PatientID: 1 (son)

KindredID: 1

Case: M, 9Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Familial isolated pheochromocytoma is described as the father is a carrier of the same mutation: R79G (c.235C>G).

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: history of fever, profuse sweating, intense headache and 190/120 blood pressure. He was currently asymptomatic with normal hormonal controls after complete tumor resection of his right adrenals

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: N/A (Case)

KindredID: 1

Case: M, 32Y0M, Thai (South Asian)

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0030405 (cerebellar hemangioblastoma; pancreatic endocrine tumor)

CaseHPOFreeText: This male was diagnosed with VHL at 20Y when he was found to have a cerebellar hemangioblastoma. Abdominal CT obtained as part of routine surveillance demonstrated multiple cystic lesions with rim enhancement in the pancreas. 10 years later, he developed abdominal discomfort, and an abdomen CT showed multiple solid and cystic enhancing lesions involving the entire pancreas with a hypervascular mass at segment 7 of liver. Given radiological findings, he was diagnosed with malignant pancreatic neuroendocrine tumor (PNET) with liver metastasis, thereupon underwent total pancreactomy with wedge resection of the liver mass. Surprisingly, the histopathology revealed a serous cystadenocarcinoma in the pancreas measuring 28 x 11.5 x 7 cm and a 4.5 x 4.5 x 3 cm metastatic lesion in the liver with hepatic capsular invasion. 

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Genetic testing revealed a large deletion of exon 3 and poly A sites of VHL gene.

MutationType: exon_loss_variant

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: M,19Y0M, South Asian (Saudi)

DiseaseAssertion: assumed VHL

FamilyInfo: History of family showed that his father had died as a complication of metastatic renal carcinoma. Screening was done for the family. 3 of his 8 siblings tested positive for the 384delT mutation, although no phenotypes for them was given.

CasePresentingHPOs: HP:0100651; HP:0006748; HP:0001737; HP:0005584 (Type I diabetes mellitus; adrenal pheochromocytoma; pancreatic cysts; renal cell carcinoma)

CaseHPOFreeText: The young man presented with primary symptoms of polyuria and polydipsia, and was later found to be in diabetic ketoacidosis (diagnosed with diabetes mellitus type I). He had persistent abdominal pain (later showing left sided pheochromocytoma (3.7 x 4.0 cm rounded lesion in the left adrenal gland) and right sided renal cell carcinoma (measuring 2.3 cm, with heterogeneous enhancement suggestive of a solid mass)). The CT scan also demonstrated multiple rounded cystic lesions in the head, body, neck and tail of the pancreas representing pancreatic cysts. Bilateral cortical lesions in the kidneys also demonstrated internal septal enhancement in the post gadolinium injection phase, highly indicative of renal cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129Trpfs*30 (c.384delT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70049452 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.384delT

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: N/A (daughter)

KindredID: 1

Case: F, 5Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Her mother tested positive for the mutation: Q164R (c.491A<G), presenting with pheochromocytoma. Her cousin (26Y) had an adrenaland pancreatic tumors neuroendocrine carcinoma of uncertain origin, although no genetic testing.

CasePresentingHPOs: N/A

CaseHPOFreeText: asymptomatic likely due to young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238 https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: To date, this germline VHL mutation was said to have been described in only 3 cases, with variable phenotypes, and in 2 cases PHEO occurred at a very young age.

MutationType: missense_variant;transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: M, 17Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient’s father and paternal aunt both had a history of pheochromocytoma. No genetic testing for them was described.

CasePresentingHPOs: HP:0006748; HP:0002668 (adrenal pheochromocytoma, paraganglioma)

CaseHPOFreeText: Presented at 11Y with a 2-week history of nausea. He was noted to have tachycardia and a heart murmur, so an echocardiogram was obtained revealing moderate concentric hypertrophy and mildly decreased left ventricular systolic and diastolic dysfunction. An MRI of the abdomen revealed a 4.6 × 4.1 × 5.7 cm mass in the right adrenal gland and a 3.3 × 2.9 × 3.2 cm rounded lesion in the left adrenal gland. MIBG scan showed MIBG localization in bilateral retroperitoneal masses, compatible with bilateral pheochromocytoma. Patient underwent bilateral adrenalectomy. Two years later (13Y), imaging revealed a right paraspinal paraganglioma which was subsequently resected.

