eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Noonan Syndrome: Differential Diagnoses & Workup

Author: Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Coauthor(s): Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Contributor Information and Disclosures

Updated: Jul 24, 2009

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.

More on Noonan Syndrome

Overview: Noonan Syndrome
Differential Diagnoses & Workup: Noonan Syndrome
Treatment & Medication: Noonan Syndrome
Follow-up: Noonan Syndrome
Multimedia: Noonan Syndrome
References
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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].

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  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].

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  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].

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  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].

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Further Reading

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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

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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

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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