RASopathies are a group of rare genetic conditions caused by mutations in the Ras-MAPK genes. Abnormalities of this gene can cause several different syndromes including Cardio-Facio-Cutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome, Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Leopard Syndrome, as well as others. Many common attributes of these syndromes include distinct facial features, developmental delays, cardiac defects, growth delays, neurologic issues, and gastrointestinal difficulties. RASopathies are one of the most common genetic conditions in the world, they are found in 1 in 1,000 people. Not all RASopathies have HCM or other heart defects as symptoms but many do.
CFC Syndrome is characterized by cardiac abnormalities (including HCM), distinct craniofacial appearances, xerosis (dry skin), eczema, ichthyosis (dry scales on skin caused by an accumulation of dead skin cells),  as well as hemangiomas (benign tumors). Hair growth may be sparse, curly, fine, or thick; eyelashes may be sparse or absent. Some form of developmental delay is seen in almost all individuals. CFC syndrome occurs in about 1 in 150,000 to 1 in 810,000 people.
CS is characterized by failure to thrive during infancy due to postnatal feeding difficulties. Symptoms of Costello syndrome includes dwarfism/short stature, developmental delays, HCM, arrhythmia, coarse facial features and more. CS occurs in approximately 1 in every 380,000 people.
NF1 is characterized by axillary(armpit) and inguinal(groin) freckles, iris Lisch nodules (sharply defined, smooth masses on the surface of the iris and are clear to yellow/brown) as well as multiple cutaneous neurofibromas. It is reported that learning disabilities are present in at least 50% of those with NF1. The prevalence of this syndrome is about 1 in 2,000 to 1 in 5,000 people.
NS is characterized by short stature, congenital heart defects, varying degrees of developmental delays, a webbed neck, as well as unusual chest shape. Congenital heart disease occurs in 50-80% of those who have Noonan syndrome. Pulmonary valve stenosis is the most common heart defect which is found in 20-50% of affected individuals. HCM is found in 20-30% of individuals.Noonan syndrome occurs in about in 1 in 1,000 to 1 in 2,500 people.
Legius syndrome is characterized by multiple café au lait macules, smooth and irregular brown spots on the skin, without neurofibromas or other tumor manifestations found in NF1. Other characteristics include lipomas, macrocephaly, learning disabilities as well as developmental delays.
Leopard Syndrome, an acronym for Noonan syndrome with multiple lentingenes, is an acronym for its characteristic features including lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Lentigines do not appear until the age of 4 or 5 but increase until puberty. Some individuals with Leopard syndrome do not have lentigines. Approximately 85% of affected individuals have heart defects including HCM.
Drugs developed for the RAS pathway in cancer have large potential for treatment of the syndromes mentioned above. Researchers have been using animal models to test the potential of RAS pathway inhibitors in the treatment of the RASopathies. Drugs targeting the RAS pathway have potential however, the complexity of the pathway dysregulation in the syndromes requires more research to be completed to determine timing, dosage, and strengths of the drugs.
Figure 1: Images of individuals with clinical diagnoses different RASopathies. (a) A young boy with neurofibromatosis type 1 (NF1). (b) A young girl with Noonan syndrome. (c) A young adult woman with Costello syndrome. (d) A juvenile male with cardio-facio-cutaneous syndrome.


“Syndromes.” The RASopathies Network, rasopathiesnet.org/rasopathies/syndromes.
“RASopathies.” RASopathies - an Overview | ScienceDirect Topics,  www.sciencedirect.com/topics/neuroscience/rasopathies.