PatientID: 1

KindredID: 1

Case: M, 51Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: Patient 2 (the patient’s brother) presented with the same mutation and was diagnosed with VHL at age 45. The two brothers had very similar VHL clinical manifestations including cerebellar hemangioblastomas, renal cell carcinoma, and cysts in the pancreas. However, patient 1 had testicular and epididymal cysts, as well as lesions in the spine, which were absent in Patient 2. No other family history was noted. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0005584; HP:0009713; HP:0006880; HP:0000107; HP:0001737; HP:0030424; HP:0033608; HP:0000541; HP:0012215 (renal cell carcinoma; spinal hemangioblastoma; cerebellar hemangioblastoma; renal cyst; pancreatic cysts; epididymal cyst; pulmonary nodule; retinal detachment; testicular microlithiasis)

CaseHPOFreeText: At 44Y, Patient 1 exhibited cerebellar and spinal hemangioblastomas, as well as retinal detachment. He also had renal cell carcinoma in both kidneys and multiple cysts in one kidney, testis, and pancreas. He also reported a history of headaches and vertigo, leading to a diagnosis of VHL disease type 1. At 49Y, multiple nodules were found in his lungs and a year later, a nodule in the testis and scrotal lithiasis were detected. At 51Y, renal cell carcinoma was identified in the left kidney and his left epididymis was enlarged. Patient continued to present with left testicular and scrotal lithiasis, right retinal detachment, and multiple nodules in both lungs. However, tMutation:Germlinehe lung phenotype was asymptomatic (see table 1).

CaseNotHPOs: HP:0001392; HP:0005264; HP:0001743 (abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/Av

PatientID: None

KindredID: 1

Case: M,53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient had a family history of VHL.

CasePresentingHPOs: HP:0006880, HP:0009713, HP:0010797, HP:0000238,HP:0005584, HP:0032241, HP:0030405, HP:0002666 (cerebellar hemangioblastoma, spinal hemangioblastoma, hemangioblastoma, Hydrocephalus, renal cell carcinoma, Cervical neoplasm, pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: At age 51, he was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs. An oncologic workup revealed bilateral RCC (grade III clear cell), pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. The patient was subsequently started on Pazopanib. Twelve months following initiation of therapy, the C7T1 HB decreased in size from 14 mm to 12 mm as measured on post-contrast axial T1 MRI. Six months later, C7T1 was further decreased to 9.5 mm, resulting in an approximately 50% decreased volume from initiation of treatment and notably reducing the mass effect on the spinal cord. The L23 lesion also demonstrated reduced size during this time period, from 8 mm to 7.5 mm, while the remaining HBs and retroperitoneal lymph nodes remained stable or increased in size. Following 21 months of TKI therapy, the patient’s systemic disease was stable, and he was placed on a drug holiday. Six months following cessation of Pazopanib, many of the CNS HBs increased slightly, including the C7T1 lesion.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A