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.

Case 2 A 41-year-old male patient was admitted to the Department of Ophthalmology and Endocrinology at the Affiliated Hospital of Zunyi Medical College between 24 September and 5 October 2014 due to blurred vision and elevated blood glucose level. During hospital admission, adrenal masses were identified on the left and right sides, and the patient was transferred to the Department of Urology on 23 October 2014. Vision was lost in the right eye due to a previous injury. The patient had hypertension and diabetes for >2 months. In September 2010, the patient underwent resection of the lesions in the right cerebellar hemisphere. Postoperative pathological analysis confirmed that the lesion was a hemangioblastoma. The mother of the patient was deceased, and the cause was unknown. The mother exhibited a brain tumor and coronary heart disease whilst alive. Multiple nodules were detected in the thyroid gland of the patient's eldest sister (II-1), but were not treated. The rest of the family members were healthy.

M 33 VHL 3 B/L PCC, DM c. 499C>T p.Arg167Trp

2. Presentation of CaseA 17-year-old girl was referred to our department for the investigation of a newly diagnosed diabetes mellitus and a severe arterial hypertension. She was the first child of consanguineous parents. Her past medical history was unremarkable. Her family history was notable for type 2 diabetes and dyslipidemia but no history of pheochromocytoma, paraganglioma, unexplained sudden death, or condition that may lead to thinking about VHL disease was reported.As symptoms, the patient complained of headaches, palpitations, diaphoresis, and hot flashes since one month. She reported also asthenia and body weight loss of five kilograms in two weeks.On examination, she had a body weight of 50 kg, a body height of 154 cm, a body mass index of 21.1 kg/m2, a blood pressure of 200/100 mmHg without orthostatic hypotension, a regular pulse of 120 bpm, and a large abdominal café-au-lait spot (Figure 1). Thyroid, abdominal, and neurological examinations were normal.Open in a separate windowFigure 1A large abdominal café-au-lait spot.Twenty-four-hour blood pressure monitoring confirmed the diagnosis of hypertension and the presence of peaks of 230/110 mmHg. Electrocardiogram showed a sinus tachycardia. Capillary glucose level was 2.68 g/l without ketosis.Fundoscopy showed grade 3 hypertensive retinopathy without any other abnormalities.The results of biological investigations are shown in Table 1.Table 1Biological parameters before and after surgery. Before surgeryAfter surgeryReference rangesFasting glucose level (mmol/l)16.394.784.12–5.55Glycated hemoglobin (%)10.125.91≤5.6Total cholesterol (mmol/l)11.835.233.1–5.18Triglycerides (mmol/l)2.431.210.57–1.71Natremia (mmol/l)135140135–145Kalemia (mmol/l)3.343.6–5Creatinine (mg/L)664–13Calcium (mg/L)111.29888–105Phosphate (mg/L)443627–45Albumin (g/l)47.22—35–52Intact PTH∗ (μg/L)1825411–62TSH (mUI/L)0.625—0.12–3.4FT4 (ng/dl)1.31—0.71–1.85Calcitonin (ng/L)2.70—<10.0024 h-urine NMN (μg/24)315057030–60024 h-urine MN (μg/24)40.21220–34524 h-urine sodium (mmol/24 h)88.5— 24 h-urine potassium (mmol/24 h)60— 24 h-urine calcium (mg/24 h)200— 24 h-proteinuria (g/24)0.3—<0.3Open in a separate windowPTH: parathormone, TSH: thyroid stimulating hormone, FT4: free-T4, NMN: normetanephrines, MN: metanephrines. ∗The intact PTH dosage was made using 3rd generation chemiluminescence immunoassay.The diagnosis of clinically suspected pheochromocytoma was confirmed by the dosage of urinary methoxylated derivatives at 5 times the upper limit of normal. In addition, the diagnosis of diabetes mellitus, dyslipidemia, and primary hyperparathyroidism were made.The abdominal computed tomography (CT) showed two adrenal masses: the first on the right measuring 35 × 55 × 70 mm with a spontaneous density of 30 HU heterogeneously enhanced in the arterial time showing areas of necrosis with an absolute washout of 40%, the second on the left measuring 24 × 27 mm with the same characteristics as the first one (Figure 2). There were neither other localizations nor lymph nodes. Metaiodobenzylguanidine (MIBG) scintigraphy exhibited a high accumulation of the tracer in both adrenal tumors with no other localization. Cervical ultrasound and 99mTc-sestamibi scintigraphy were normal. Cardiac ultrasound was normal.Open in a separate windowFigure 2Abdominal computed tomography showing the two adrenal masses (two white arrows).