von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome predisposing to the development of retinal and central nervous system haemangioblastomas, pheochromocytomas, renal and pancreatic cancer. In the course of a molecular analysis conducted to detect germline mutations of this gene in von Hippel-Lindau patients and individuals affected by sporadic tumors, we have identified a case of somatic mosaicism in the asymptomatic mother of a VHL patient who was subsequently diagnosed with pheochromocytoma. This is the first report providing molecular evidence of somatic mosaicism in von Hippel-Lindau disease. Mosaicism could provide some genetic explanation for the clinical heterogeneity and variable severity of the VHL phenotype, and should be considered, as a possible event when evaluating sporadic cases of VHL or patients with isolated VHL-related tumors. Hum Mutat 15:114, 2000.
PatientID: mother
KindredID: 1
Case: F, 48Y0M, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: The 50 year-old husband and 22 year-old sister were asymptomatic. Her 26 year-old son displayed pheochromocytoma, renal cysts, cerebellar hemangioblastoma, and retinal capillary hemangioma. He presented with the c.481C>G mutation.
CasePresentingHPOs: HP:0000107; HP:0002666 (renal cyst; pheochromocytoma)
CaseHPOFreeText: Originally referred to as referred to as totally asymptomatic, until testing on her son. A renal ultrasound revealed the presence of bilateral micro-cysts; a CT scan detected a pheochromocytoma that was subsequently removed. Both were clinically silent.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161G (c.481C>G)
LegacyVariant: p.R161G (c.694C>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 618484 https://www.ncbi.nlm.nih.gov/clinvar/variation/618484
CAID: N/A
gnomAD: N/A
VariantEvidence: Despite the identical bandshifting to her son, there were differences in the intensity of the aberrant bands (Fig.1a), suggested that the mother could be a somatic mosaic. To test this hypothesis the molecular analysis was repeated on tissues of different embryonic origin. DNA extracted from the mother's buccal mucosa showed higher levels of intensity of the same altered bands (Fig. 1b). The amplification products of exon 3 of the two mutated individuals were subjected to Fok I digestions that further confirmed the presence of mosaicism in the mother, as evidenced by the lower intensity of the fragments generated by the newly created restriction site (Fig.2).
MutationType: missense_variant; transversion
CivicName: R161G (c.481C>G)
MultipleGeneVariants: N/A