PatientID: None

KindredID: 1

Case: M, 75Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's brother had hypertension at age 77 and was found to carry the mutation. The patient's niece had breast cancer at age 33. Refer to Figure 4 for Pedigree.

CasePresentingHPOs: HP:0006770, HP:0040276, HP:0006748, HP:0001407, HP:0002716, HP:0032618, HP:0100526, HP:0100598 (clear cell renal cell carcinoma, adenocarcinoma of the colon, adrenal pheochromocytoma, hepatic cysts, lymphadenopathy, renal necrosis, neoplasm of the lung, pulmonary edema)

CaseHPOFreeText: Patient admitted at age 64 for intermittent abdominal pain, loss of appetite and constipation. He was found to have a solid tumor with areas of colliquative necrosis in the upper pole of the left kidney. The scans also showed distension of the colon with concomitant wall thickening, indicating possible neoplasia. Colonoscopy revealed a small polyp in the rectum-sigmoid junction, and a subsequent histological exam confirmed a diagnosis of adenocarcinoma. Both tumours were removed via a left hemicolectomy and left radical nephrectomy. A histologic examination of the kidney revealed renal clear cell carcinoma. Five years later, an abdominal CT scan revealed an adrenal pheochromocytoma in the right adrenal gland and multiple hepatic cysts in the right kidney and liver. The patient underwent a right adrenalectomy which found no convincing evidence of malignancy. At age 73 total body positron emission tomography (PET)-CT revealed the presence of several metastatic sites (both lungs, a 12×10 mm right sovraclaveare lymphadenopathy, and a 32×12 mm lesions at the mediastinum). An agobiopsy and cytologic broncholavage showed lymphocytes and epithelial cells with voluminous clear cytoplasm and large nuclei with prominent nucleoli, confirming the presence of metastatic lesions of clear cell renal carcinoma. In the same year, CT imaging revealed progression of pulmonary disease. One year later, a new CT scan revealed hepatic metastases and worsening of the mediastinal adenopathy and pulmonary metastases. At age 75, a new CT scan showed stable disease at various metastatic sites with minimal pleural effusion. Later in the month the patient was hospitalized for severe dyspnea, fatigue, and lower limb edema and died a few days later.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: Fundoscopy revealed no vascular abnormalities of the retina.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: IV-3

KindredID: 1

Case: M, 77Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother and two brothers had died with cerebellar hemangioblastoma, although genetic testing was not performed. One of the patient’s four children, a 46Y male, also presented with a small renal tumour, renal cysts, and pancreatic cysts; he was found to carry the same mutation the patient carried. One of the patient’s grandsons, a 10Y male, was also found to carry the same mutation as the patient but was asymptomatic. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0006770; HP:0006748; HP:0000479 (Cerebellar hemangioblastoma, pancreatic serous cystadenoma, clear cell renal cell carcinoma, adrenal pheochromocytoma, retinal lesions)

CaseHPOFreeText: The patient was originally diagnosed with metastatic bilateral clear cell renal cell carcinoma at 68Y and underwent chemotherapy for three months. The metastases were later reinterpreted to be a cystic hemangioblastoma and a benign serous cystadenoma. The patient was also found to have a non-secreting adrenal pheochromocytoma at 73Y and a clear cell renal cell carcinoma metastasis in the thyroid at 74Y. The patient had also previously presented with retinal lesions, although detailed records were unavailable.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82P(c.245G>C)

LegacyVariant: N/A

ClinVarID: 193118, http://www.ncbi.nlm.nih.gov/clinvar/variation/193118

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P(c.245G>C)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: 30Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Thus far, it has not been possible to study the parents or close relatives of this patient.

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0000107 (hemangioblastoma; clear cell renal cell carcinoma; renal cysts)

CaseHPOFreeText: Aged 29Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS hemangioblastoma diagnosed at 29Y, ccRCC and renal cysts were diagnosed at 30Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Q73Pfs*59 (c.217dupC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030271 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030271

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: Q73Pfs*59 (c.217dupC)

MultipleGeneVariants: N/A