GroupID: None

DiseaseAssertion: VHL

GroupSize: 125

GroupNumberMales: 58

GroupNumberFemales: 67

GroupEthnicity: German

GroupAgeRange: 4-86 Y

GroupInfo: The subjects included 64 patients belonging to 15 families with a known VHL c.505 T/C mutation. From their test programme, another 10 c.505 T/C mutation carriers were identified. As well, all consenting first degree relatives (at risk subjects) of mutation carriers, irrespective of disease status, were subjected to mutation analysis, resulting in another 51 mutation carriers detected.

GroupPresentingHPOs: HP:0002666, HP:0009713, HP:0009711, HP:0010797, HP:0006748, HP:0006737, HP:0006770, HP:0002893, HP:0100616, HP:0030357, HP:0002894 (pheochromocytoma, spinal hemangioblastoma, retinal capillary hemangioma, hemangioblastoma, adrenal pheochromocytoma, extraadrenal pheochromocytoma, clear cell renal cell carcinoma, pituitary adenoma, testicular teratoma, small cell lung carcinoma, neoplasm of the pancreas)

GroupHPOFreeText: 96 patients had clinical manifestations of VHL. 55 subjects (31 males, 24 females) developed pheochromocytoma during their lifetime. Overall penetrance for pheochromocytomas was estimated to be 31% by age 35 and 60% by age 70. Other frequent lesions were retinal angioma (36%), hemangioblastoma of the spine (36%), and, to a lesser extent, hemangioblastoma of the brain (16%). One patient with angiomatosis retinae developed at least 25 retinal angiomas, whereas the remaining patients had an average of two angiomas with no more than five lesions in one patient. 15 patients had bilateral and 25 unilateral involvement of the retinae. Pheochromocytoma was observed as a single tumour with adrenal or extra-adrenal localization in 32 patients, but 23 mutation carriers developed multiple pheochromocytomas. Four patients developed renal clear cell carcinoma (estimated overall penetrance 13% by the age of 70). Two of these patients died of metastases. All renal clear cell carcinomas were unilateral, single tumours, and no kidney showed renal cysts. Three of the patients with renal cell carcinoma were female. The kidney tumours were detected at the ages of 46 (male patient), 48, 63, and 74 years. Two patients with renal cell carcinoma also had multiple spinal hemangioblastomas. Other rare tumours were one pancreatic islet cell tumour and one pituitary adenoma; both neoplasms had been incidentally found in a dead 34 year old woman at necropsy. One 68 year old male patient was noted to have small cell lung cancer, and two other males developed testicular teratocarcinoma both at 39 years of age.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

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