Novel Features of <scp>RASopathies</scp> : Liver Disease as an Emerging Phenotype

RASopathies are a clinically and genetically heterogeneous group of conditions caused by pathogenic variants in genes encoding RAS/MAPK pathway components. Liver involvement has been reported, but systematic evaluation of liver involvement in individuals with RASopathies has not been performed, limiting anticipatory guidance and screening development. We aim to characterize liver involvement in RASopathies. The cohort consisted of individuals with molecularly confirmed RASopathy evaluated at a single center between January 2006 and October 2024. Clinical histories were abstracted from the medical record. The cohort included 192 participants. Liver involvement was noted in 36.5%. Neonatal hyperbilirubinemia was present in 33.3%, and 24% required phototherapy, representing a significantly increased risk (OR 7.1, 95% confidence interval [CI] 4.66-10.95, p < 0.0001). Other liver pathology was noted in 15 participants (7.8%), including elevated aminotransferases (n = 9) and cholestasis (n = 7). Participants with BRAF variants were more likely to have cholestasis than those with other genotypes (OR 6.2, 95% CI 1.45-24.03, p = 0.038). Comprehensive evaluation of liver involvement in a large RASopathy cohort revealed a strong association with neonatal liver disease, most commonly hyperbilirubinemia and cholestasis. Evaluation for liver disease may be warranted in infants with RASopathies, especially individuals with BRAF variants.