Noonan syndrome

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Noonan syndrome
Classification and external resources
Noonan syndrome.PNG
A 12-year-old female with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.
ICD-10Q87.1
ICD-9759.89
OMIM163950
DiseasesDB29094
MedlinePlus001656
eMedicinearticle/947504
MeSHD009634
 
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Noonan syndrome
Classification and external resources
Noonan syndrome.PNG
A 12-year-old female with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.
ICD-10Q87.1
ICD-9759.89
OMIM163950
DiseasesDB29094
MedlinePlus001656
eMedicinearticle/947504
MeSHD009634

Noonan syndrome (NS) is a relatively common autosomal dominant congenital disorder that affects both males and females equally[1]:550. It used to be referred to as the male version of Turner's syndrome[2] (and is still sometimes described in this way);[3] however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect (typically pulmonary valve stenosis) also ASD, 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. The syndrome is named after Dr. Jacqueline Noonan. It is a RASopathy, as the syndrome is in the family of RAS-MAPK pathway disorders.

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[edit]

Often called a "hidden" condition, the person affected may have no obvious casual signs to the onlooker, but the problems may be many and complex. The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

By organ system[edit]

Heart[edit]

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

Gastrointestinal system[edit]

Genito-urinary system[edit]

Lymphatic system[edit]

Developmental[edit]

Hematologic[edit]

Musculoskeletal[edit]

Neurological[edit]

Arnold-Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome

By physical appearance[edit]

Stature and posture[edit]

Head[edit]

Eyes[edit]

Nose[edit]

Ears and hearing[edit]

Mouth and speech[edit]

Limbs/extremities[edit]

Skin[edit]

Cause[edit]

NS may be 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.[5]

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

  1. manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivity)
  2. a high proportion of cases represent new, sporadic mutations or
  3. Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
TypeOMIMGeneDescription
NS1163950PTPN11In most of the families with multiple affected members, NS maps to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.[6] The SHP2 protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves.
Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome.[7]
NS2605275unknown (autosomal recessive)[8]
NS3609942KRASAdditional mutations in KRAS [9] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome.
NS4610733SOS1It has recently been shown that activating mutations in SOS1 also give rise to NS.[10] Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.[11]
NS5611553RAF1Additional mutations in RAF1[12] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome.

A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin.[13]

Diagnosis[edit]

Despite identification of six causative genes, the diagnosis of Noonan syndrome 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 indicating association.

The following genes are known to cause NS with the percentage of cases in brackets. PTPN11 (50%) RAF1 (3-17%) SOS1 (10%), KRAS (1%) , NRAS (unknown) or BRAF (unknown).

An absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making such a 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 hypotrophic cardiomyopathy in patients with a mutation on the KRAS gene, and patients with a mutation on PTPN11 have an increased risk of Juvenile myelomonocytic leukemia. In the future, there will be scope for targeted management of Noonan Syndrome, depending on what genetic mutation the patient has.

History[edit]

The oldest known case of Noonan syndrome, 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. Even though these characteristics were sometimes seen running in families, chromosomes appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 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 faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.

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 later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.

See also[edit]

References[edit]

  1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  2. ^ 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. 
  3. ^ "Noonan syndrome" at Dorland's Medical Dictionary
  4. ^ Reinker, Kent; Stevenson DA, Tsung A (July–August 2011). "Orthopaedic conditions in Ras/MAPK related disorders.". Journal of Pediatric Orthopeadics 31 (5). doi:10.1097/BPO.0b013e318220396e. PMID 21654472. 
  5. ^ Razzaque MA, Komoike Y, Nishizawa T, Inai K, Furutani M, Higashinakagawa T, Matsuoka R (2012) Characterization of a novel KRAS mutation identified in Noonan syndrome. Am J Med Genet A doi:10.1002/ajmg.a.34419.
  6. ^ 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. 
  7. ^ Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8
  8. ^ 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.  edit
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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.  edit
  14. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.

External links[edit]