Diagnosis Of Von Hippel-Lindau Disease Research Articles

Novel Manifestation of Retinal Hemangioblastomas Detected by OCT Angiography in von Hippel-Lindau Disease

To elucidate the clinical characteristics of atypical retinal vascular proliferation in patients with von Hippel-Lindau (VHL) disease using OCT angiography (OCTA). Prospective, observational study. Fifty-seven consecutive patients with a diagnosis of VHL disease who visited Kyoto University Hospital between January 2019 and March2022. Retinal hemangioblastomas (RHs) were assessed using multimodal imaging including OCTA. Retinal hemangioblastomas were classified into 2 phenotypes: nodular and flat. Nodular RHs were defined as typical RHs that were globular, well-circumscribed tumors, often accompanied with dilated feeder arterioles and draining venules. Flat RHs lacked a protruded red or colored mass, had variable and indistinct borders, and were not accompanied with feeder and draining vessels. The prevalence, distribution, and description of atypical flat RHs. Among 57 consecutive patients with VHL disease, 37 patients (64.9%) showed RHs in at least 1 eye. Bilateral RHs were seen in 23 patients (62.2%). Among 58 eyes of 37 patients with RHs, typical nodular RHs were detected in 54 eyes. Nodular RHs were seen mainly in the peripheral retina and occasionally in the peripapillary region, and they showed exudative changes in some cases. Flat RHs were detected in 7 eyes (12.1%). Four eyes showed only flat RHs, and 3 eyes showed both types in the same eye. Most flat RHs appeared as retinal hemorrhages or faint flat abnormal retinal vessels in the inner retina on the fundus examination, often within the macula area or peripapillary. In all eyes with flat RHs, OCTA showed abundant blood flow in the lesions. OCT revealed that flat RHs were seen mainly between the retinal nerve fiber layer and the ganglion cell layer, and occasionally within the inner nuclear layer. During a mean follow-up period of 20.4 ± 15.0 months, no flat RHs accompanied exudative change, tractional retinal detachment, or progression in size. Patients with VHL disease can demonstrate 2 distinct types of RHs: the classic nodular type and an atypical flat type. OCT angiography can be useful in improving the detection of atypical flat RHs, which can be difficult to detect clinically. Proprietary or commercial disclosure may be found after the references.

Von Hippel-Lindau disease: A case report.

Introduction and importanceVon Hippel-Lindau (VHL) disease is a rare autosomal dominantly inherited genetic condition. Von Hippel characterized the illness independently in 1911, and Lindau in 1926. Its prevalence is estimated to be about 1 in every 36,000 live births. VHL is characterized by the production of several benign and malignant tumors, as well as cysts in other organs. For proper prognosis, good clinical judgement and timely diagnosis is warranted.Case presentationHerein, we report a case of a 50-year-old man with several central nervous system (CNS) lesions, retinal lesions, and renal cortical cysts with a diagnosis of VHL disease who was surgically treated. At a 3-month follow-up, he improved drastically with a marked alleviation of his signs and symptoms.DiscussionVHL is characterized by the creation of various benign and malignant tumors, as well as cysts in multiple organs, and is passed down through generations in an autosomal dominant pattern with near-complete penetrance. CNS lesions are surgically treated. Regular follow-up should be ensured.ConclusionsVHL disease is an extremely complicated disease with the need for diagnosis and genetic tests in the patient and family members, as well as intensive supervision of carriers of the mutated gene, thereby improving early diagnosis and successful treatment of the malignancies. The high cost of diagnostics and surgical therapies is a severe issue. Government care and financial assistance are critical considerations.

