Clinical and molecular spectra of BRAF-associated RASopathy

How can same-gene mutations promote both cancer and developmental disorders?

“…Recently, there has been a rapid hike in the number of reports relating to the linkage between neurodevelopmental disorders and cancer. These include many excellent reviews on the various aspects of neurodevelopmental disorders, such as RASopathy including, e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS) [e.g., (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)], PIK3CA-related overgrowth spectrum (PROS) [e.g., (24)(25)(26)], ASD [e.g., (27)(28)(29)(30)(31)(32)(33)], cerebral palsy, and more [e.g., (34)(35)(36)(37)], and one uniquely also covering genetically engineered mouse models to study cancer or congenital disorders (38). The linkage between developmental signaling cascades and aggressive central nervous system (CNS) tumors has also been reviewed [e.g., (37,39)].…”

Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients

“…BRAF is an established causal gene for several autosomal dominant RASopathies, including Cardiofaciocutaneous syndrome (MIM 115150), Noonan syndrome (MIM 613706), and LEOPARD syndrome (MIM 613707). Common manifestations of BRAF -related syndromes include growth retardation, intellectual/motor developmental delay, congenital heart defects, craniofacial deformities, abnormal pigmentation of the skin, spare/curly hair, and cryptorchidism [ 13 – 15 ]. In the follow-up examination, we only observed trivial overlap between BRAF -related phenotypes and the clinical manifestation of the two patients (Table 1 ).…”

“…In previous studies, pathogenic BRAF variants have been associated with a series of RASopathies. Phenotypes of BRAF -related RASopathies include intellectual instability, motor development delay, short stature, sparse/curly hair, pigmentation abnormality of skin, congenital heart defects, and craniofacial dysmorphism [ 13 , 15 ]. Our patients, however, presented with only hypospadias but not the typical manifestations of BRAF -associated RASopathies.…”

RASopathies: From germline mutations to somatic and multigenic diseases

“…They seem to be characterized by a high prevalence of hypertrophic cardiomyopathy (∼75%) compared to the prevalence in the general population of NS (∼18%) and a high proportion of patients with multiple nevi lentigines and café-au-lait spots. BRAF mutations have also been found in some patients with features of NS or LS (<2% of NS) [ 31 ]. These mutations do not overlap with the cardio-facio-cutaneous syndrome (CFC) in which this gene is frequently involved [ 31 ].…”

“…BRAF mutations have also been found in some patients with features of NS or LS (<2% of NS) [ 31 ]. These mutations do not overlap with the cardio-facio-cutaneous syndrome (CFC) in which this gene is frequently involved [ 31 ].…”