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    1. A female patient observed reduced vision in the right eye at age 17 years. She was diagnosed with retinal angiomatosis of the right eye. Laser therapy and brachytherapy were performed. Vision of the right eye remained reduced to 15%. At age 24, a hemangioblastoma of the cervical spinal cord was resected. At age 27, she underwent craniotomy for a cerebellar hemangioblastoma. Genetic testing revealed the mutation VHL c.394 C > T, which predict a truncated VHL protein (Q132X). In 2007, a 20 mm diameter left renal tumor was detected but not resected owing to its small size, as internationally recommended [1].In 2009 at age 38, abdominal MRI and CT angiography showed, in the axial view, a solid, 3.6 × 3.3 cm tumor of the pancreatic tail (Fig. 2a). Early arterial phase imaging after contrast injection revealed that the tumor had significant hyperperfusion. In addition, multiple pancreatic cysts were noted.

      PatientID: 2

      KindredID: 2

      Case: F, 38Y0M, German

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo:All patients from the German registry for VHL with PNETs >3 cm diameter with tumours located in the pancreatic body or tail region.

      CasePresentingHPOs: HP:0009711, HP:0009713, HP:0006880, HP:0009726, HP:0030405, HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm, pancreatic endocrine tumour, pancreatic cysts)

      CaseHPOFreeText: Retinal angiomatosis at age 17, hemangioblastoma of the cervical spinal cord at age 24, cerebellar hemangioblastoma at age 27, left renal tumor at age 36. Pancreatic endocrine tumour and pancreatic cysts at age 38. She had a laparoscopy which found an 8-cm retrogastric cyst, 3.2-cm benign PNET, and a serous cystadenoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q132* (c.394C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Q132* (c.394C>T)

      MultipleGeneVariants: N/A

    1. Gene sequencing revealed a heterozygous germline mutation ({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3(VHL):c.464-1G > C) in the splice site in intron 2 of VHL in the DNA from the peripheral blood of the male patient and nine of his family members (male 4, female 5) (Fig. 3a). In total, five of these nine patients from three generations underwent a total of nine surgical resections for CNS-related HGBs, with an average of 1.8 ± 1.3 surgeries (range: 1–4). All resected lesions were located in the cerebellum. Figure 4 shows the genetic investigation used in this study. In the first, second, and third generations, the ages at which the first operation for CNS HGBs was performed were 67, 32.3, and 17 years, respectively. Notably, the age at which the first operation for CNS HGBs was performed was younger in the children (younger generation) than in their parents (older generation). Additionally, only the mother of the male patient with the {"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3(VHL):c.464-1G > C variant was diagnosed with renal cell carcinoma and underwent left nephrectomy.

      PatientID: III-1

      KindredID: 1

      Case: M, 17Y0M, Chinese (East Asian)

      DiseaseAssertion: assumed VHL

      FamilyInfo: A total of 9 of family members (4 male; 5 female) in a 3 generation family were associated with VHL at the splice mutation: c.464-1G>C. 5 members underwent cerebellar HB lesion resections, including his mother, aunt and uncle, and 1 member had RCC. (See Fig 4).

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: He had his first operation for HB at 17Y. No further details were discussed.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.464-1G>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223220 https://www.ncbi.nlm.nih.gov/clinvar/variation/223220

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.464-1G>C)

      MultipleGeneVariants: N/A

    1. 45-year old Japanese woman

      PatientID: None

      KindredID: 1

      Case: F, 45Y0M, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: No evidence of a family history of VHL.

      CasePresentingHPOs: HP:0001737; HP:0030405; HP:0006880; HP:0006748; HP:0009711; HP:0001732; HP:0002896 (Pancreatic cysts, Pancreatic endocrine tumor, Cerebellar hemangioblastoma, Adrenal pheochromocytoma, Retinal capillary hemangioma, Abnormality of the pancreas, Neoplasm of the liver)

      CaseHPOFreeText: The proband had a cerebellar hemangioblastoma resected at age 17, retinal hemangioblastoma surgery at age 26, and an adrenalectomy for pheochromocytoma at age 30. An abdominal CT revealed a 4cm abdominal mass and diffuse pancreatic cystic lesions, diagnosed as pancreatic neuroendocrine tumor.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText:

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q132* (c.394C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 288749, (https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/)

      CAID: CA10606205 (http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA10606205)

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Q132* (c.394C>T)

      MultipleGeneVariants: N/A