両側副腎摘出後，ステロイド内服下に妊娠・出産に至ったvon Hippel-Lindau 病の1 例

両側副腎摘出後，ステロイド内服下に妊娠・出産に至ったvon Hippel-Lindau 病の1 例

Jugular Foramen's Paraganglioma in a Patient with Von Hippel-Lindau Disease: Case Report

AbstractGlomus jugular tumors, also known as paragangliomas (PGLs), are rare and related to several clinical syndromes described. These are located in the carotid body, the jugular glomus, the tympanic glomus and the vagal glomus. The symptoms are directly related to the site of involvement and infiltration. These lesions have slow growth, are generally benign and hypervascularized, have a peak incidence between the age of 30 to 50 years old; however, when associated with hereditary syndromes, they tend to occur a decade earlier. Several familial hereditary syndromes are associated with PGLs, including Von Hippel-Lindau disease (VHL) in < 10% of the cases. The diagnosis and staging of PGLs are based on imaging and functional exams (bone window computed tomography [CT] with a “ground moth” pattern and magnetic resonance imaging (MRI) with a “salt and pepper” pattern). The cerebral angiography is a prerequisite in patients with extremely vascularized lesions, whose preoperative embolization is necessary. The histopathological finding of cell clusters called “Zellballen” is a characteristic of PGLs. Regarding the jugular foramen, the combination of two or three surgical approaches may be necessary: (1) lateral group, approaches through the mastoid; (2) posterior group, through the retrosigmoid access and its variants; and (3) anterior group, centered on the tympanic and petrous bone. In the present paper, we report a case of PGL of the jugular foramen operated on a young female patient who underwent a surgery with a diagnosis of Von Hippel-Lindau Disease (VHL) at the Neurosurgery Service of the Hospital Heliópolis, São Paulo, state of São Paulo, Brazil in 2018, by the lateral and posterior combined route.

Von Hippel–Lindau disease with concomitant Hodgkin’s disease and congenital hypertrophy of the retinal pigment epithelium

The article presents a rare case of combination of von HippelLindau disease and Hodgkins disease. The disease began with neurological symptoms with gradual progression over the next 3 years. The diagnosis of von HippelLindau disease was made after MRI of brain and spinal cord, abdominal MICTs, and detection of brain stem and spinal cord tumors, multiple pancreatic cysts. We performed resection trepanation of the posterior cranial fossa and microsurgical total removal of hemangioblastoma of the medulla oblongata. After 1.5 years the patient is diagnosed with Hodgkins disease and several courses of chemotherapy are carried out, reaching full remission, confirmed by PET with CT. 14 months later, the patient consulted an ophthalmologist due to visual impairment and floating opacities in her left eye. The ophthalmologic examination for the first time revealed multiple bilateral retinal hemangiomas and vitreal hemorrhages from tractional retinal tears caused by posterior hyaloid detachment and unrelated to hemangiomas in the left eye. The barrier laser coagulation of the left eye retinal tears was performed, and the observation tactics was adopted.

MANAGEMENT OF RETINAL HEMANGIOBLASTOMA IN VON HIPPEL-LINDAU DISEASE.

To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel-Lindau (VHL) disease. A review of the literature was performed. Consensus was reached among authors regarding current practice, with reference to published data where possible. von Hippel-Lindau disease and its ocular manifestations are relatively rare, and there is limited evidence in the literature on which to base management. There was consensus on core principles, including 1) recognition and diagnosis of von Hippel-Lindau disease when present, with appropriate referral for care of this potentially lethal systemic condition; 2) regular ophthalmic evaluation for individuals with von Hippel-Lindau disease, to identify and offer timely treatment for new or active retinal hemangioblastomas; 3) ablative treatment of retinal hemangioblastomas that can be safely destroyed, to lower risk of vision loss; 4) observation or consideration of nonablative treatments for retinal hemangioblastomas that cannot be safely destroyed; and 5) observation of asymptomatic retinal vascular proliferation, with consideration of vitrectomy for lesions exerting effects on vision. Ocular outcomes can be gratifying in many cases with appropriate management. Improved understanding of the molecular basis for the disease creates an opportunity for rational design of better therapies.

