymphatic, eye, and skin findings may be present to varying degrees.[1, 2]

Noonan syndrome was first recognized as a unique entity in 1963, when Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart disease. These patients were previously thought to have a form of Turner syndrome, with which Noonan syndrome shares numerous clinical features. The observation that patients with Noonan syndrome have normal karyotypes was important in allowing the distinction to be made between the Turner and Noonan syndromes.

Signs and symptoms of Noonan syndrome

Symptoms of Noonan syndrome vary in severity but may include the following:

  • Characteristic facial features affecting the eyes, ears, nose, mouth, head shape, and skin
  • Congenital heart defects - Valve disorders, hypertrophic cardiomyopathy, ventricular septal defect
  • Growth insufficiencies, short stature in adulthood
  • Musculoskeletal issues
  • Learning disabilities
  • Eye and eyelid abnormalities
  • Hearing deficits
  • Bleeding issues
  • Lymphatic issues
  • Genital and renal issues
  • Skin issues

Diagnosis of Noonan syndrome

Diagnosis is usually based on characteristic signs. Molecular genetic testing, however, can aid in confirmation.

Treatment of Noonan syndrome

Treatment is focused on the symptoms of Noonan syndrome and may include cardiac therapy, growth hormone therapy, physical and speech therapy, ophthalmologic treatment, management of bleeding disorders, treatment of lymphatic problems, and urologic therapy (in males).

Pathophysiology

The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. Mutations in KRAS, NRAS, BRAF, and MAP2K1 also have been identified, but in smaller numbers of patients.

Epidemiology

Frequency of Noonan syndrome

United States

The incidence of Noonan syndrome is estimated to be 1 case per 1000 to 1 case per 2500 live births.

International

The incidence of Noonan syndrome appears to be consistent worldwide.

Mortality/Morbidity

The primary source of morbidity and mortality in patients with Noonan syndrome depends on the presence and type of congenital heart disease.

Noonan syndrome is also characterized by a slight increase in the risk for certain cancers. In a literature review spanning 1937-2010, Kratz et al found the most commonly reported cancers in Noonan syndrome, as diagnosed in a total of 1051 patients, to be neuroblastoma (8 cases), acute lymphoblastic leukemia (8 cases), low-grade glioma (6 cases), and rhabdomyosarcoma (6 cases); like Noonan syndrome, all of these cancers are associated with RAS signaling pathway mutations.[3] Juvenile myelomonocytic leukemia and myeloproliferative disorder have also been associated with Noonan syndrome.

A study by Jongmans et al also demonstrated an elevated cancer risk in patients with Noonan syndrome.[4] Twelve of 297 patients with a PTPN11 mutation developed a malignancy—a 3.5-fold increased risk compared with that of healthy individuals. Hematologic malignancies occurred most frequently, while 2 malignancies not previously observed in Noonan syndrome were found: a malignant mastocytosis and malignant epithelioid angiosarcoma.

A study by Cessans et al comparing growth patterns in patients with Noonan syndrome based on genotype found that at birth, patients with PTPN11 mutations tended to be shorter and thinner than were those with mutations in SOS1, KRAS, or Noonan syndrome with multiple lentigines–associated PTPN11 (NSML-PTPN11). Additionally, at age 2 years, growth retardation was more severe and frequent in patients with PTPN11 mutations than in those with mutations in SOS1 or NSML-PTPN11. At age 10 years, although patients with Noonan syndrome had lower body mass indexes in general, no growth differences were found between the different genotypes.[5]

A study by Croonen et al indicated that feeding problems contribute to growth impairment during the first year of life in children with Noonan syndrome. Although PTPN11 mutation, greater gestational age, and cardiac surgery also had a negative effect on weight gain and length in the study, the investigators found that at age 1 year, children with feeding problems weighed, on average, 290 g less than children without feeding problems and were, on average, 0.8 cm shorter.[6]

A study by Draaisma et al indicated that in children with Noonan syndrome, feeding problems frequently arise in infancy—particularly in patients in whom the syndrome developed from mutations in genes other than PTPN11 and SOS1—but typically resolve between age 1-2 years. The report found that out of a cohort of 108 patients with Noonan syndrome, 71 (65.7%) had feeding problems, including 40 who required tube feeding. Of the 71 patients, 52 (73.2%) developed feeding problems before age 1 year.[7]

Race

Noonan syndrome is panethnic.

