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The development of hereditary von Hippel-Lindau (VHL) disease and the majority of sporadic kidney cancers are due to the functional inactivation of the VHL gene. The product of the VHL gene, pVHL, in association with elongins B and C, cullin 2, and Rbx1 form an E3 ubiquitin-ligase complex VEC that targets the alpha subunits of hypoxia-inducible factor (HIF) for ubiquitination. Ubiquitin-tagged HIF-alpha proteins are subsequently degraded by the common 26S proteasome. pVHL functions as the substrate-docking interface that specifically recognizes prolyl-hydroxylated HIF-alpha. This hydroxylation occurs only in the presence of oxygen or normoxia. Thus, under hypoxia, HIF-alpha subunits are no longer subjected to degradation and are thereby able to dimerize with the common and constitutively stable beta subunits. The heterodimeric HIFs upregulate a myriad of hypoxia-inducible genes, triggering our physiologic response to hypoxia. Inappropriate accumulations of HIF-alpha in VHL disease are believed to contribute to the pathogenesis via the upregulation of several of these HIF target genes. Our current molecular understanding of the roles of HIF and pVHL in the development of VHL-associated clear-cell renal cell carcinoma (CC-RCC) is the focus of this review., (Copyright 2004 S. Karger AG, Basel)

Purpose of Review: Although pathological findings including tumour grade and tumour-node-metastasis stage provide prognostic information, the outcome for patients with renal cell carcinoma is occasionally unpredictable. Many studies have been undertaken to improve prediction of the prognosis of renal cell carcinoma, along with efforts to clarify the pathogenesis of renal cell carcinoma at the molecular level. This article reviews the advances in renal cell carcinoma research relevant to pathology published between 1 May 2002 and 30 April 2003., Recent Findings: The establishment of a strict tumour grading system or adding microscopic venous invasion or tumour necrosis is potentially useful for predicting patient outcomes. The contribution of the von Hippel-Lindau-related pathway in early carcinogenesis has been partly revealed with regard to angiogenesis and cell cycle control. Tumour development in renal cell carcinoma can be considered as accumulating heterogenous molecular events related to cytokine production, cell cycle control, anti-apoptotic signal machinery and angiogenesis., Summary: Finding the target genes related to the von Hippel-Lindau pathway may explain the resistance of chemotherapy, and also provide a clue to finding a novel therapeutic option. Molecular targeting therapy can be applicable after more general molecules leading to tumour development and the metastasis of renal cell carcinoma have been identified.

Purpose: To assess the retinal function in patients with von Hippel-Lindau disease (VHL)., Patients: Studies were undertaken in 12 patients (17 eyes) with detected VHL gene mutation and 12 normal healthy controls (17 eyes)., Methods: Pattern ERG (PERG), standard flash electroretinogram (ERG) recordings were performed in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards., Results: In VHL patients, electrophysiological statistically significant changes were found. In PERG examination, increased latency of P50 was found in the total VHL group (p < 0.02) and in the VHL subgroup with retinal angiomas (p < 0.04). In ERG examination, photopic b-wave latency was increased in the total VHL group (p < 0.03) and also in the VHL subgroup without retinal angiomas (p < 0.05). In OPs, latency increase of OP2, OP3 waves and reduced amplitude of OP3 wave in the total VHL group (OP2 latency, p < 0.05; OP3 latency, p < 0.01; OP3 amplitude, p < 0.03) and in the VHL subgroup with retinal angiomas (OP2 latency, p < 0.02; OP3 latency, p < .008; OP3 amplitude, p < 0.02) were obtained., Conclusions: It can be hypothesized that dysfunction of the inner retinal layer is present in individuals with VHL disease even in patients without retinal angiomas.

Recently, work on the mechanism of action of the von Hippel-Lindau tumour suppressor protein (pVHL) and studies on hypoxic gene regulation have converged, providing insights into both cellular oxygen sensing and cancer pathogenesis. pVHL is the recognition component of the E3-ubiquitin ligase complex involved in the degradation of hypoxia-inducible factor-1 (HIF) alpha-subunits, a process regulated by oxygen availability and blocked by disease causing pVHL mutations. In normoxic cells, pVHL targeting of HIF-alpha subunits follows hydroxylation of critical HIF prolyl residues by a group of oxygen, 2-oxoglutarate- and iron-dependent enzymes. In this review, we outline current understanding of HIF/pVHL/prolyl hydroxylase pathway and consider the implications for VHL-associated cancer., (Copyright 2002 Elsevier Science Ltd.)

