Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for mutations and was significantly associated with PHEO (90% 38%; = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with missense mutations compared with other mutations (89.5% 0% and 73.7% 16.7%; = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% 26.3%; = 0.0001), renal cysts (66.7% 26.3%; = 0.027), and central nervous system hemangioblastomas (91.7% 47.3%; = 0.012) were more frequent in VHL with nonmissense mutations. missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.