MON-324 Bilateral Scrotal Masses as a Clue to Diagnosis of Von Hippel-Lindau Disease

Introduction: Scrotal mass is a common clinical problem among men of all ages. The etiologies range from benign to malignancy. We herein report an insulin-treated patient with a 10-year history of bilateral benign scrotal masses. An advanced stage of renal cell carcinoma and pancreatic cysts were discovered due to the presentation of metastatic pleural effusion. Genetic test confirmed von Hippel-Lindau (VHL) disease. Case report: A 42-year-old man came to emergency department with progressive dyspnea on exertion for 1 month. He was diagnosed as type 1 diabetes mellitus since 20 years ago. Other underlying diseases were hypertension and dyslipidemia. Ten years ago, he had a history of bilateral scrotal masses that had been diagnosed as benign cysts and underwent cyst removal. After careful physical examination and chest x-ray, unilateral pleural effusion was found. The pleural effusion profile was compatible with metastatic effusion. Computed tomography of the chest and abdomen showed multiple lung nodules accompanying with moderate left pleural effusion and mediastinal lymphadenopathy. A 7.6-cm left renal mass with invasion to the left renal vein and a few small hypodense cysts at right kidney were demonstrated. Diffuse pancreatic cysts with calcification were also found. Clear cell renal cell carcinoma was confirmed by renal biopsy. He had received palliative treatment with Pazopanib. After meticulous review of clinical information, VHL was suspected. The cause of diabetes mellitus may be from pancreatic etiology rather than type 1 diabetes mellitus. Family history revealed intracranial tumor in his brother, father and grandfather. Review of ultrasonography of the testes showed bilateral mixed solid/cystic masses. Despite normal testis or epididymis cannot be identified, radiographic findings compatible with bilateral papillary cystadenomas of the epididymis. These bilateral lesions are virtually pathognomonic of VHL disease. In contrast, unilateral lesion can be found in general population. Genetic test for VHL gene was performed and reported heterozygous nonsense mutation of c.263G>A (p.Trp88Stop) in exon 1 of VHL gene. Unfortunately, the patient was passed away in the next few months after diagnosis of renal cell carcinoma. Conclusions: Bilateral papillary cystadenomas of the epididymis are usually needed work up for VHL disease. Early recognition of common clinical problem may lead to the early diagnosis of a rare serious condition.

Dysphagia: an unusual presentation of Von Hippel-Lindau disease

A 25-year-old man presented with 2-week history of progressively worsening dysphagia to solids and liquids. There was no history of anorexia or significant weight loss. On examination, his blood pressure...

Imaging spectrum of von hippel–lindau disease

Von Hippel–Lindau (VHL) disease is a rare phakomatosis with autosomal dominant inheritance. It is the result of inactivation of tumor suppressor gene located on short arm of chromosome 3 and is characterized by the development of a variety of benign and malignant tumors of various organs. These include retinal and central nervous system hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytomas, pancreatic cysts and tumors, epididymal cystadenoma, and ductal ectasia of rete testis. Imaging plays a key role in the diagnosis of VHL disease. It is also useful for screening of patients with family history of VHL disease and in follow-up after treatment. This coupled with advanced surgical management helps in reducing the morbidity and mortality in VHL. The aim of this pictorial essay is to demonstrate the imaging spectrum of VHL disease.

Bilateral Optic Nerve Head Angiomas and Retrobulbar Haemangioblastomas in von Hippel-Lindau Disease

A 39-year-old man presented with progressive visual loss in both eyes. His past medical history was remarkable for biopsy-proven bilateral adrenal phaeochromocytomas. Ophthalmoscopy revealed an optic nerve head angioma and macular lipid exudates in the right eye and a regressed optic nerve head angioma in the left eye. A fluorescein angiogram revealed a lobulated pattern of leakage and venous staining from the optic nerve head angioma. Brain and orbital magnetic resonance imaging showed haemangioblastomas of the right intraorbital and left paraclinoid optic nerves and in the left cerebellopontine angle area. These findings were consistent with a clinical diagnosis of von Hippel-Lindau disease.

