Orthopedic Issues of the RASopathies

Neurofibromatosis type 1 (NF1), Noonan (NS), Costello (CS), and cardio-facio-cutaneous syndrome (CFC) belong to the RASopathies, a group of phenotypically overlapping disorders caused by a dysregulated RAS/mitogen-activated protein kinase (MAPK) pathway. The musculoskeletal system may be compromised in all of these syndromes. Dystrophic scoliosis and long bone dysplasia are distinctive manifestations involving NF1. Short stature, spine, and anterior chest wall abnormalities are usually observed in individuals with NS. Patients with CS can have severe orthopedic manifestations, with short stature, dystonic posture, anomalies of the vertebral column, pectus deformities, joint contractures, and hands and feet abnormalities. CFC can have scoliosis (and other spine disorders) commonly present, in addition to contractures of large joints and other feet deformities. Skull abnormalities as relative macrocephaly, craniosynostosis, and sphenoid wing dysplasia (NF1) are also described in RASopathies. Several studies show that the RAS pathway has an important role in bone development and homeostasis. Further studies are necessary to determine whether such alterations are linked to an increased risk of fractures. Muscle development is also impaired, having negative implications on the functional status and consequently on the quality of life of individuals with RASopathies.