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

Fetal Alcohol Syndrome

Workup

Romano AA, Allanson JE, Dahlgren J, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010 Oct. 126(4):746-59. [QxMD MEDLINE Link]. [Full Text].
Bhambhani V, Muenke M. Noonan syndrome. Am Fam Physician. 2014 Jan 1. 89 (1):37-43. [QxMD MEDLINE Link]. [Full Text].
Roberts AE, Adam MP, Ardinger HH, et al. Noonan Syndrome. GeneReviews. Updated 2022 Feb 17. [QxMD MEDLINE Link]. [Full Text].
Allen MJ, Sharma S. Noonan Syndrome. StatPearls. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
Dahlgren J, Noordam C. Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome. J Clin Med. 2022 Apr 5. 11 (7):[QxMD MEDLINE Link]. [Full Text].
Kratz CP, Rapisuwon S, Reed H, et al. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011 May 15. 157C(2):83-9. [QxMD MEDLINE Link]. [Full Text].
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. 2011 Aug. 19(8):870-4. [QxMD MEDLINE Link].
Cessans C, Ehlinger V, Arnaud C, et al. Growth patterns of patients with Noonan syndrome: correlation with age and genotype. Eur J Endocrinol. 2016 May. 174 (5):641-50. [QxMD MEDLINE Link].
Croonen EA, Draaisma JMT, van der Burgt I, Roeleveld N, Noordam C. First-year growth in children with Noonan syndrome: associated with feeding problems?. Am J Med Genet A. 2018 Apr. 176 (4):951-8. [QxMD MEDLINE Link].
Draaisma JMT, Drossaers J, van den Engel-Hoek L, Leenders E, Geelen J. Young children with Noonan syndrome: evaluation of feeding problems. Eur J Pediatr. 2020 May 11. [QxMD MEDLINE Link]. [Full Text].
Niemczyk J, Equit M, Borggrefe-Moussavian S, Curfs L, von Gontard A. Incontinence in persons with Noonan Syndrome. J Pediatr Urol. 2015 Jun 18. [QxMD MEDLINE Link].
van Trier DC, van Nierop J, Draaisma JM, et al. External ear anomalies and hearing impairment in Noonan Syndrome. Int J Pediatr Otorhinolaryngol. 2015 Jun. 79 (6):874-8. [QxMD MEDLINE Link].
National Institutes of Health. Noonan-like/Multiple Giant Cell Lesion Syndrome. Genetic and Rare Diseases Information Center (GARD). Available at http://rarediseases.info.nih.gov/gard/4006/noonan-likemultiple-giant-cell-lesion-syndrome/resources/1. Accessed: Dec 1 2014.
Allanson JE, Bohring A, Dörr HG, et al. The face of Noonan syndrome: Does phenotype predict genotype. Am J Med Genet A. 2010 Aug. 152A(8):1960-6. [QxMD MEDLINE Link]. [Full Text].
van Trier DC, Vos AM, Draaijer RW, van der Burgt I, Draaisma JM, Cruysberg JR. Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology. 2016 Oct. 123 (10):2137-46. [QxMD MEDLINE Link].
Tokgoz-Yilmaz S, Turkyilmaz MD, Cengiz FB, Sjostrand AP, Kose SK, Tekin M. Audiological findings in Noonan syndrome. Int J Pediatr Otorhinolaryngol. 2016 Oct. 89:50-4. [QxMD MEDLINE Link].
Miyamoto JJ, Yabunaka T, Moriyama K. Cervical characteristics of Noonan syndrome. Eur J Orthod. 2013 May 9. [QxMD MEDLINE Link].
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. 2002 Jun. 70(6):1555-63. [QxMD MEDLINE Link].
Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan. 39(1):75-9. [QxMD MEDLINE Link].
Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug. 39(8):1007-12. [QxMD MEDLINE Link].
Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar. 38(3):331-6. [QxMD MEDLINE Link].
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. 2006 Jul. 79(1):129-35. [QxMD MEDLINE Link].
Aoki Y, Niihori T, Banjo T, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11. 93 (1):173-80. [QxMD MEDLINE Link].
Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Seidenberg MS. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr. 8(3):275-82. [QxMD MEDLINE Link]. [Full Text].
Lee BH, Kim JM, Jin HY, et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec. 159(6):1029-35. [QxMD MEDLINE Link].
Meier AB, Raj Murthi S, Rawat H, et al. Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome. iScience. 2022 Jan 21. 25 (1):103596. [QxMD MEDLINE Link]. [Full Text].
Roelofs RL, Janssen N, Wingbermuhle E, Kessels RP, Egger JI. Intellectual development in Noonan syndrome: a longitudinal study. Brain Behav. 2016 May 3. e00479. [QxMD MEDLINE Link]. [Full Text].
Lepri FR, Scavelli R, Digilio MC, et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23. 15:14. [QxMD MEDLINE Link]. [Full Text].
Sekhri N. Noonan Syndrome. RCPU Newsletter. Jan 2009. XX(2):[Full Text].
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. 2009 Apr 28. [QxMD MEDLINE Link].
Binder G. Noonan syndrome, the Ras-MAPK signalling pathway and short stature. Horm Res. 2009 Apr. 71 Suppl 2:64-70. [QxMD MEDLINE Link].
Ozono K, Ogata T, Horikawa R, et al. Efficacy and safety of two doses of Norditropin^® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients. Endocr J. 2018 Feb 26. 65 (2):159-74. [QxMD MEDLINE Link]. [Full Text].
Horikawa R, Ogata T, Matsubara Y, et al. Long-term efficacy and safety of two doses of Norditropin^® (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients. Endocr J. 2020 Apr 9. [QxMD MEDLINE Link].
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. 2010 Mar. 30(3):284-6. [QxMD MEDLINE Link].
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan. 12(1):86-92. [QxMD MEDLINE Link].
Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013 Jan 26. 381(9863):333-42. [QxMD MEDLINE Link].

Media Gallery

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.

of 2

Author

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

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 Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

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.