Table 2.

Mutations in genes that predispose to NB

GeneaMutation/alterationDomainReference(s)
ALKR1275QKinase69–73
L1204FKinase
R1192PKinase
I1183TKinase
T1151RKinase
G1128AKinase
PHOX2B676delGNPARM79, 80, 83, 85, 86
R100LNPARM
R141GNPARM
G197DNPARM
PARM-28–33+PARM
TP53R337H, (other?)NLS domain-1102
CDKN1CInactivatingNonfocal103, 104
RASopathiesbActivatingHotspots90–96
  • Abbreviations: NLS, nuclear localization sequence; NPARM, nonpolyalanine repeat mutation; PARM, polyalanine repeat expansion mutation.

  • aOther genes have been implicated in NB predisposition, including GALNT14 and SDHB, but the data on prevalence and relative risk are limited at this time.

  • bCostello syndrome is cause by mutations in HRAS, and Noonan syndrome is caused by mutations in PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1. Costello syndrome is the only RASopathy that warrants NB screening at the present time. However, patients with Costello syndrome may have elevated catecholamine metabolites, so only very high levels or significantly rising levels would warrant further evaluation for NB (92).