Spinal Hemangioblastomas in Von Hippel-Lindau Disease Mimicking a Spinal Dural Arteriovenous Fistula

Introduction Spinal hemangioblastomas (HBs) are rare tumors that are closely associated with a diagnosis of Von Hippel-Lindau disease (VHL). A tissue diagnosis is needed to make the diagnosis of HB because many other entities can present similarly, which may require different management strategies. We present the first case in the literature of multiple intramedullary spinal HBs and VHL that mimicked a spinal dural arteriovenous fistula (dAVF) on radiological imaging. Material and Method Case illustration and literature review. Results A 60-year-old man was referred to our clinic for evaluation of progressive radiculomyelopathy and evidence of a T10 dAVF on MRI and MRA. MRI demonstrated perimedullar hypervascularity dorsal to the spinal cord from T10 to L1, and associated T2 signal change within the spinal cord. Prominent radicular arteries were identified at the exiting right T10 nerve root sleeve which was suspicious for the fistulous point. The patient underwent a T10-T12 laminoplasty for intradural exploration and possible ligation of the fistula; however, intraoperative findings included multiple small intra- and extramedullary vascular nodules along the spinal cord. Six lesions were biopsied, revealing a diagnosis of HB and VHL. Indocyanine green angiography (ICG) was used to rule out a concomitant dAVF. He is being managed expectantly and undergoing routine screening for VHL. He was discharged on postoperative day 3, and he reported symptom improvement at 2-week follow-up. Conclusion The present case is the first reported in the literature to describe multiple spinal HBs, in the setting of VHL, that appeared to be dAVF preoperatively. The patient's late clinical presentation, the greater degree of associated hypervascularity, and atypical vascular morphology were unique features, which highlight the diversity of this disease. Disclosure of Interest None declared References Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 2003;98(1):82–94 Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990;77(283):1151–1163 Murota T, Symon L. Surgical management of hemangioblastoma of the spinal cord: a report of 18 cases. Neurosurgery 1989;25(5):699–707, discussion 708 Neumann HP. Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1987;16(3):220–226 Yasargil MG, Antic J, Laciga R, de Preux J, Fideler RW, Boone SC. The microsurgical removal of intramedullary spinal hemangioblastomas. Report of twelve cases and a review of the literature. Surg Neurol 1976; (3):141–148 Ammerman JM, Lonser RR, Dambrosia J, Butman JA, Oldfield EH. Long-term natural history of hemangioblastomas in patients with von Hippel-Lindau disease: implications for treatment. J Neurosurg 2006;105(2):248–255 Killory BD, Nakaji P, Maughan PH, Wait SD, Spetzler RF. Evaluation of angiographically occult spinal dural arteriovenous fistulae with surgical microscope-integrated intraoperative near-infrared indocyanine green angiography: report of 3 cases. Neurosurgery 2011;68(3):781-787, discussion 787 Wong GK, Zhu XL, Ng HK, et al. Hemangioblastoma of filum terminale associated with arteriovenous shunting. Surg Neurol 2007;68(2):211–214, discussion 214–215 Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 2003;98(1):106–116 Tamura Y, Hirota Y, Miyata S, Yamada Y, Tucker A, Kuroiwa T. The use of intraoperative near-infrared indocyanine green videoangiography in the microscopic resection of hemangioblastomas. Acta Neurochir (Wien) 2012;154(8):1407–1412, discussion 1412 Cramer F, Kimsey MW. 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A 10-year retrospective study of hemangioblastomas of the central nervous system with reference to von Hippel–Lindau (VHL) disease

