FIG 77.6 Facial appearance of RASopathies (A) Noonan, (B) cardiofaciocutaneous, (C) Costello Table 77.7 Prevalence of Clinical Features in Patients With RASopathies Clinical Feature Noonan Frequency LEOPARD (%) Frequency (%) CFC Frequency Costello Frequency (%) (%) Facial anomalies Short stature Congenital heart defect Pulmonary valve stenosis Hypertrophic cardiomyopathy Atrial septal defect Atrioventricular canal defect Arrhythmia Cryptorchidism Curly hair Thorax anomalies Developmental delay Feeding difficulties Pterygium colli Sensorineural deafness Keratosis pilaris Lentigines 95 75 80 55 85 35 80 25 100 80 85 40 100 100 65 45 25 70 25 40 15 20 0 80 65 65 40 40 30 5 25 50 20 40 20 30 15 25 95 70 95 60 100 75 10 95 30 80 90 75 100 100 40 In most cases of the classic Noonan syndrome, cognitive abilities fall within the normal range, even though attention-deficit/hyperactivity disorder, mood disturbances, and problems with social interaction have been reported Patients with LEOPARD syndrome have clinical features similar to those of Noonan syndromes but specific signs are multiple lentigines, café-au-lait spots, and hearing deficit.68,69 CFC and Costello syndromes are associated with significant developmental delay, predisposition to epilepsy, and specific cutaneous involvement consisting of dry hyperkeratotic skin, sparse or absent eyebrows, and curly hair.70,71 Cardiac Defects CHDs occur in 60% to 90% of patients affected by RASopathies, and most commonly include pulmonary valve stenosis, hypertrophic cardiomyopathy, AVCD, and atrial septal defect (see Table 77.7).72–75 Minor CHDs, such as mitral or aortic valve anomalies, tetralogy of Fallot, and aortic coarctation have been previously described.76,77 Vascular anomalies also are associated with RASopathies, mainly aortic dissection, aortic root dilation, aneurysm of the sinuses of Valsalva, and coronary arteries dilation.78–83 Pulmonary valve stenosis has a quite distinct anatomic pattern, with thickened, elongated and redundant cusps In some cases, pulmonary valve stenosis is “supraannular,” consisting of fusion of the valvar cusps with the wall of the pulmonary artery.84 This complex anatomic condition may explain the frequent unsuccessful percutaneous pulmonary valve treatment by balloon angioplasty.75 Hypertrophic cardiomyopathy may be mild or severe and may present from the prenatal period to late childhood but generally appears early in life, with more than half of cases being diagnosed by 6 months of age Hypertrophy involves the left ventricle, consisting of asymmetric septal thickening and frequent systolic anterior motion of the mitral valve.85,86 The association with structural mitral anomalies, like prolapsing, myxomatous, redundant, or thick valve leaflets are common Anomalous insertion of the mitral valve causing subaortic stenosis is reported.87 AVCD is usually of the partial type and may be associated with subaortic stenosis, manifesting as left ventricular outflow obstruction due to anomalous insertion of the mitral valve.73,88 Vascular malformations and aortic valve enlargement with coronary anomalies are reported in a minor percentage In patients with Costello syndrome, cardiac rhythm disturbances such as atrial tachycardia like supraventricular, chaotic, or multifocal are common.89 Specific outcomes for cardiac defects in these patients in terms of mortality or freedom from reintervention could be considered RASopathies have a low risk of death from cardiac morbidity, but in the meantime, it is associated with a higher risk for cardiac reintervention, particularly in the subgroup of patients with AVCD or hypertrophic cardiomyopathy.75 Genetic Defect Different genes are involved in the etiology of RASopathies.90,91 Mutations in PTPN11 are detectable in approximately half of patients with Noonan syndrome Heterozygous mutations in 15 additional disease genes have been identified in Noonan syndrome and related conditions CFC syndrome is linked to mutations in BRAF, MEK1, and MEK2.92 HRAS mutations are etiologically related to Costello syndrome.93 The majority of these genes encode for proteins that are directly involved in the RAS-mitogen activated protein kinase (MAPK) signaling pathway, a major signal transduction cascade.66 Clinically relevant genotype-phenotype correlations have been established In