A 42-year-old man was admitted to our Urology unit with a one-year history of repeating left lumbago. Ten years ago, this patient received gamma knife treatment for cerebral hemangioblastomas. There was no history of hypertension disease (blood pressure at admission: 134/79mmHg). Eyesight and fundus examinations were normal.Prior to the operation, levels of blood creatinine and urea nitrogen were normal (82 μmol/L and 6.05 mmol/L, respectively). However, the routine urine test showed an elevated level of RBCs with 9,298 cells per liter. Common tumor markers such as AFP, CEA, and PSA were normal. Magnetic resonance (MR) of the abdomen showed multiple solid lesions in the bilateral kidneys (53 mm was the largest diameter) with enhanced density after contrast, multilocular renal cysts, a right adrenal nodule, multiple cysts and a solid lesion in the pancreas (42.7 mm was the largest diameter), and multiple cysts in the liver with 2 highly vascular lesions located in the S7/8 and S2 sections (Fig. 1A and 1B). Special tests for adrenal lesions included plasma cortisol, renin angiotensin aldosterone, and urinary VMA, which were normal. The patient underwent 3 consecutive surgeries. The first surgery was partial nephrectomy that removed most of the tumors in the right kidney. Three weeks later, the second surgery removed most of the tumors on the surface of the left kidney, and radiofrequency ablation guided by ultrasound aided in treating the inner tumors. Two weeks after the second surgery, the patient received an emergency nephrectomy on the left side kidney due to a severe hemorrhage. Open in a separate windowFigure 1.Imaging findings of 2 patients. (A) and (B) Abdomen magnetic resonance (MR) of the brother (II:1) showed a solid lesion (1) and multiple cysts (2) in the pancreas; liver vascular lesion located in the S7/8 section (3); solid lesions (4) and multilocular renal cysts (5) in the kidney; and a right adrenal nodule (6). (C) Scrotum magnetic resonance (MR) of the brother (II:1) showed a malignant tumor in the right side epididymis (arrow). (D) Abdomen computed tomography (CT) of the sister (II:6) showed multiple cysts in the pancreas (7) and a right adrenal nodule (8).Pathologic reviews and an immunohistochemical test (IHC) were performed to confirm the diagnosis. Tumor sections from the right side kidney stained with hematoxylin and eosin (H&E) showed sheet-like, solid clear cells in the tumor lesions and cysts lined by clear cells with uniform nuclei in some areas (Fig. 2A and 2B). The pathological manifestations confirmed ccRCC concurrent with simple renal cysts. The left side kidney showed multilocular cysts lined by clear cells with plenty of plasm and high nuclear to cytoplasmic ratios by microscopy. Clusters of clear cells were present in the septal walls (Fig. 2C), and mcRCC was confirmed pathologically. The IHC staining of the bilateral kidney tumor was positive for CD10, CK and Vim (data not shown). Open in a separate windowFigure 2.Pathological images of the brother. (A) Clear cell renal cell carcinoma (ccRCC) from the right kidney. The tumor consists of sheet-like, solid clear cells (H&E 40×).The image in the yellow-boxed area displays part (B). Multilocular renal cysts with clear cell renal carcinoma from the right kidney. The yellow-boxed area displays a renal cyst that is lined by a single-layer of clear cells with uniform nuclei (H&E 100×). Additionally, the green-boxed area displays part of the ccRCC with sheet-like, solid clear cells. (C) Cystic renal cell carcinoma from the left kidney. Cysts are lined by clear cells with uniform nuclei. Clusters of clear cells are present in the septal walls (H&E 40×). The image in the yellow-boxed area displays the aggregates of similar-appearing clear cells scattered without permeating the septa and forming solid nodules (H&E 100×).During this patient's hospitalization, a mass was palpable in his right side scrotum, which had no tenderness, redness or itching. The scrotum MR suspected a malignant tumor on the right side epididymis (Fig. 1C). However, the patient refused to accept a biopsy of this mass.
PatientID: II:1 (proband)
KindredID: 1
Case: M, 42Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband presented with VHL Type 2B. Sister presented with features of VHL Type 2A including cerebral hemangioblastomas, a right adrenal nodule, multiple cysts in the pancreas, multiple cysts in the liver, two brain lesions. The younger brother and their deceased father had hemangioblastomas in the central nervous system and ocular diseases, respectively. Despite having no information of detailed clinical data, it is reasonable to assume that they had VHL diseases. The father was also blind, but the reasons are unknown. The mother had no history of disease. Pedigree: see Figure 3.
CasePresentingHPOs: HP:0010797; HP:0005584; HP:0006770; HP:0030421 (Hemangioblastoma, Renal cell carcinoma, Clear cell renal cell carcinoma, Epididymal neoplasm)
CaseHPOFreeText: Ten years prior (at the age of 32), the patient received gamma knife treatment for cerebral hemangioblastomas. Magnetic resonance (MR) of the abdomen showed multiple solid lesions in the bilateral kidneys, multilocular renal cysts, a right adrenal nodule, multiple cysts and a solid lesion in the pancreas, and multiple cysts in the liver. The pathological manifestations confirmed ccRCC concurrent with simple renal cysts. The left side kidney showed multilocular cysts lined by clear cells. Pathology confirmed the presence of clusters of clear cells. mcRCC was confirmed pathologically. Scrotum MR suspected a malignant tumor on the right side epididymis.
CaseNotHPOs: HP:0000822; HP:0100631 (Hypertension, Neoplasm of the adrenal gland)
CaseNotHPOFreeText: No history of hypertension disease. Common tumor markers such as AFP, CEA, and PSA were normal. Special tests for adrenal lesions included plasma cortisol, renin angiotensin aldosterone, and urinary VMA, which were normal.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.340+5G>C
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/
CAID: CA020288, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020288
gnomAD: 0.01119, https://gnomad.broadinstitute.org/variant/3-10183876-G-C
VariantEvidence: Direct sequencing of DNA strands revealed 2 recurrent mutations of c.256C > T (p.P86S) and c.340 + 5G > C. Haplotype construction displayed that the c.256C > T (p.P86S) mutation in cis with c.340 + 5G > C were located on the disease haplotype. Bioinformatics analysis revealed that this mutation might severely destabilize the hydrophobic core of pVHL and cause VHL manifestations. This variant’s large allele frequency means this is likely non disease causing (not deleterious).
MutationType: splice_site_variant
CivicName: P86S (c.256C>T) and Splice Region (c.340+5G>C)
MultipleGeneVariants: Germline, VHL, c.256C>T (p.Pro86Ser)