PatientID: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied. This mutation was said to be a de novo, although no more inforation provided. However the asymptomatic father of patient was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198P (c.593T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223235 https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)

Thirteen patients from four families (A, B, C and D) with known VHL disease and known mutations in the VHL gene were examined.  MLPA using venous blood showed 4 genetic variants. Family C was found with a p.L198P mutation in the VHL gene, only confirmed in patient II-1 (male), and was identified together with the polymorphism c.74C>T, p.P25L. The asymptomatic father was also a carrier of the same polymorphism (c.74C>T, p.P25L). No further familial information was provided although suggestion of a de novo mutation. Patient II-1 presented with adrenal pheochromocytoma. pancreatic neuroendocrine tumour, and retinal hemangioblastoma.

A 55-year-old male presented to the emergency room due to shortness of breath, chest pain, and coughing. A chest X-ray and CT scan found a perihilar mass on the left lung, as well as a left renal lesion. A CT scan of the abdomen and pelvis revealed a mass on the left kidney and right adrenal gland. A biopsy showed that the left kidney mass was a renal cell carcinoma. The patient had a left-sided radical nephrectomy and right-sided adrenalectomy. Pathology confirmed clear cell renal cell carcinoma (ccRCC) and pheochromocytoma. Two pieces of lung tissue were orally expelled and examination supported metastatic ccRCC. Spinal MRI and chest CT identified both bone metastases and two spinal lesions consistent with spinal hemangioblastomas. Histology also confirmed liver metastases from the ccRCC. 10 months after his initial presentation, the patient succumbed to his disease 10 months. The patient had no family history of VHL and no other VHL-associated manifestations. The patient was clinical diagnosis with Type 2B VHL. Germline DNA from peripheral blood leukocytes was isolated and sent for gene panel genetic testing targeting known hereditary renal cell cancer and hereditary paraganglioma-pheochromocytoma genes. The gene panel targeted FH, FLCN, MET, MITF, MLH1, MSH2, MSH6, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, TP53, TSC1, TSC2, MAX, MEN1, NF1, RET, SDHAF2, TMEM127, and VHL. The patient tested negative for both single nucleotide or copy number variants in any of the genes. The variant allele threshold for this germline panel was >10%. Subsequent sequencing analysis of all four postmortem tumor tissues revealed an L198P(c.593T>C) missense VHL mutation at varying allele fractions (range: 10–55%) in all four tissues. Both of the patient's daughters underwent germline genetic analysis of VHL and were negative. However, due to family history, both daughters underwent full VHL screening including ophthalmologic assessment, brain, spine, and abdominal MRI. They have no VHL manifestations at the ages of 25 and 30. The germline genetic testing results of the proband's blood sample were re-analyzed and the VHL missense variant was detected at 6% variant allele frequency (below the standard 10% threshold), strongly suggesting that this case is a result of somatic mosaicism.

PatientID: 14

KindredID: 5

Case: Sex Unknown, 40Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 2 other members of this family presented with the same variant. Patient 13 (Gen 2) presented with bilateral pheochromocytoma. Patient 12 (Gen 2) presented with bilateral pheochromocytoma and sympathetic paraganglioma.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma.

CaseNotHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0030405; HP:0002668 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma, Pancreatic endocrine tumor, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198P (c.593T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223235, https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C)

MultipleGeneVariants: N/A