We aimed to analyze the clinical, radiological, surgicopathological and clinical outcome data of patients who underwent surgery for central nervous system (CNS) hemangioblastoma (HBL) with or without von Hippel–Lindau (VHL) disease. The clinico pathological and radiological findings, management and clinical outcome of patients with CNS HBL (operated between 2000 and 2009) were analyzed retrospectively. The differences between sporadic and VHL-associated HBL were analyzed. Forty-nine patients (28 male, 21 female) underwent surgery for CNS hemangioblastoma. Thirty-nine patients (80%) harbored sporadic HBL whereas 10 (20%) had VHL disease. The mean age at diagnosis for VHL-associated HBL was 32 years when compared to 40 years in sporadic HBL. The lesions were solitary in 41 patients and multiple in eight. The cerebellum was the most common site of HBL (35/49, 71%). Six patients with sporadic and two with VHL disease had spinal lesions. On imaging (available in 43/49 patients), a cyst with a mural nodule was the most common finding, seen in 16 patients (37.2%) whereas nine patients (21%) had solid and cystic lesions. Clinical presentation, radiological features, and histomorphology of HBL with or without VHL disease were similar. Multiple cysts in the pancreas, kidney, broad ligament, epididymis, clear cell renal cell carcinoma, phaeochromocytoma and retinal angiomas were the visceral manifestations seen in patients with VHL disease. Of all patients with VHL disease, three required multiple surgeries for new lesions and one died of renal failure and sepsis. Among the patients with sporadic disease (31/39), two died of surgical complications, one died of postoperative sepsis, three were lost to follow-up and the remainder had resolution of symptoms at 1 year following surgery. We concluded that the diagnosis of VHL disease is important as management is more difficult and lifelong follow-up and counseling are required in these patients and for their at-risk relatives.

Serous Cystic Neoplasms of the Whole Pancreas in a Patient with von Hippel-Lindau Disease

We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare.

Metachronous Pituitary Stalk And Cerebellar Hemangioblastomas In A Patient Without Von Hippel-Lindau Disease: Case Report And Review Of Literature

Background: Hemangioblastomas (HBs) are benign neoplasms of the central nervous system (CNS) that account for 10–15% of posterior fossa tumors in adults. HBs most commonly arise in the cerebellum but also occur in the spinal cord and medulla. They occur sporadically as solitary lesions or in association with von Hippel-Lindau (VHL) disease and are usually multiple. HBs can arise in the supratentorial space (>100 reported cases) but only 16 cases of pituitary stalk HBs have been reported—87.5% of which occurred in the setting of VHL disease. Although multiple, metachronous and disseminated HBs can occur in the setting of VHL disease, there are no reported cases of focal, metachronous HBs in patients without this disease. Case Description: We report the case of a 61-year old man with no personal or family history of VHL disease who presented with a pituitary stalk HB 9 years after complete resection of a cerebellar HB. He underwent complete resection complicated by diabetes insipidis and visual field deterioration.Conclusion: The occurrence of HB at different times and in disparate locations within the CNS is not synonymous with the diagnosis of VHL disease. While diffuse dissemination has been reported following surgery, this is the first reported case of a focal metachronous HBs arising in a patient without VHL disease. Although its unusual location within the pituitary stalk complicated the diagnosis preoperatively, a second HB should be considered in the differential diagnosis and close follow-up may be warranted to identify such lesions prior to irreversible neurological deficits.

Familial and genetic researches on three Chinese families with von Hippel-Lindau disease

Objective: Hemangioblastoma of the central nervous system (CNS) occur as sporadic tumors or as a part of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary tumor syndrome caused by germline mutation of the VHL tumor suppressor gene. This study shows the clinical characteristics of three large Chinese families with VHL disease and evaluates the consequence of the genetic test for the diagnosis of VHL disease and clinical screening of the family members.Methods: DNA is extracted from peripheral blood in 43 members from three large families with VHL disease and amplified by PCR to three exons of the VHL gene. The PCR products were directly sequenced and the mutations compared with the Human Gene Mutation Database.Results: The ages of the patients who are given the initial diagnosis ranged from 16 to 47 years (mean: 31 years), and the mean time was 17.3 months (2–30 months) from the emergence of the symptom to patients' first visit. Furthermore, the gender distribution was 20% female (4) and 80% male (16). Twenty VHL disease patients in the three families have the most common manifestation of CNS hemangioblastoma. The cytosine replaced the 716th guanine on four patients and three carriers of virulence gene from the first family, which made the 168th serine replaced by threonine. And no mutation was found on the 22 members of the second family. Meanwhile, it was also found that the guanine replaced the 559th cytosine on one patient and two carriers from the third family, which made the 116th leucine replaced by valine.Conclusion: The DNA analysis of VHL germline mutations is clearly superior to clinical information to diagnose VHL disease. The CNS hemangioblastoma is the early manifestation in VHL disease. It is recommended that every patient with CNS hemangioblastoma should be screened for VHL gene mutation. The test for the VHL gene plays a key role in the discovery of asymptomatic patients and the carriers of virulence gene.

