Noonan syndrome

Noonan syndrome

A 12-year-old girl with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.
Classification and external resources
Specialty Medical genetics, pediatrics
ICD-10 Q87.1
ICD-9-CM 759.89
OMIM 163950 605275 609942 610733 611553
DiseasesDB 29094
MedlinePlus 001656
eMedicine article/947504
Patient UK Noonan syndrome
MeSH D009634
GeneReviews

Noonan syndrome (NS) is a relatively common autosomal dominant congenital disorder that affects both males and females [1][2]:550 and is named after Jacqueline Noonan, a pediatric cardiologist. It is referred to as the male version of Turner's syndrome[3] (and is still sometimes described in this way);[4] however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect (typically pulmonary valve stenosis; also atrial septal defect and hypertrophic cardiomyopathy), short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. NS is a RASopathy, and is one of several disorders that are caused by a disruption of RAS-MAPK pathway signaling.

It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.

Characteristics

Organ system

Anesthesia risk

Heart

Up to ~85% of people with NS have one of the following heart defects:

Lungs

Gastrointestinal system

Genito-urinary system

Lymphatic system

Developmental

Recommendations

Hematologic

Musculoskeletal

Neurological

Physical appearance

Stature

Head

Eyes

Nose

Ears and hearing

Mouth and speech

Limbs/extremities

Skin

Causes

NS is typically inherited in an autosomal dominant pattern with variable expression.

Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for ~70% of NS cases.[11]

A person with NS has up to a 50% chance of transmitting it to their offspring. The fact that an affected parent is not always identified for children with NS suggests several possibilities:

  1. Manifestations could be so subtle as to go unrecognized (variable expressivity)
  2. NS is heterogeneous, comprising more than one similar condition of differing causes, and some of these may not be inherited.
  3. A high proportion of cases may represent new, sporadic mutations.
Type Online Mendelian Inheritance in Man database Gene Year found Locus % of cases Description Refs.
NS1 163950 PTPN11 2001 12q24.1 50% The PTPN11 gene encodes the protein tyrosine phosphatase SHP-2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the semilunar heart valves.
Duplication of the chromosome region containing PTPN11 can also result in NS.		 [12]
[13]
NS2 605275 Unknown; autosomal recessive [14]
NS3 609942 KRAS 2006 12p12.1 <5% [15]
NS4 610733 SOS1 2006 2p21 10% Activating mutations in SOS1 can give rise to NS. SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation mediates NS development.[16] [17]
NS5 611553 RAF1 2007 3p25 3–17% [18]

Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes.[19]

A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin.[20]

Diagnosis

NS can be confirmed genetically by the presence of any of the known mutations listed above. However, despite identification of fourteen causative genes, the absence of a known mutation will not exclude the diagnosis, as there are more, as-yet-undiscovered genes that cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, there is an increase in hypertrophic cardiomyopathy in patients with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia for a mutation of PTPN11. In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a patient has.

History

The oldest known case of NS, described in 1883 by Kobylinski

Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance, with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. These characteristics were sometimes seen running in families but were not associated with gross chromosomal abnormalities. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1963 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic facial features, chest deformities and short stature.

Dr. John Opitz, a former student of Dr. Noonan, first began to call the condition "Noonan syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan produced a paper entitled "Hypertelorism with Turner Phenotype" in 1968,[21] and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan syndrome' became officially recognized.

See also

References

  1. ↑ Speroff, Leon; Fritz, Marc A. (2005). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. https://books.google.com.ph/books?id=8sIkqPT2gh4C&pg=PA350 350. ISBN 978-0-7817-4795-0.
  2. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0.
  3. ↑ Curcić-Stojković O, Nikolić L, Obradović D, Krstić A, Radić A (1978). "[Noonan's syndrome. (Male Turner's syndrome, Turner-like syndrome)]". Med Pregl 31 (7–8): 299–303. PMID 692497.
  4. ↑ "Noonan syndrome" at Dorland's Medical Dictionary
  5. ↑ "Does Noonan Syndrome Increase Malignant Hyperthermia Susceptibility?". Malignant Hyperthermia Association of the United States. Retrieved 24 October 2014.
  6. ↑ "Imbalance of plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (t-PA) activity in patients with Noonan syndrome.". J Pediatr Hematol Oncol 32 (7): 532–6. Oct 2010. doi:10.1097/MPH.0b013e3181e0d152. PMID 20686427.
  7. ↑ Reinker, Kent; Stevenson DA; Tsung A (July–August 2011). "Orthopaedic conditions in Ras/MAPK related disorders.". Journal of Pediatric Orthopeadics 31 (5): 599–605. doi:10.1097/BPO.0b013e318220396e. PMID 21654472.
  8. ↑ Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature
  9. ↑ http://dx.doi.org/10.7243/2052-8000-2-1
  10. ↑ http://www.hoajonline.com/hormones/2052-8000/2/1
  11. ↑ Razzaque MA, Komoike Y, Nishizawa T, et al. (March 2012). "Characterization of a novel KRAS mutation identified in Noonan syndrome". Am. J. Med. Genet. A 158A (3): 524–32. doi:10.1002/ajmg.a.34419. PMID 22302539.
  12. ↑ Tartaglia M, Mehler EL, Goldberg R, et al. (2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome". Nat. Genet. 29 (4): 465–8. doi:10.1038/ng772. PMID 11704759.
  13. ↑ Shchelochkov OA, Patel A, Weissenberger GM, et al. (April 2008). "Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome". Am. J. Med. Genet. A 146A (8): 1042–8. doi:10.1002/ajmg.a.32215. PMID 18348260.
  14. ↑ Van Der Burgt, I.; Brunner, H. (2000). "Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form". American Journal of Medical Genetics 94 (1): 46–51. doi:10.1002/1096-8628(20000904)94:1<46::AID-AJMG10>3.0.CO;2-I. PMID 10982482.
  15. ↑ Schubbert S, Zenker M, Rowe SL, et al. (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
  16. ↑ Bentires-Alj M, Kontaridis MI, Neel BG (2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5. doi:10.1038/nm0306-283. PMID 16520774.
  17. ↑ Roberts AE, Araki T, Swanson KD, et al. (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4. doi:10.1038/ng1926. PMID 17143285.
  18. ↑ Razzaque MA, Nishizawa T, Komoike Y, et al. (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7. doi:10.1038/ng2078. PMID 17603482.
  19. ↑ http://www.mayomedicallaboratories.com/interpretive-guide/?alpha=N&unit_code=61851
  20. ↑ De Luca, A.; Bottillo, I.; Sarkozy, A.; Carta, C.; Neri, C.; Bellacchio, E.; Schirinzi, A.; Conti, E.; Zampino, G.; Battaglia, A.; Majore, S.; Rinaldi, M. M.; Carella, M.; Marino, B.; Pizzuti, A.; Digilio, M. C.; Tartaglia, M.; Dallapiccola, B. (2005). "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome". American Journal of Human Genetics 77 (6): 1092–1101. doi:10.1086/498454. PMC 1285166. PMID 16380919.
  21. ↑ Noonan, JA (1968). "Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease". Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Noonan JA. Am J Dis Child. Oct; 116 (4): 373–80. doi:10.1001/archpedi.1968.02100020377005. PMID 4386970.
  22. ↑ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.

External links

Wikimedia Commons has media related to Noonan syndrome.
This article is issued from Wikipedia - version of the Wednesday, April 27, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.