Cause
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.
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:
- manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivity)
- a high proportion of cases represent new, sporadic mutations or
- Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
| 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. 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. |
| NS2 | 605275 | unknown (autosomal recessive) | |
| NS3 | 609942 | KRAS | Additional mutations in KRAS 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. 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. |
| NS5 | 611553 | RAF1 | Additional mutations in RAF1 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.
Read more about this topic: Noonan Syndrome