eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Noonan Syndrome

Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York

Updated: Jul 24, 2009

Introduction

Background

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.

The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, down-slanting eyes, webbed neck), congenital heart disease (in 50%), 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.

Pathophysiology

The pathophysiology of Noonan syndrome is not fully understood. Four disease-causing genes (PTPN11, SOS1, RAF1, and KRAS) have been identified. All 4 genes are part of the RAS/RAF/MEK/ERK signal transduction pathway, which is an important regulator of cell growth.

Frequency

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 these patients depends on the presence and type of congenital heart disease.

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.

Clinical

History

The prenatal history is typically unremarkable; however, some cases are complicated by polyhydramnios, fetal edema, or cystic hygroma.

• 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 might only present with developmental delay and history of congenital heart disease. A history of abnormal bleeding is present in as many as 50% of patients.

Physical

• Growth parameters
  • Size at birth is usually within the reference range.
  • Short stature is present in as many as 80% of patients. Average adult height for is 5 ft 5 inches in males and 5 ft in females.
• Facial features
  • Triangular-shaped face
  • Hypertelorism
  • Down-slanting eyes
  • Ptosis
  • Strabismus (48%)
  • Amblyopia (33%)
  • Refractive errors (61%)
  • Low-set ears with thickened helices
  • High nasal bridge
  • Short webbed neck
• Chest/back features
  • Pectus carinatum or excavatum
  • Scoliosis
• Cardiac features: 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 and nonobstructive types) is present in as many as 30% of patients.
• 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.
  • 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.
• Skin findings
  • Lymphedema
    
    

    

    Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.

    
    
    
    

    

    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 face and extensor surfaces (14%)
  • Multiple lentigines (3%)
• Neurologic findings
  • Hypotonia
  • Seizure disorder (13%)
  • Unexplained peripheral neuropathy (infrequent)

Causes

Both sporadic and autosomal dominant cases have been identified. At least 4 disease-causing genes have been found.^1,2,3,4,5

• PTPN11 mutations account for approximately 50% of clinically recognized cases.
• SOS1 mutations account for approximately 10% of cases.
• RAF1 mutations account for 3-17% of cases.
• KRAS mutations account for approximately 1% of cases.
• Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations.⁶

Differential Diagnoses

Fetal Alcohol Syndrome

Other Problems to Be Considered

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

Workup

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 CBC count with platelet count, coagulation profile, and measurement of factor XI level should be obtained at a minimum.
• If full phenotypic expression is not apparent, karyotyping may be necessary.
• Mutation analysis may confirm the diagnosis. However, the failure to identify a germline mutation in any of the associated genes does not rule out Noonan syndrome. 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.

Other Tests

• Any child suspected of having Noonan syndrome requires a detailed cardiac workup. This includes ECG, echocardiography (ECHO), 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.
• 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 4 known causative genes is available on a commercial basis and can be considered for confirmation of diagnosis. 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 hormone has been used to accelerate growth in some patients with Noonan syndrome.
• Significant improvement of near-adult height has now been documented. 
• This treatment is well tolerated, with very few adverse events reported.^7,8

Surgical Care

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

Consultations

• 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

Growth hormone may be used to treat short stature associated with Noonan syndrome.

Growth Hormone

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.

Dosing

Adult

Not established

Pediatric

Norditropin: Up to 0.066 mg/kg/d SC

Interactions

Glucocorticoids may decrease growth promoting effects

Contraindications

Documented hypersensitivity; sensitivity to benzyl alcohol; active neoplasia; acute critical illness following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rotate injection sites; may cause moderate fluid retention and arthralgias (treat symptomatically or reduce dose by 50%); discontinue for up to 5 d for severe toxicity (may reinitiate at 50% of original dose), discontinue permanently is toxicity not resolved with 5 d or recurs; may cause allergic reaction, acute pancreatitis, or glucose intolerance; caution with renal or hepatic impairment

Follow-up

Further Outpatient Care

• All patients with Noonan syndrome require ongoing developmental, audiologic, and ophthalmologic follow-up. Direct other follow-up at specific findings (eg, hematology follow-up for patients with bleeding disorders).