Sex

Noonan syndrome occurs in either a sporadic or autosomal dominant fashion. In either case, males and females are equally affected.

Age

The disorder is present from birth, but age impacts the facial phenotype. Infants with Noonan syndrome can be difficult to recognize by facial appearance alone. The phenotype becomes more striking in early childhood, but with advancing age, it may again become quite subtle. Careful examination of an affected child's parents may in fact reveal that they are mildly affected.

 

Presentation

History

The prenatal history in Noonan syndrome is typically unremarkable; however, some cases are complicated by polyhydramnios, fetal edema, increased nuchal fold translucency, cystic hygroma, or congenital heart disease (particularly pulmonary valvular dysplasia).

A careful family history should be obtained, paying particular attention to the presence of congenital heart disease, mental retardation, short stature, or unusual facies among the parents or siblings of an affected child.

A child with mild expression of the facial phenotype may present only with developmental delay and history of congenital heart disease. A history of abnormal bleeding is present in as many as 50% of patients.

A study by Niemczyk et al suggested that incontinence affects a significant proportion of children with Noonan syndrome. The study, of 19 children and 10 adults with Noonan syndrome, found that among the younger children (aged 4-12 years), the incidence of daytime urinary incontinence, nocturnal enuresis, and fecal incontinence was 36.4%, 27.3%, and 11.1%. However, only one adolescent and one adult experienced incontinence, indicating that the condition tends not to persist into adulthood.[8]

Physical

Growth parameters associated with Noonan syndrome

Size at birth is usually within the reference range in Noonan syndrome. Short stature is present in as many as 80% of patients. Average adult height for is 5 feet 5 inches in males and 5 feet in females.

Facial features

These include the following:

  • Triangular-shaped face

  • Hypertelorism

  • Down-slanting palpebral fissures

  • Ptosis

  • Strabismus (48%)

  • Amblyopia (33%)

  • Refractive errors (61%)

  • Low-set ears with thickened helices: In a study of 97 patients with Noonan syndrome, van Trier et al found that 75 of them (77%) had external ear anomalies, including 69 patients whose ears were low set, 28 whose ears were posteriorly rotated, 14 whose ears protruded, and 18 who had thickened helices[9]

  • High nasal bridge

  • Short, webbed neck

A subgroup of patients have Noonan-like/multiple giant cell lesion syndrome (NS/MGCLS), which is characterized by benign, tumorlike lesions, usually occurring in the jaws. This condition was once thought to be separate from Noonan syndrome but is now considered to be a variant of it. NS/MGCLS is associated with PTPN11 and SOS1 gene mutations.[10]

A study by Allanson et al, however, indicated that facial phenotype by itself is not sufficient to predict the presence of specific Noonan syndrome mutations. In an examination of facial photos of 81 persons with Noonan syndrome, the investigators determined that even though mutations in PTPN11 are associated with the cardinal physical characteristics of the disorder, some individuals with these mutations have facial features that are atypical for the syndrome. On the other hand, although a correlation can be seen between KRAS mutations and an intellectual and physical phenotype that is somewhat atypical for Noonan syndrome, some patients with these mutations have the characteristic facial features of the disorder.[11]

Ocular features

A prospective study by van Trier et al reported that in addition to hypertelorism and eyelid abnormalities, ocular anomalies in patients with Noonan syndrome also include amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, abnormal stereopsis, and posterior embryotoxon. At least three ocular abnormalities were found in each of the study’s 25 patients, with more than 95% of these individuals having at least one external ocular feature.[12]

Auditory features

The incidence of progressive high-frequency sensorineural hearing loss may be as high as 50%. A study by Tokgoz-Yilmaz et al indicated that children with Noonan syndrome have higher hearing thresholds and lower transient evoked otoacoustic emissions amplitudes than do children without the syndrome. However, hearing sensitivity was found to be within normal limits, as were middle ear pressures and auditory brainstem response values.[13]

Chest/back features

These include pectus carinatum and/or excavatum. Scoliosis is another feature.

