PatientID: DHPLC 1

KindredID: 1

Case: M, 51Y0M, Unknown Ethnicity

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter (DHPLC 1) had a pheochromocytoma at 11Y. At 18Y, she had a pheochromocytoma in the contralateral adrenal gland and two concurrent paragangliomas of the abdominal aorta and urinary bladder. At 25Y, she was found to have a right frontal meningioma. A family history obtained from his daughter’s other parent, one son and one other daughter (not DHPLC 1) was uninformative. The patient’s relatives (except for his daughter) were normal both clinically and biochemically.

CasePresentingHPOs: HP:0001028; HP:0000277; HP:0009715; HP:0000107 (Angioma, abnormality of the mandible, papillary cystadenoma of the epididymis, renal cyst)

CaseHPOFreeText: The patient had an attenuated VHL phenotype caused by mosaicism which led to what initially appeared to be a de novo mutation in his daughter (DHPLC 3). The patient was found to have an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas at age 43Y. Abdominal ultrasonography and total-body magnetic resonance imaging (MRI) conducted at the time of the study (51Y) revealed a 2.3-cm cyst in his right kidney. His blood pressure and levels of plasma free metanephrines, fractionated urinary metanephrines, chromogranin A were normal.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 44Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient has a notable family history. Her eldest brother had multiple RCCs in both kidneys, bilateral cerebellar hemangioblastomas, and pheochromocytoma in his left adrenal gland (see Patient 2). Her daughter also underwent cortex-sparing adrenalectomies for bilateral pheochromocytomas as well as hemangioblastoma resection in her left cerebellum at age of 19 years, although no testing for VHL was stated.

CasePresentingHPOs: HP:0006748, HP:0030405, HP:0006880, HP:0000107, HP:0005584 (adrenal pheochromocytomas, pancreatic endocrine tumour, cerebellar hemangioblastoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: Patient diagnosed at age 29 with bilateral pheochromocytomas when she presented with severe hypertension and two large masses (greater than 6 cm) in her bilateral adrenal glands. At 38 years old, she underwent a resection for a mass found on her pancreas, with pathological analysis of the mass revealing a pancreatic neuroendocrine tumor. At 42 years old, a follow-up CT scan revealed two heterogeneous contrast-enhanced masses, one on the right kidney and one on the left adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

ClinVar: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAiD: CA16621914 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 3

Case: M, 45Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL disease was described for this patient. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0000107; HP:0001737; HP:0000787 (cerebellar hemangioblastoma; spinal hemangioblastoma; renal cyst; pancreatic cysts; nephrolithiasis)

CaseHPOFreeText: At 40Y, Patient 4 was diagnosed with spinal and cerebellar hemangioblastomas, as well as multiple renal and pancreatic cysts. He was diagnosed with VHL disease type 1. At 43Y, renal cysts and stones were discovered. A year later, more spinal hemangioblastomas and renal stones were found. A year later, cerebellar lesions, as well as renal and pancreatic cysts were reported (see table 1).

CaseNotHPOs: HP:0002088; HP:0001392; HP:0005264; HP:0001743 (abnormal lung morphology; abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.N90del (c.268_270del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524783, https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA645524783

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: N90del (c.268_270del)

MultipleGeneVariants: N/A