**4. Conclusion**

In this syndrome, learning disability are reported in the 30% of cases [54] and are more evident in verbal recall memory performance but relative sparing of visual and spatial

Costello syndrome is one of the rare syndromes of the group of RASopathies. It is caused by heterozygous activating germline mutations in *HRAS*. Typically, it is a missense mutation that induced the reduction of the intrinsic GTPase activity of RAS, which remains in the active form facilitating the synaptic trafficking of AMPA receptors. Besides, it has been seen that its action occurs in the spine dendritic structures too, which presents an increased density [14, 16, 35, 72]. This syndrome is phenotypically characterized by failure to thrive; short stature; developmental delay or intellectual disability; coarse facial features, curly, or sparse fine hair; loose, soft skin with deep palmar and plantar creases; papillomatosis of the face and perianal region; diffuse hypotonia and joint laxity; cardiac involvement (cardiac hypertrophy, valvar pulmonic stenosis, arrhythmia); relative or absolute macrocephaly Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Moreover, they present an

Particularly, in these patients, it has been observed that verbal learning and memory are impaired but are better than the nonverbal cognitive abilities, while the visual associative memory is performed in the mildly disabled, but the related data are not completely clear [35, 73].

Cardiofaciocutaneous (CFC) syndrome is a very rare RASopathy. It is caused by heterozygous activating mutations in *BRAF* (~75%), *MAP2K1,* and *MAP2K2* (~25%), *KRAS* (<2%) that cause a deregulation of the RAS-MAPKinase cascade in a positive way. It is inherited in an

CFC is characterized by craniofacial dysmorphology, congenital heart disease (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, and rhythm disturbances), dermatologic abnormalities (xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis), growth retardation, and intellectual and learning disability [14, 16, 74, 75].

Assessing the learning ability, CFC patients present significant delay in adaptive skills, impaired spatial learning, and hippocampal long-term potentiation. It has been evidenced disability in verbal skills, especially the communication abilities were more impaired than the

Mutations in MAP2K1, which are frequently associated with neurological complications and intellectual disability, can be associated with a milder clinical and neurocognitive profile more typical of individuals with Noonan syndrome. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and

increased risk, approximately 15%, to malignant tumors [14, 16, 72].

recognition memory [16, 66, 71].

36 Learning Disabilities - An International Perspective

**3.5. Costello syndrome**

**3.6. CFC syndrome**

autosomal dominant manner [14, 16, 74, 75].

comprehension and in spatial learning [35, 75].

obstetric factors, and environmental influences [76].

Children with RASopathies show commonly learning disabilities, such as impaired reading/ vocabulary, visuospatial functions, motor coordination, planning, and organizational skills. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and obstetric factors, and environmental influences. Emerging insights from the pathophysiology of these different genetic syndromes may facilitate the development of mechanism-based individualized treatment and may provide new potential targets for learning disability therapy in patients with RASopathies.