Cardiovascular findings

Cardiac defects occur in up to 80% of patients. The characteristic lesion is dysplastic/stenotic pulmonic valve, but virtually all types of congenital heart defects have been described in patients with Noonan syndrome. Hypertrophic cardiomyopathy (obstructive or nonobstructive type) is present in up to 30% of patients and can present at birth or in infancy or childhood. Other cardiac defects frequently include atrial and ventricular septal defects, branch pulmonary artery stenosis, tetralogy of Fallot, and coarctation of the aorta.[1]

Abdominal features

Hepatosplenomegaly unrelated to cardiac status is present in approximately 25% of patients.

Genitourinary features

Renal anomalies are present in 10% of patients but are not clinically significant. However, more than half of male patients have undescended testes.

Skeletal features

Joint laxity is present in more than half of patients. Talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures are less common findings.[14]

Skin findings

These include the following:

  • Lymphedema (See the images below)

    Lymphedema of the feet in an infant is shown. The Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.
    Generalized lymphedema is seen here in an infant. Generalized lymphedema is seen here in an infant. The loose skin folds around the neck will form a webbed neck later in life.
  • Prominent pads of fingers and toes (67%)

  • Follicular keratosis of the face and extensor surfaces (14%)

  • Multiple lentigines (3%)

Neurologic findings associated with Noonan syndrome

These include the following:

  • Hypotonia

  • Seizure disorder (13%)

  • Unexplained peripheral neuropathy (infrequent)

Causes

Sporadic and autosomal dominant cases have been identified. Female patients with Noonan syndrome have normal pubertal development and fertility, while fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases.

Causative gene mutations in Noonan syndrome include the following[15, 16, 17, 18, 19, 20] :

  • PTPN11 mutations: Account for approximately 50% of clinically recognized cases

  • SOS1 mutations: Account for approximately 13% of cases

  • RAF1 mutations: Account for 5-17% of cases

  • RIT1 mutations: Account for 5% of cases

  • KRAS, NRAS, BRAF, and MAP2K1 mutations: Account for a smaller number of cases

Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations.[21]

Correlations have been demonstrated between patient phenotype in Noonan syndrome and mutations in specific genes. A study by Lee et al found that patients with Noonan syndrome who had SOS1 mutations tended to have normal stature, while RAF1 mutations appeared to be associated with hypertrophic cardiomyopathy and developmental delay.[22]

 

DDx

Diagnostic Considerations

These include the following:

  • Costello syndrome

  • Craniofaciocutaneous syndrome

  • Fetal hydantoin syndrome

  • Lentigines, electrocardiographic (conduction abnormalities), ocular (hypertelorism), pulmonary (stenosis), abnormal (genitalia), retardation (of growth), and deafness (LEOPARD) syndrome

  • XO/XY mosaicism

  • Turner syndrome

  • Neurofibromatosis type 1

  • SPRED1 spectrum

Differential Diagnoses

 

Workup

Approach Considerations

All patients with Noonan syndrome should be evaluated to determine which disease manifestations they display. A complete physical and neurologic examination should be performed, and a genetics consultation should be sought. In addition, the following assessments should be made at the time of diagnosis:

  • Cardiac evaluation: Including echocardiographic and electrocardiographic assessment

  • Ophthalmologic and audiologic evaluation

  • Coagulation screen

  • Renal ultrasonographic examination

  • Developmental assessment

Before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed.

