In conclusion, NS mutations in patients, such as those in KRAS, NRAS, SHOC2, MRAS, PP1, CBL, RIT1, LZTR1, PTPN11, SOS1, NF1, SPRED1, RAF1, BRAF, MEK1, and MEK2, deserve further investigation of the specific mechanism of action in primary lymphedema. Here, PTPN11 is linked to lymphedema.