In January 2013, a 74-year-old man was admitted to the Department of Neurosurgery at Yonsei University College of Medicine due to gait disturbance and tingling sensation of both legs. The patient was receiving beta-adrenergic antagonist and calcium channel blocker for arterial hypertension. He had lost his vision in the left eye due to cataract and amblyopia in the right eye due to retinitis which had occurred 30 years ago. The patient’s family history included a mother with a brain tumor of unconfirmed pathology, and both brothers with renal cell carcinoma with VHL gene mutation (Fig. 1). Serum carcinoembryonic antigen (CEA) was elevated to 11.78 ng/mL (normal value, 0.0 to 5.0 ng/mL). Although he had no history of diabetes mellitus, serum glucose level was 462 mg/dL and HbA1c was 11.7%, which led to a new diagnosis of diabetes mellitus, and initiation of insulin therapy. Whole spine magnetic resonance imaging (MRI) showed multiple enhancing nodular lesions of the spinal canal suspected leptomeningeal metastasis of unknown primary malignancy (Fig. 2A). Positron emission tomography whole body scan showed intense fludeoxyglucose uptake in a 3-cm-sized heterogeneous mass in the right kidney and focal mural thickening in the sigmoid colon (Fig. 2B and andC).C). Colonoscopy showed a 5-cm-sized ulceroinfiltrative lesion in the sigmoid colon and a polypoid lesion in the rectum. Subsequent histological examination confirmed the diagnosis of adenocarcinoma and high grade tubular adenoma with focal carcinoma in situ transformation, respectively. Incisional biopsy of the spinal mass was performed and the histological examination revealed hemangioblastoma.Open in a separate windowFig. 1.Pedigree presenting VHL gene mutation status and malignancy. Both brothers were diagnosed with renal cell carcinoma (RCC) with VHL gene mutation and one of his sons was confirmed VHL mutation without clinical manifestation.Open in a separate windowFig. 2.(A) Spine magnetic resonance imaging showed multiple enhancing nodular lesions of the spinal canal suspected leptomeningeal metastasis of unknown primary malignancy. Positron emission tomography computed tomography whole body scan showed a 3-cm enhancing heterogenous mass in the right kidney (arrow) (B), focal mural thickening with intense fludeoxyglucose uptake in the sigmoid colon (C).The patient underwent laparoscopic right partial nephrectomy, laparoscopic anterior resection of the sigmoid colon, and transanal endoscopic operation of the rectum. Histologic examination of the kidney revealed renal clear cell carcinoma (size, 1.9×1.7 cm), Fuhrman nuclear grade 3 (pT1aN0M0; stage I). In the sigmoid colon, gross pathology showed an ulcerofungating tumor (size, 4.2×3.6 cm) and 3 of 23 examined regional lymph nodes were metastasis. Subsequent histological examination confirmed typical features of colon adenocarcinoma (pT3N1bM0; stage IIIB). The rectum specimen was confirmed to be a 0.5-cm-sized well differentiated adenocarcinoma (pT1N0M0; stage I). The postoperative CEA level was 4.24 ng/mL.Regarding clinical decision processes, we initially suspected VHL disease. Subsequently, polymerase chain reaction (PCR) sequencing analysis of VHL gene showed p.Glu70Lys (c.208G > A) mutation in exon 1, confirming the diagnosis of VHL disease (Fig. 3). Result of endocrine hormonal evaluation for pheochromocytoma was within normal range.Open in a separate windowFig. 3.Polymerase chain reaction sequencing analysis of von Hippel–Lindau (VHL) gene showed a p.Glu70Lys (c.208G > A) mutation in exon 1, confirming the diagnosis of VHL disease.His two sons were screened for VHL disease using PCR sequencing analysis, and one progenity showed p.Glu70Lys (c.208G > A) mutation in exon 1, identical to his father. He underwent ophthalmic examination, abdomen-pelvic computed tomography scan and blood test for catecholamine metabolites, but there were no abnormal findings.After 3 weeks from discharge, he was admitted to hospital complaining of worsened gait disturbance and numbness of both soles. Brain MRI showed three enhancing lesions in bilateral cerebellar hemispheres and left cerebellar tonsil, suggesting hemangioblastomas (Fig. 4). The patient underwent gamma knife surgery in cerebellar lesions and palliative radiotherapy to T9-S1 spine with a total of 45 Gy in 25 daily fractions.Open in a separate windowFig. 