RASopathy

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RASopathies are a class of developmental disorders caused by germline mutations in genes that encode for components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway.

Epidemiology

As a group, RASopathies represent one of the most common malformation syndromes, with an incidence estimated to be approximately 1 in 1,000 .

Clinical presentation

Although each RASopathy is a distinct condition with a unique phenotype, due to common mechanisms of Ras/MAPK pathway dysregulation, there are clinical commonalities, many of which may evident as early as in the first year of life, including :

  • craniofacial dysmorphia
  • congenital heart disease
  • cutaneous anomalies
  • musculoskeletal anomalies
  • gastrointenstinal anomalies
  • ocular anomalies
  • neurocognitive impairment
  • hypotonia
  • increased risk of malignancy (e.g. juvenile myelomonocytic leukemia)

The specific clinical presentations of each RASopathy are beyond the scope of this article, but are detailed in the article of each specific condition (see below).

Pathology

The Ras/MAPK pathway plays an essential role in the control of the cell cycle and cell differentiation, and thus, overactivation of this pathway has the potential to cause significant developmental issues . Although the specific mechanisms of this pathway are beyond, mutations to different genes that encode for various proteins involved in the Ras/MAPK pathway can result in its overactivation .

It is important to note that the Ras/MAPK pathway can also be affected by somatic mutations, as can be seen in numerous malignancies . Although many of the activating mutations in RASopathies may be similar to the somatic mutations seen in malignancies, RASopathy germline mutations tend to activate the pathway less strongly than the somatic mutations .

Classification and genetics

The two most common and well-known syndromes are:

  • neurofibromatosis type 1: autosomal dominant disorder caused by a mutation to the NF1 gene which encodes for neurofibromin, a negative regulator of Ras, which when dysfunctional results in increased signaling of the Ras/MAPK pathway
  • Noonan syndrome: autosomal dominant disorder caused by a mutation to one of many possible genes, the most common being the PTPN11 gene which encodes for SHP2, which results in an inability to inactivate SHP2 causing increased signaling of the Ras/MAPK pathway; other genes that may be implicated include SOS1, KRAS, RAF1, NRAS, and SHOC2 
    • some authors consider patients with the SHOC2 mutation to have a distinct phenotypical disorder termed Noonan syndrome-like disorder with loose anagen hair 

However, there are also a number of rarer RASopathies:

  • capillary malformation-arteriovenous malformation syndrome: an autosomal dominant disorder caused by mutation to the RASA1 gene which encodes for p120-RasGAP, a negative regulator of Ras (similar to neurofibromin), which when dysfunctional results in increased signaling of the Ras/MAPK pathway
  • cardiofaciocutaneous syndrome: an autosomal dominant Noonan-like disorder caused by a mutation to one of many possible genes, the most common being the BRAF gene which encodes for BRAF, an oncoprotein, which when dysfunctional results in increased signaling of the Ras/MAPK pathway
  • Costello syndrome: an autosomal dominant Noonan-like disorder caused by a mutation to the HRAS gene which encodes for HRAS, which when dysfunctional results in increased signaling of the Ras/MAPK pathway
  • hereditary gingival fibromatosis 1: an autosomal dominant disorder caused by mutation to the SOS1 gene (a different mutation to the one implicated in Noonan syndrome) which encodes for SOS1, which when dysfunctional results in an inability to covert active Ras to inactive Ras causing increased signaling of the Ras/MAPK pathway
  • Legius syndrome: an autosomal dominant NF1-like disorder caused by a mutation to the SPRED1 gene which encodes for SPRED1, a negative regulator of Ras (similar to neurofibromin), which when dysfunctional results in increased signaling of the Ras/MAPK pathway
  • Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome): an autosomal dominant Noonan-like disorder caused by mutations to the same genes involved in Noonan syndrome (albeit different mutations) 

Radiographic features

In additional to having an overlap of clinical features, RASopathies are also likely to have an overlap in radiographic features, although this is an area with limited research. Detailed discussion of the specific radiographic features of each RASopathy can be found in the individual articles (see above).

Treatment and prognosis

There is no specific treatment for any RASopathy and management generally hinges on symptomatic relief, regular monitoring for complications (including malignancy), and having allied health input . However, there is ongoing research into the potential role of oncological therapies that target various aspects of the Ras/MAPK pathway in RASopathies if given from birth .

Detailed discussion of the specific treatment and prognosis of each RASopathy can be found in the individual articles (see above).