Laboratory Studies

Bleeding diatheses are common among patients with Noonan syndrome. The most frequent abnormality is factor XI deficiency, but various disorders have been reported in patients with Noonan syndrome. A complete blood count (CBC) with platelet count, coagulation profile, and measurement of factor XI level should be obtained at a minimum. Moreover, before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed.

If full phenotypic expression is not apparent, karyotyping may be necessary. Mutation analysis may confirm the diagnosis of Noonan syndrome, but failure to identify a germline mutation in any of the associated genes does not rule out the disorder; this entity remains a clinical diagnosis.

Many individuals with Noonan syndrome have reduced insulinlike growth factor-1 (IGF-1) and IGF-binding protein 3, but these tests are not diagnostic of the syndrome itself.

Imaging Studies

Appropriate imaging studies in Noonan syndrome include the following:

  • Echocardiography

  • Renal ultrasonography

  • Brain and cervical spine magnetic resonance imaging (MRI): If neurologic symptoms are present

  • Radiography: To examine the chest and back if abnormalities are present[1] and to evaluate the patient for Noonan-like/multiple giant cell lesion syndrome (NS/MGCLS)

Other Tests

Any child suspected of having Noonan syndrome requires a detailed cardiac workup. This includes electrocardiography, echocardiography, and consultation with a pediatric cardiologist.

Assessment of development is necessary to identify any delays and allow for intervention. Full-scale intelligence quotient (IQ) ranges from 48-130, with a mean of 86.1 (approximately one standard deviation [SD] below the general population mean). Approximately 25% of patients with Noonan syndrome have mental retardation. A study by Roelofs et al found that in persons with Noonan syndrome, full-scale and performance IQs saw significant improvement in adult scores compared with childhood values, with performance IQ reaching normal levels. However, verbal IQ did not advance proportionately to performance IQ by adulthood. The investigators suggested that the improvement in performance IQ in individuals with Noonan syndrome points to a developmental delay in executive functioning that is outgrown in adulthood. However, maturation of motor skills was also suggested as a reason for the improvement. The study included 16 patients, whose intelligence was evaluated in childhood and adulthood.[23]

As previously mentioned, the incidence of progressive high-frequency sensorineural hearing loss may be as high as 50%. Thus, audiologic evaluation is indicated.

DNA-based testing of the known causative genes, which can be performed via next-generation sequencing, can be considered for confirmation of diagnosis.[24] Unless a known mutation is present in a family, negative (ie, normal) test findings do not rule out a diagnosis of Noonan syndrome.

 

Treatment

Medical Care

Growth charts specific for Noonan syndrome are available and can be used to plot an individual's height, weight, and head circumference.[25] Growth hormone has been used to accelerate growth in some patients with the disorder, and achievement of near-adult height has been documented. Such therapy is well tolerated, with very few adverse events reported.[26, 27]

Careful follow-up evaluation of patients with Noonan syndrome is needed for early identification of bleeding diathesis, malignancy, and hypertrophic cardiomyopathy.

Surgical Care

Certain types of congenital heart lesions are amenable to surgical correction.

Consultations

The following consultations may be indicated in Noonan syndrome:

  • Geneticist

  • Cardiologist

  • Hematologist

  • Ophthalmologist

  • Neurologist

  • Audiologist

Diet

No special dietary restrictions apply.

Activity

Activity may be limited by cardiac status and the presence of hematologic abnormalities.

 

Medication

Medication Summary

Growth hormone may be used to treat short stature associated with Noonan syndrome. A randomized, double-blind, multicenter trial from Japan, by Horikawa et al, reported that prepubertal children with Noonan syndrome–associated short stature can achieve increased height through a 208-week regimen of somatropin administered at doses of 0.033 mg/kg/day or 0.066 mg/kg/day. However, the report found that the higher dose had a greater effect on height, with the investigation revealing the drug to be well tolerated.[28, 29]

Growth Hormone

Class Summary

Physiologic replacement for conditions of growth hormone deficiency.