4.Brain magnetic resonance imaging showed three enhancing lesions (arrows) in bilateral cerebellar hemispheres (A,B) and left cerebellar tonsil (C), suggesting hemangioblastomas.nAfter one month, follow-up imaging studies showed stable lesions in the brain and spine, but there was a newly developed hepatic metastasis in S6 and an enlarged aortocaval lymph node (Fig. 5). Concurrent serum CEA level increased to 19.54 ng/mL. The multidisciplinary team decided to perform surgery, laparoscopic wedge resection of liver and excision of aortocaval lymph node. Histologic examination of liver revealed a 1.6×1.2-cm-sized metastatic adenocarcinoma, moderately differentiated, clinically from colon. Pathologic finding indicated that the aortocaval lymph node was metastatic carcinoma, favoring renal clear cell carcinoma. He is on regular follow-up in the outpatient clinic and imaging studies show no evidence of recurrence and CEA level is stabilized within normal range.
PatientID: None (Proband)
KindredID: 1
Case: M, 74Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo:Mother with a brain tumor of unconfirmed pathology, and both brothers (70Y and 79Y) with renal cell carcinoma with the same VHL gene mutation as this patient. One son (44Y) has the same mutation but was asymptomatic. Daughter (40Y) had a brain hemorrhage, niece had hematologic malignancy, nephew has pancreatic cancer; genetic information is unclear or not provided for these family members.
CasePresentingHPOs: HP:0010797; HP:0000822; HP:0000518; HP:0000572; HP:0000646; HP:0000819; HP:0040276; HP:0006770; HP:0032118, HP:0030439; HP:0009713; HP:0002672; HP:0006880 (Hemangioblastoma, Hypertension, Cataract, Visual loss, Amblyopia, Diabetes mellitus, Adenocarcinoma of the colon, Clear cell renal cell carcinoma, Retinitis, Anal canal adenocarcinoma, Spinal hemangioblastoma, Gastrointestinal carcinoma, Cerebellar hemangioblastoma)
CaseHPOFreeText: History of arterial hypertension and retinitis causing loss of vision in the left eye due to cataract and amblyopia in the right eye. History of retinal hemangioblastoma was presumed. Diagnosed with diabetes mellitus at the time of the study. MRI showed multiple enhancing nodular lesions of the spinal canal, later confirmed to be a hemangioblastoma. Whole body PET scan showed a heterogeneous mass in the right kidney and focal mural thickening in the sigmoid colon. Colonoscopy showed an ulceroinfiltrative lesion in the sigmoid colon and a polypoid lesion in the rectum subsequently confirmed as a adenocarcinoma and high grade tubular adenoma with focal carcinoma, respectively. Histologic examination of the kidney revealed renal clear cell carcinoma. In the sigmoid colon, gross pathology showed an ulcerofungating tumor and some regional lymph nodes were metastasis. The rectum specimen was confirmed to be a well differentiated adenocarcinoma. Brain MRI showed three enhancing lesions in bilateral cerebellar hemispheres and left cerebellar tonsil, suggesting hemangioblastomas. Histologic examination of liver revealed a metastatic adenocarcinoma. Pathologic finding indicated that the aortocaval lymph node was metastatic carcinoma, favoring renal clear cell carcinoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Figure 1
Variant: p.E70K (c.208G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/
CAID: N/A
gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: E70K (c.208G>A)
MultipleGeneVariants: N/A