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{{See also|List of conditions associated with café au lait macules}}
{{See also|List of conditions associated with café au lait macules}}
*Lymphedema (swelling of the extremities)
*Lymphedema (swelling of the extremities)
*[[Keloid]] formation
*]] (scar [[Organ hypertrophy|hypertrophy]])
*[[Hyperkeratosis]] - overdevelopment of outer skin layer
*[[Hyperkeratosis]] - overdevelopment of outer skin layer
*[[nevus|Pigmented nevi]] (birthmark)
*[[nevus|Pigmented nevi]] (birthmark)

Revision as of 17:38, 23 April 2013

Noonan syndrome
SpecialtyMedical genetics Edit this on Wikidata
Frequency0.007% (Europe)

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

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

Heart

2/3 of people have one of the following heart defects:

Gastrointestinal system

Genito-urinary system

Lymphatic system

  • Posterior cervical hygroma (webbed neck)
  • Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)

Developmental

Hematologic

Musculoskeletal

  • Many people affected by Noonan Syndrome suffer from joint pain or muscle pain, particularly in adulthood, which varies in severity. Recent research confirms this, however, the etiology is unknown, therefore more extensive research is required.[4]

Neurological

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

By physical appearance

Stature and posture

  • Excess skin on the back of the neck
  • Low hairline at the nape of the neck
  • High hairline at the front of the head
  • Large head
  • Triangular face shape
  • Broad forehead
  • Short neck, webbed neck, posterior cervical
  • Curly hair

Eyes

Nose

  • Small, upturned nose

Ears and hearing

  • Low set ears —(over 90%)
  • Backward rotated ears —(over 90%)
  • Thick helix of ear (outer rim) —(over 90%)
  • Incomplete folding of ears
  • Chronic Otitis media (ear infections)

Mouth and speech

  • Deeply grooved philtrum (top lip line) —(over 90%)
  • Micrognathia (undersized lower jaw)
  • High Arched palate
  • Dental problems
  • Articulation Difficulties
  • Poor tongue control

Limbs/extremities

  • Bluntly ended fingers
  • Extra padding on fingers and toes
  • Edema of the back of hands and tops of feet
  • Cubitus valgus (elbow deformity: with abnormal turning-in)

Skin

See also: List of conditions associated with café au lait macules

Cause

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.
Type OMIM Gene Description
NS1 Template:OMIM2 PTPN11 In 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]
NS2 Template:OMIM2 unknown (autosomal recessive)[8]
NS3 Template:OMIM2 KRAS Additional mutations in KRAS [9] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome.
NS4 Template:OMIM2 SOS1 It 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]
NS5 Template:OMIM2 RAF1 Additional 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

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 (unknwown) 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

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

  • Turner syndrome — a different disorder which is often confused with Noonan syndrome because of several physical features that they have in common.
  • Fetal alcohol syndrome — another disorder that is sometimes confused with Noonan syndrome because of some common facial features and mental retardation[14]
  • Leopard syndrome— A related disorder caused by mutations in PTPN11 that are catalytically inactivating.
  • Cardiofaciocutaneous syndrome — A related disorder which also affects genes encoding elements of the Ras/MAP kinase pathway.
  • Dermatoglyphics

References

  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ "Noonan syndrome" at Dorland's Medical Dictionary
  4. ^ Reinker, Kent (2011). "Orthopaedic conditions in Ras/MAPK related disorders". Journal of Pediatric Orthopeadics. 31 (5). doi:10.1097/BPO.0b013e318220396e. PMID 21654472. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  7. ^ Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8
  8. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10982482, please use {{cite journal}} with |pmid=10982482 instead.
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16380919, please use {{cite journal}} with |pmid=16380919 instead.
  14. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.
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