Table 1 Table 1 Clinical and molecular aspects of RAS related disorders

	Mutated gene(s)	Protein(s)	Intellectual function	Heart	Skin	Face	Neoplasias	Other
Autoimmune lymphoproliferative syndrome (ALPS)	(FASFASLCASP10CASP8)NRAS	(CD95CD95-ligandCaspase-10Caspase-8)NRAS	Normal	–	–	–	Haematological malignancies	Autoimmunity, excessive lymphocyte accumulation

Capillary malformation-arteriovenous malformation	RASA1	P120-GAP	Normal	–	Atypical multifocal capillary malformations, cutaneous and subcutaneous AVM and AVF	–	–	Intramuscular, intraosseus and cerebral AVM and AVF, Parkes Weber syndrome

Neurofibromatosis type1	NF 1	Neurofibromin	Normal to mild retardation (lower IQ in microdeletion patients)	PS in some	Café-au-lait macules, intertriginal freckling, juvenile xanthogranulomas	Sometimes “Noonan-like” and hypertelorism	Benign tumours of central and peripheral nervous system, MPNST, neuroblastoma, rhabdomyosarcoma, JMML, GIST, glomus tumours	Iris Lisch nodules, macrocephaly and short stature

Costello syndrome	HRAS	HRAS	Mild to moderate retardation	PS, HCM, rhythm disturbances	Deep palmar and plantar creases	Coarse face with wide forehead, depressed nasal bridge, full cheeks, low set posteriorly rotated ears with thick lobes	Solid tumours: rhabdomyosarcoma, neuroblastoma, bladder carcinomaPapillomata: peri-oral, peri-anal	Short stature, macrocephaly

Noonan syndrome	PTPN11KRASSOS1RAF1	SHP2KRASSOS1RAF1	Normal to mild retardation	PS, HCM	Sometimes a few café-au-lait macules	Hypertelorism, ptosis, epicanthal folds, low set posteriorly rotated ears, clear blue irises	Haematologic malignancies like JMML, solid tumours: rhabdomyosarcoma, giant cell tumours of jaw	Short stature, bleeding diathesis, cryptorchidism

LEOPARD syndrome	PTPN11RAF1	SHP2RAF1	Normal to mild retardation	PS, HCM,	Multiple lentigines and café-noir patches	“Noonan-like”	?	Short stature, deafness, cryptorchidism

Cardiofaciocutaneous syndrome	BRAFKRASMEK1MEK2	BRAFKRASMEK1MEK2	Moderate to severe	PS, ASD, HCM	Hyperkeratotic, dry skin; sparse, curly, friable hair	“Noonan-like” with bitemporal constriction, ulerythaema ophryogenes	No increased tumour risk?	Short stature, macrocephaly

Neurofibromatosis type 1 like syndrome	SPRED1	SPRED1	Learning difficulties in some cases	PS in one case	Café-au-lait macules, axillary freckling	Sometimes “Noonan-like”	?	Macrocephaly, short stature, no irisLisch nodules, no neurofibromas

ASD, atrial septum defect; AVF, arteriovenous fistula; AVM, arteriovenous malformation; GIST, gastrointestinal stromal tumour; HCM, hypertrophic cardiomyopathy; JMML, juvenile myelomonocytic leukaemia; MPNST, malignant peripheral nerve sheath tumour; PS, pulmonary valve stenosis.