CaseNotHPOs: N/A

CaseNotHPOFreeText: An ophthalmology examination was notable only for hypertensive retinopathy.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84M (c.250G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428813, https://www.ncbi.nlm.nih.gov/clinvar/variation/428813/

CAID: N/A

gnomAD: 0.000004376, https://gnomad.broadinstitute.org/variant/3-10183781-G-A

VariantEvidence: At the time of publication, the mutation had not been previously characterized however was clinically consistent with a diagnosis of VHL.

MutationType: missense_variant;transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 8Y0M, Ethnicity Unknown

DiseaseAssertion: endolymphatic sac tumor (ELST)

FamilyInfo: N/A

CasePresentingHPOs: HP:0030393 (endolymphatic sac tumor)

CaseHPOFreeText: ELST that occurred in the left temporal bone who presented with profound sensorineural hearing loss, intermittent vertigo. A CT demonstrated a destructive mass involving the posterior aspect of the left petrous temporal bone centered midway between the internal auditory canal and the sigmoid sinus. Bony erosion extends into the posterior semicircular canal, and there are areas of stippling and central calcification within the mass suggestive of an aggressive, erosive process

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: c.601G>C mutation in the vHL gene on chromosome 3

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: N/A (case)

KindredID: 1

Case: F, 30Y0M, South-Asian (Indian)

DiseaseAssertion: VHL

FamilyInfo: Not stated - although she was counselled through a planned conception, and she delivered a healthy child

CasePresentingHPOs: HP:0006748; HP:0001732; HP:0006880 (adrenal pheochromocytoma; pancreatic mass; cerebellar hemangioblastoma)

CaseHPOFreeText: Here is a case report describing a young woman presenting with hypertension, diagnosed to have VHL with right adrenal pheochromocytoma, and a pancreatic mass. Subsequent brain scan revealed a cerebellar hemangioblastoma. The patient underwent an adrenalectomy where her diagnosis was confirmed. Additionally, surgery for cebellar haemangioblastoma and distal pancreaticospleenectoy were done.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 29Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Negative family history, suggesting a de novo mutation.

CasePresentingHPOs: HP:0010797; HP:0002858; HP:0012503; HP:0000141 (hemangioblastoma; meningioma; pituitary lesion; amenorrhea)

CaseHPOFreeText: 1-year history of amenorrhea, she was found to have a brainstem hemangioblastoma, posterior fossa meningiomas and a pituitary spaceoccupying lesion causing hyperprolactinemia. Complete resection of the brainstem hemangioblastoma and posterior fossa meningiomas was achieved in one single operation via a sub-occipital posterior combined with retrosigmoid approach. The patient was later discharged without obvious postoperative complications.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial deletion of Exon 1

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: N/A (father)

KindredID: 1

Case: M, Age Unknown (deceased), South Asian (Saudi)

DiseaseAssertion: assumed VHL

FamilyInfo: History of family showed that his 4/8 children tested positive for the 384delT mutation. suggesting that he likely passed it onto them. One son (case) presented with adrenal pheochromocytoma, pancreatic cysts, and renal cell carcinoma.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: He died as a complication of metastatic renal carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129Trpfs*30 (c.384delT) [assumed]

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70049452 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.384delT

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 37Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: Her one sister had died just after delivery, following a severe hypertensive crisis. Her 26-year-old niece presented with a 3 cm left adrenal tumor, an 8 cm pancreatic tumor and disseminated hepatic metastasis, evolving to death within a few months. Her liver biopsy was compatible with a moderately differentiated neuroendocrine carcinoma of uncertain origin. Molecular diagnosis was not performed in the affected sister and niece. Her asymptomatic 5Y old daughter tested positive for the mutation: Q164R (c.491A<G).

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: She first presented with paroxisms of severe hypertension associated with headaches, diaphoresis and, ocasionally, fainting, started one year before. She had had acute pulmonary edema and a cardiorespiratory arrest during her first caesarean section. A CT scan revealed a right adrenal tumor (6.0 cm), showing increased 123I-MIBG uptake. After conventional adrenalectomy, a PHEO was immunohistochemically confirmed. Close follow-up has shown no signs of recurrence or evidence of new tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238 https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: To date, this germline VHL mutation was said to have been described in only 3 cases, with variable phenotypes, and in 2 cases PHEO occurred at a very young age.

MutationType: missense_variant;transition

CivicName: N/A

MultipleGeneVariants: N/A