Noonan Syndrome Clinical Presentation

  • Author: Jennifer Ibrahim, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 24, 2011
 

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.
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Physical

The following is noted in patients with Noonan syndrome:

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

Both sporadic and autosomal dominant cases have been identified. At least 4 disease-causing genes have been found.[2, 3, 4, 5, 6]

  • 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.[7]
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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

Specialty Editor Board

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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina School of Medicine; 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.

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 and Genetics, Director RSA, 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.

References

  1. Zenker M. Genetic and pathogenetic aspects of Noonan syndrome and related disorders. Horm Res. Dec 2009;72 Suppl 2:57-63. [Medline].

  2. 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].

  3. 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].

  4. 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].

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

  6. 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].

  7. 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].

  8. 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].

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

  10. Houweling AC, de Mooij YM, van der Burgt I, et al. Prenatal detection of Noonan syndrome by mutation analysis of the PTPN11 and the KRAS genes. Prenat Diagn. Mar 2010;30(3):284-6. [Medline].

  11. Jongmans MC, van der Burgt I, Hoogerbrugge PM, et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. Aug 2011;19(8):870-4. [Medline].

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

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

  14. 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].

  15. 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].

  16. 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].

  17. 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].

  18. 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].

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

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

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

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

  23. 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].

  24. 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].

  25. 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].

 
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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.
 
 
 
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