| Noonan syndrome | |
|---|---|
| Classification and external resources | |
A 12-year-old female with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity. |
|
| ICD-10 | Q87.1 |
| ICD-9 | 759.89 |
| OMIM | 163950 |
| DiseasesDB | 29094 |
| eMedicine | article/947504 |
| MeSH | D009634 |
Noonan Syndrome (NS) is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, 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), 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.
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.
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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.
Arnold-Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. 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:
| Type | OMIM | Gene | Description |
|---|---|---|---|
| NS1 | 163950 | 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.[4] 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.[5] |
| NS2 | 605275 | unknown (autosomal recessive)[6] | |
| NS3 | 609942 | KRAS | Additional mutations in KRAS [7] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. |
| NS4 | 610733 | SOS1 | It has recently been shown that activating mutations in SOS1 also give rise to NS.[8] 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.[9] |
| NS5 | 611553 | RAF1 | Additional mutations in RAF1[10] 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.[11]
Despite identification of four 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 patient can be screened for mutations in the PTPN11, SOS1, or KRAS genes, however 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.
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.
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