Somatropin (Norditropin)

Human growth hormone produced by recombinant DNA technology (mouse C127 cell line). Elicits anabolic and anticatabolic influence on various cells including: myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Stimulates growth of linear bone, skeletal muscle, and organs. Exerts activity on specific cell receptors including insulinlike growth factor-1 (IGF-1). Indicated for short stature associated with Noonan syndrome.

 

Follow-up

Deterrence/Prevention

If a causative mutation is found in patients, parental studies should be offered in order to distinguish familial cases from sporadic ones. If an individual carries a germline mutation, prenatal diagnosis can be offered in future pregnancies.[30] The presentation of Noonan syndrome can vary widely within families.

Prenatal testing for Noonan syndrome can be considered in the absence of a family history when cystic hygroma is seen on ultrasonography and karyotyping of amniocytes is normal.

Recurrence risk for parents who do not appear to be affected or who have only some facial features of Noonan syndrome is 5%. Gonadal mosaicism may account for this increase over population risk. Affected individuals have a 50% chance of passing on the disorder with each pregnancy.

Patient Education

Once the pattern of inheritance has been identified, parents need to be counseled regarding recurrence risk with each pregnancy. Sporadic cases present minimal recurrence risk to the siblings of the affected child; the exception is parental gonadal mosaicism. Offspring of an affected individual have a 50% chance of developing Noonan syndrome.

Patients with bleeding disorders must be advised against the use of aspirin and aspirin-containing products or other medications that may interfere with coagulation or platelet function.

 

Questions & Answers

Overview

What is Noonan syndrome?

What is the pathophysiology of Noonan syndrome?

What is the prevalence of Noonan syndrome in the US?

What is the global prevalence of Noonan syndrome?

What is the mortality and morbidity associated with Noonan syndrome?

What is the racial predilection of Noonan syndrome?

What is the sexual predilection of Noonan syndrome?

How does age affect the facial phenotype of Noonan syndrome?

Presentation

Which clinical history findings are characteristic of Noonan syndrome?

How does Noonan syndrome affect stature?

What are the characteristic facial features of Noonan syndrome?

Which ocular findings are characteristic of Noonan syndrome?

Which auditory findings are characteristic of Noonan syndrome?

Which chest abnormalities are associated with Noonan syndrome?

Which cardiovascular findings are characteristic of Noonan syndrome?

How prevalent is hepatosplenomegaly in Noonan syndrome?

Which genitourinary findings are characteristic of Noonan syndrome?

Which skeletomuscular findings are characteristic of Noonan syndrome?

Which dermatologic findings are characteristic of Noonan syndrome?

Which neurologic findings are characteristic of Noonan syndrome?

What causes Noonan syndrome?

Which genetic mutations cause Noonan syndrome?

DDX

Which conditions should be included in the differential diagnoses of Noonan syndrome?

What are the differential diagnoses for Noonan Syndrome?

Workup

How is Noonan syndrome diagnosed?

What is the role of lab testing in the workup of Noonan syndrome?

What is the role of imaging studies in the workup of Noonan syndrome?

What is included in the cardiac workup of Noonan syndrome?

How is development assessed in Noonan syndrome?

Why is audiologic evaluation performed in Noonan syndrome?

What is the role of genetic testing in the evaluation of Noonan syndrome?

Treatment

How is Noonan syndrome treated?

What is the role of surgery in the treatment of Noonan syndrome?

Which specialist consultations are beneficial to patients with Noonan syndrome?

Which dietary modifications are used in the treatment of Noonan syndrome?

Which activity modifications are used in the treatment of Noonan syndrome?

Medications

What is the role of medications in the treatment of Noonan syndrome?

Which medications in the drug class Growth Hormone are used in the treatment of Noonan Syndrome?

Follow-up

How is Noonan syndrome prevented?

What is included in patient education about Noonan syndrome?