Noonan Syndrome with Multiple Lentigines

Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant RASopathy with complete penetrance and variable expressivity. Like other RASopathies, NSML presents with skin, craniofacial, and cardiac anomalies. However, this disorder also has a unique etiology, including the presence of multiple lentigines and development of hypertrophic cardiomyopathy (HCM). Moreover, unlike other RASopathies, which induce hyperactivation of the RAS-mitogen-activated protein kinase (RAS/MAPK) cascade, NSML is caused by distinct mutations in genes that modulate both RAS/MAPKRAS/MAPK and RASRat sarcoma viral oncogene homolog (RAS)/phosphoinositide 3-kinase (PI3K)-AKT (RAS/PI3K/AKT) signaling pathways. In this regard, most mutations in NSML are heterozygous loss-of-function (LOF) missense mutations in the catalytic domain of PTPN11, which encodes the protein tyrosine phosphatase SHP2, leading to diminished RAS/MAPK signalingRAS/MAPK signaling but enhanced RAS/PI3K/AKT activity. Interestingly, additional gain-of-function (GOF) mutations have also been identified to be causal to NSML, including mutations in RAF1Rapidly Accelerated Fibrosarcoma (RAF), BRAF, and MAP2K1, suggesting that the functional mechanisms for NSML are complicated, and perhaps incompletely defined. Here, we will review our current understanding of NSML, its phenotypic characteristics, diagnostic criteria, and its molecular basis. We will also discuss current applications, limitations, and future directions for potential therapeutics and treatment strategies for this rare, but unique, RASopathy disorder.