Object: Hemangioblastomas of the brainstem constitute 5 to 10% of central nervous system (CNS) tumors in patients with von Hippel-Lindau (VHL) disease. At present, optimal management of brainstem hemangioblastomas associated with VHL disease is incompletely defined. In an attempt to clarify some of the uncertainty about the operative treatment of these lesions and its outcome, the authors reviewed all cases of VHL disease in which resection of brainstem hemangioblastomas was performed at the National Institutes of Health during a 10-year period., Methods: Twelve consecutive patients with VHL disease (six male and six female patients [mean age 31.7 +/- 9 years; range 15-46 years]) who underwent 13 operations to remove 17 brainstem hemangioblastomas were included in this study (mean follow-up period, 88.4 +/- 37.4 months; range 37-144 months). Serial examinations, hospital charts, magnetic resonance images, and operative records were reviewed. To evaluate clinical course, clinical grades were assigned to each patient before and after surgery. Preoperative neurological function was the best predictor of long-term outcome. In addition, patients who underwent CNS surgeries for hemangioblastomas were more likely to improve or to remain neurologically stable. Tumor or cyst size, the presence of a cyst, or the location of the tumor (intramedullary, extramedullary, or mixed; posterior medullary, obex, or lateral) did not affect outcome. No patient was neurologically worse after brainstem surgery. At long-term follow-up review (mean 88.4 months), only one patient had declined neurologically and this was due to the cumulative neurological effects caused by eight additional hemangioblastomas of the spinal cord and their surgical treatment., Conclusions: Brainstem hemangioblastomas in patients with VHL disease can be removed safely; they generally should be resected when they become symptomatic or when the tumor has reached a size such that further growth will increase the risks associated with surgery, or in the presence of an enlarging cyst. Magnetic resonance imaging is usually sufficient for preoperative evaluation and presurgical embolization is unnecessary. The goal of surgery is complete resection of the lesion before the patient experiences a disabling neurological deficit.

Object: Von Hippel-Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients., Methods: Forty-four consecutive patients with VHL disease (26 men and 18 women) who underwent 55 operations with resection of 86 spinal cord hemangioblastomas (mean age at surgery 34 years; range 20-58 years) at the National Institutes of Health were included in this study (mean clinical follow up 44 months). Patient examination, review of hospital charts, operative findings, and magnetic resonance imaging studies were used to analyze surgical management and its outcome. To evaluate the clinical course, clinical grades were assigned to patients before and after surgery. Preoperative neurological status, tumor size, and tumor location were predictive of postoperative outcome. Patients with no or minimal preoperative neurological dysfunction, with lesions smaller than 500 mm3, and with dorsal lesions were more likely to have no or minimal neurological impairment. Syrinx resolution was the result of tumor removal and was not influenced by whether the syrinx cavity was entered., Conclusions: Spinal cord hemangioblastomas can be safely removed in the majority of patients with VHL disease. Generally in these patients, hemangioblastomas of the spinal cord should be removed when they produce symptoms or signs.

Object: Von Hippel-Lindau (VHL) disease is an autosomal-dominant neoplastic syndrome with manifestations in multiple organs, which is evoked by the deletion or mutation of a tumor suppressor gene on chromosome 3p25. Spinal hemangioblastomas (40% of VHL disease-associated lesions of the central nervous system) arise predominantly in the posterior aspect of the spinal cord and are often associated with an intraspinal cyst. Rarely, the tumor develops in the anterior aspect of the spinal cord. Ventral spinal hemangioblastomas are a surgical challenge because of difficult access and because vessels feeding the tumor originate from the anterior spinal artery. The goal of this study was to clarify whether an anterior or posterior surgical approach is better for management of hemangioblastomas of the ventral spinal cord., Method: . The authors performed a retrospective analysis of clinical outcomes and findings on magnetic resonance (MR) imaging studies in eight patients (two women and six men with a mean age of 34 +/- 15 years) who underwent resection of ventral spinal hemangioblastomas (nine tumors: five cervical and four thoracic). Two surgical approaches were used to resect these tumors. A posterior approach was selected to treat five patients (laminectomy and posterior myelotomy in four patients and the posterolateral approach in one patient); an anterior approach (corpectomy and arthrodesis) was selected to treat the remaining three patients. Immediately after surgery, the ability to ambulate remained unchanged in patients in whom an anterior approach had been performed, but deteriorated significantly in patients in whom a posterior approach had been used, because of motor weakness (four of five patients) and/or proprioceptive sensory loss (three of five patients). This difference in ambulation, despite significant improvements over time among patients in the posterior access group, remained significant 6 months after surgery. In all cases, MR images revealed complete resection of the tumor and in five patients significant or complete resolution of the intramedullary cyst was demonstrated (present in six of eight patients)., Conclusions: The outcomes of these eight patients with hemangioblastomas of the ventral spinal cord indicate that both immediate and long-term results are better when an anterior approach is selected for resection.

