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 |
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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.
