Pathogenesis of Growth Failure in Rasopathies

The RASopathies are a group of developmental genetic syndromes that are caused by germline mutations in genes encoding proteins of the Ras-Mitogen-Activated Protein kinase (RAS-MAPK) pathway. RASopathies include Noonan Syndrome (NS), Neurofibromatosis Type 1 (NF1), Noonan syndrome with multiple lentigines (NSML/LEOPARD), Costello syndrome (CS), Cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM) and Legius Syndrome. These syndromes have many overlapping features; however, the most persistent feature common to all is the postnatal growth failure. The mechanism of growth failure in Rasopathies is highly complex and there are many proposed hypotheses including partial growth hormone insensitivity, growth hormone deficiency, neurosecretory dysfunction of growth hormone secretion, delayed puberty, poor feeding and skeletal abnormalities. Amongst these causes, the most widely accepted is partial growth hormone insensitivity due to a post-receptor signaling defect. Growth hormone therapy seems to be effective in improving height velocity in these syndromes, although the long-term effects on final height remain unproven. However, it is important to consider the potential risk of tumors and cardiomyopathy before and during growth hormone therapy.