Hypothesis

The index case was a 14 year-old boy who presented to us in 1971 with severe hypertension. On evaluation he was found to have a right adrenal mass with elevated urinary VMA (normal <7 mg/24 hr), confirming the diagnosis of a right adrenal pheochromocytoma. He underwent right adrenalectomy and the post-operative period was uneventful. He was subsequently lost to follow. In 1979, he presented to us again with severe headache and recurrent seizures. On examination his pulse rate was 100/min, blood pressure was 160/130 mm of Hg. Cardiac auscultation revealed a loud 2nd heart sound and a 3rd heart sound. There were no murmurs. Examination of the abdomen revealed a palpable mass in the left hypochondrium. This mass was confirmed as a pheochromocytoma. After adequately controlling his blood pressure he underwent left cortical sparing adrenalectomy. The post-operative period was uneventful. He was on steroid replacement that was subsequently withdrawn after his serum cortisol levels had normalized. His 8 AM cortisol after withdrawal of steroids was 12 µg/dl.He subsequently got married and had two children as shown in Figure 1, who also eventually developed similar tumors.

PatientID: II-1

KindredID: 1

Case: M, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family in India but Ethnicity not explicitly confirmed. Two children with the same mutation. Eldest son presented at age 10 with severe hypertension and bilateral pheochromocytoma. Daughter presented at age 17 with palpitation, blurred vision, blurring vision, bilateral papilledema and bilateral pheochromocytoma. Wife and brother were negative for the mutation.

CasePresentingHPOs: HP:0000822; HP:0002666; HP:0006748; HP:0002315; HP:0001250; HP:0031657 (Hypertension, Pheochromocytoma, Adrenal pheochromocytoma, Headache, Seizure, Abnormal heart sound)

CaseHPOFreeText: Presented at 14 years-old with severe hypertension. On evaluation he was found to have a right adrenal mass with elevated urinary VMA, confirming the diagnosis of a right adrenal pheochromocytoma. Presented at age 22 with severe headache and recurrent seizures. Cardiac auscultation revealed a loud 2nd heart sound and a 3rd heart sound. Examination of the abdomen revealed a palpable mass in the left hypochondrium. This mass was confirmed as a pheochromocytoma. Asymptomatic at age 57.

CaseNotHPOs: HP:0030148 (Heart murmur)

CaseNotHPOFreeText: There were no heart murmurs during evaluation at age 22.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.R82L (c.245G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors carried out analysis of VHL variant p.Arg82Leu with six different in silico tools namely SIFT, I-Mutant3, PhD-SNP, MutPred, PolyPhen2 and SNPs&GO in order to determine the pathogenic potential of the variant.

MutationType: missense_variant;transversion

CivicName: R82L (c.245G>T)

MultipleGeneVariants: N/A

InheritancePattern:AutosomalDominant DiseaseEntity:VHL DiseaseEntity:pheochromocytoma DiseaseEntity:adrenalpheochromocytoma DiseaseEntity:hypertension DiseaseEntity:seizure DiseaseEntity:headache AgeOfPresentation:pheochromocytoma:22 AgeOfPresentation:adrenalpheochromocytoma:14 AgeOfPresentation:hypertension:14 AgeOfPresentation:headache:22 AgeOfPresentation:seizure:22 Mutation:Germline AssumedRefSeq:NM_000551.3 cDNAposition:245 ProteinPosition:82 AminoAcidChange:ARGtoLEU ClinVarID:526675 ClinVarID:Yes MutationType:missense_variant;transversion CivicName:R82L(c.245G>T) Familial SupplementalData inferred_gene_hgnc:12687 inferred_gene_source:ClinVar VHL Hypothesis Annotation

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