Deterrence/Prevention

• If a causative mutation is found in patients, parental studies should be offered in order to distinguish familial cases from sporadic cases. If an individual carries a germline mutation, prenatal diagnosis can be offered in future pregnancies. The presentation 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.

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.

Miscellaneous

Medicolegal Pitfalls

• 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.

Special Concerns

• Before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed.
• Female patients have normal pubertal development and fertility. Fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases.

Multimedia

Media file 1: Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.

Media file 2: Generalized lymphedema is seen here in an infant. The loose skin folds around the neck will form a webbed neck later in life.

References

1. Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. Jun 2002;70(6):1555-63. [Medline].

2. Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. Jan 2007;39(1):75-9. [Medline].

3. Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. Aug 2007;39(8):1007-12. [Medline].

4. Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. Mar 2006;38(3):331-6. [Medline].

5. Carta C, Pantaleoni F, Bocchinfuso G, et al. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. Jul 2006;79(1):129-35. [Medline].

6. Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Seidenberg MS. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. Apr 2009;8(3):275-82. [Medline].

7. Romano AA, Dana K, Bakker B, et al. Growth Response, Near-Adult Height, and Patterns of Growth and Puberty in Patients With Noonan Syndrome Treated With Growth Hormone. J Clin Endocrinol Metab. Apr 28 2009;[Medline].

8. Binder G. Noonan syndrome, the Ras-MAPK signalling pathway and short stature. Horm Res. Apr 2009;71 Suppl 2:64-70. [Medline].

9. Allanson JE. Noonan syndrome. J Med Genet. Jan 1987;DA - 19870320(1):9-13. [Medline].

10. Allanson JE, Hall JG, Hughes HE, et al. Noonan syndrome: the changing phenotype. Am J Med Genet. Jul 1985;21(3):507-14. [Medline].

11. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. Aug 2008;29(8):992-1006. [Medline].

12. Bader-Meunier B, Tchernia G, Mielot F, et al. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr. Jun 1997;130(6):885-9. [Medline].

13. Ferrero GB, Baldassarre G, Delmonaco AG, Biamino E, Banaudi E, Carta C, et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. Nov-Dec 2008;51(6):566-72. [Medline].

14. Marino B, Digilio MC, Toscano A, et al. Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. Dec 1999;135(6):703-6. [Medline].

15. Noonan JA. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child. Oct 1968;116(4):373-80. [Medline].

16. Noonan JA. Noonan syndrome revisited. J Pediatr. Dec 1999;135(6):667-8. [Medline].

17. Noonan JA. Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr (Phila). Sep 1994;33(9):548-55. [Medline].

18. Qiu WW, Yin SS, Stucker FJ. Audiologic manifestations of Noonan syndrome. Otolaryngol Head Neck Surg. Mar 1998;118(3 Pt 1):319-23. [Medline].

19. Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child. Feb 1992;67(2):178-83. [Medline].

20. Sharland M, Morgan M, Smith G, et al. Genetic counseling in Noonan syndrome. Am J Med Genet. Feb 15 1993;45(4):437-40. [Medline].

21. Singer ST, Hurst D, Addiego JE Jr. Bleeding disorders in Noonan syndrome: three case reports and review of the literature. J Pediatr Hematol Oncol. Mar-Apr 1997;19(2):130-4. [Medline].

22. van der Burgt I, Thoonen G, Roosenboom N, et al. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr. Dec 1999;135(6):707-13. [Medline].

Keywords

Noonan syndrome, Noonan's syndrome, hypertelorism, down-slanting eyes, webbed neck, congenital heart disease, congenital heart disease, short stature, chest deformity, polyhydramnios, fetal edema, cystic hygroma, ptosis, strabismus, amblyopia, high nasal bridge, pectus carinatum, pectus excavatum, scoliosis, hepatosplenomegaly, talipes equinovarus, radioulnar synostosis, cervical spine fusion, lymphedema, LEOPARD syndrome, bleeding diatheses, treatment, diagnosis

Contributor Information and Disclosures

Author

Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Jennifer Ibrahim, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Coauthor(s)

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

Medical Editor

Elaine H Zackai, MD, Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia
Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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