4.001 Twin pregnancy after double factor PGD analysis: diagnosis of Von Hippel-Lindau disease and aneuploidy screening

4.001 Twin pregnancy after double factor PGD analysis: diagnosis of Von Hippel-Lindau disease and aneuploidy screening

Preimplantation genetic diagnosis of Von Hippel-Lindau disease cancer syndrome by combined mutation and segregation analysis

Von Hippel-Lindau (VHL) disease is an autosomal dominant cancer syndrome, associated with the development of tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The VHL disease tumor suppressor gene (VHL) maps to 3p25-p26 and mutations ranging from a single base change to large deletions have been detected in patients with VHL disease. We developed a single cell PCR protocol for preimplantation genetic diagnosis (PGD) of VHL disease to select unaffected embryos on the basis of the detection of the specific mutation and segregation analysis of polymorphic linked markers. Multiplex-nested PCR using single buccal cells of an affected individual were performed in order to test the accuracy and reliability of this single-cell protocol. For each locus tested, amplification efficiency was 83% to 87% and allelic drop-out rates ranged from 12% to 8%. Three VHL disease PGD cycles were performed on cells from a couple with paternal transmission of a 436delC mutation in exon 2 of the VHL gene, leading to the identification of three unaffected embryos. Independent of the mutation present, this general PGD protocol for the diagnosis of VHL disease can be used in families informative for either the D3S1038 or D3S1317 microsatellite markers.

The impact of molecular genetic analysis of theVHL gene in patients with haemangioblastomas of the central nervous system

OBJECTIVESHaemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with the major additional components retinal angioma, renal cancer, and...

Molecular diagnosis of von Hippel-Lindau disease in a kindred with a predominance of familial phaeochromocytoma.

To study the presence of germline mutations in the von Hippel-Lindau gene (vhl) in a kindred with a predominance of familial phaeochromocytoma in order to confirm the diagnosis of von Hippel-Lindau disease (VHLD) as well as to identify asymptomatic members. DNA extracted from peripheral blood was amplified by the polymerase chain reaction using oligonucleotide primers corresponding to exon 3 of the vhl gene. Specific mutations in codon 238 were screened by restriction endonuclease digestion of PCR products with Msp I. The results were confirmed by DNA sequence analysis. Two generations of a family consisting of 15 individuals were studied. A germline missense point mutation at codon 238 of the vhl gene (CGG-->TGG; Arg-->Trp) was detected in all patients with phaeochromocytoma and in only one of the asymptomatic family members. Mutational analysis of the vhl gene in patients with familial phaeochromocytoma may permit specific diagnosis of von Hippel-Lindau disease, and is a good method for the identification of asymptomatic individuals at risk of von Hippel-Lindau disease.

Molecular genetic diagnosis of von Hippel-Lindau disease: analysis of five Japanese families.

We analyzed deoxyribonucleic acids from blood samples of five Japanese von Hippel‐Lindau (VHL) disease families (three familial cases, two new mutations) for the presence of VHL gene mutations by single‐strand conformational polymorphism analysis and direct sequencing. Four of the five families showed germ line mutations in VHL gene, comprising 2 missense mutations, 1 deletion, and 1 splice‐site mutation. Two families had VHL gene mutations at exon 1; 1 family at exon 3; and 1 family at the splice‐site adjacent to exon 3. Presymptomatic patients were accurately diagnosed by these methods. However, one family did not show a VHL gene mutation in the germ line but showed a somatic mutation at exon 2 in the hemangioblastoma tissue. The consequence of the somatic mutation was a microdeletion leading to a frameshift mutation. Our study is the first report of VHL gene analyses of Japanese VHL disease families, and suggests that not only germ line mutation, but also somatic mutation can lead to development of a tumor associated with the VHL disease.