Table 1.

The clinical features of the RASopathies.

	NF1	Cardio-facio-cutaneous syndrome	Costello syndrome	Noonan syndrome	LEOPARD syndrome	Capillary malformation-arteriovenous malformation
Gene	NF1	BRAF, MEK1, MEK2, KRAS	HRAS	PTPN11, KRAS, SOS1, RAF1, NRAS, SHOC2, CBL*	PTPN11, RAF, BRAF	RASA1
Predominant cutaneous features	Café au lait macules Intertriginous freckling Neurofibromas Plexiform neurofibroma	Ulerythema ophryogenes Keratosis pilaris Melanocytic nevi Infantile hemangiomas	Papillomata of the nose and perianal region Palmoplantar hyperkeratosis Redundant skin on the hands and feet	Congenital lymphedema Café au lait macules	Lentigenes Café noir patches	Capillary malformations Arteriovenous malformations
Cardiac defects	Pulmonic stenosis	Pulmonic stenosis Hypertrophic cardiomyopathy	Pulmonic stenosis Hypertrophic cardiomyopathy	Pulmonic stenosis Hypertrophic cardiomyopathy	EKG abnormalities Pulmonic stenosis Hypertrophic cardiomyopathy	Rare
Cancer predisposition	Yes Optic glioma Hematologic malignancies Meningioma and other brain cancers Malignant peripheral nerve sheath tumor Pheochromocytoma	Rare possible risk for ALL and lymphoma	Yes malignant solid tumors (rhadmyosarco ma, neuroblastoma, transitional cell carcinoma of the bladder)	Rare hematologic malignancies	Rare hematologic malignancies	Rare possible increased risk for neural tumors
Other	Lisch nodules Learning disability Pseudoarthrosis Macrocephaly Sphenoid wing dysplasia Renal artery stenosis Hypertension	Failure to thrive (severe) Developmental delay	Failure to thrive (mild) Developmental delay Sociable, outgoiong personality	Low posterior hairline Webbed neck Pectus excavatum Bleeding tendency Short stature	Ocular hypertelorism Sensorineural hearing loss Short stature	Risk for intracranial arteriovenous malformation Parkes-Weber syndrome

^*Martinelli et al recently reported germline mutations in CBL (a tumor-suppressor gene commonly mutated in myeloid leukemias) in patients with a Noonan phenotype who had negative screening for mutations in the other genes linked with Noonan syndrome³⁹.