Object: The goals of this study were to define the natural history and growth pattern of hemangioblastomas of the central nervous system (CNS) that are associated with von Hippel-Lindau (VHL) disease and to correlate features of hemangioblastomas that are associated with the development of symptoms and the need for treatment., Methods: The authors reviewed serial magnetic resonance images and clinical histories of 160 consecutive patients with VHL disease who harbored CNS hemangioblastomas and serially measured the volumes of tumors and associated cysts Six hundred fifty-five hemangioblastomas were identified in the cerebellum (250 tumors), brainstem (64 tumors, all of which were located in the posterior medulla oblongata), spinal cord (331 tumors, 96% of which were located in the posterior half of spinal cord), and the supratentorial brain (10 tumors). The symptoms were related to a mass effect. A serial increase in hemangioblastoma size was observed in cerebellar, brainstem, and spinal cord tumors as patients progressed from being asymptomatic to symptomatic and requiring surgery (p < 0.0001). Twenty-one (72%) of 29 symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of 221 nonsymptomatic cerebellar tumors had tumor-associated cysts (p < 0.0001). Nine (75%) of 12 symptomatic brainstem tumors had associated cysts, compared with only four (8%) of 52 nonsymptomatic brainstem lesions (p < 0.0001). By the time the symptoms appeared and surgery was required, the cyst was larger than the causative tumor; cerebellar and brainstem cysts measured 34 and 19 times the size of their associated tumors at surgery, respectively. Ninety-five percent of symptom-producing spinal hemangioblastomas were associated with syringomyelia. The clinical circumstance was dynamic. Among the 88 patients who had undergone serial imaging for 6 months or longer (median 32 months), 164 (44%) of 373 hemangioblastomas and 37 (67%) of 55 tumor-associated cysts enlarged. No tumors or cysts spontaneously diminished in size. Symptomatic cerebellar and brainstem tumors grew at rates six and nine times greater, respectively, than asymptomatic tumors in the same regions. Cysts enlarged seven (cerebellum) and 15 (brainstem) times faster than the hemangioblastomas causing them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) and then stabilize in a period of arrested growth (quiescent phase). Of 69 patients with documented tumor growth, 18 (26%) harbored tumors with at least two growth phases. Of 160 patients with hemangioblastomas, 34 patients (median follow up 51 months) were found to have 115 new hemangioblastomas and 15 patients new tumor-associated cysts., Conclusion: In this study the authors define the natural history of CNS hemangioblastomas associated with VHL disease. Not only were cysts commonly associated with cerebellar, brainstem, and spinal hemangioblastomas, the pace of enlargement was much faster for cysts than for hemangioblastomas. By the time symptoms appeared, the majority of mass effect-producing symptoms derived from the cyst, rather than from the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth, and many untreated tumors may remain the same size for several years. These characteristics must be considered when determining the optimal timing of screening for individual patients and for evaluating the timing and results of treatment.

Purpose: To present a case of rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome and optic nerve head hemangioblastoma after systemic treatment with the vascular endothelial growth factor (VEGF) receptor inhibitor SU5416., Design: Interventional case report., Methods: Visual function parameters, including visual acuity, automated visual field, and contrast sensitivity, were evaluated using standardized methods repeatedly over a 15-month period. Fundus photographs and fluorescein angiograms were also obtained. Central nervous system lesions were monitored by computed tomography (CT) and magnetic resonance imaging (MRI) scans. Treatment involved the systemic administration of the VEGF receptor inhibitor SU5416., Main Outcome Measures: Clinical presentation, visual acuity using Early Treatment Diabetic Retinopathy Study protocol, Humphrey automated perimetry, (Zeiss Humphrey Systems, Dublin, CA) Vistech contrast sensitivity (Vistech Consultants Inc., Dayton, OH) Farnsworth (Farnsworth-Munsell Color Services, New Windsor, NY) dichotomous panel D-15, retinal photography, fluorescein angiography, and CT and MRI scans., Results: Within 4 weeks of therapy, visual acuity had improved from 20/32(-2) to 20/16(-1), the visual field had expanded from being circumferentially constricted to within 8 degrees of fixation to normal, and contrast sensitivity improved in all but the lowest spatial frequency (1.5 cycles/degree). No change was observed in lesion size by fundus photography. Improvement has been maintained over 18 months with intermittent SU5416 therapy., Conclusions: We report rapid, extensive, and durable recovery of visual function after systemic administration of the VEGF receptor inhibitor SU5416 to a patient with VHL syndrome and optic nerve head hemangioblastoma. These findings suggest that continued evaluation of VEGF inhibitors for ocular neovascular disorders is warranted.

Purpose: To describe disease evolution and clinical follow-up of 10 patients in three Spanish families., Patients and Methods: Patients were contacted through the von Hippel-Lindau Family Alliance (VHLFA). Compilation of medical reports and patient interviews were carried out in May of 2001. This is a retrospective study of a case series., Results: Family history was suggestive of von Hippel-Lindau disease in two of the families. A 'de novo' mutation is described in the third family. The mean patient age is 30.8 (range: 15-53). The age of presentation was < 30 in 9 patients. In 8 of the patients, eye involvement was the first VHL presentation. 7 patients currently have hemangioblastomas of the CNS. Most patients are not participants in management protocols for the coordinate care of their various VHL lesions. 6 patients had documented pancreatic involvement and 3 patients had renal cancer. Clinical screening for occult pheochromocytomas were performed in 5 patients. 4 were deceased from VHL-related complication. Genetic studies had been performed in 4 of the 6 survivors., Conclusions: Disease progression in our series is similar to that previously described for other families. Diagnosis was delayed in two of the families. Suboptimal patient management may have contributed to the high morbidity and mortality.

Metastatic renal cell cancer remains a disease which is difficult to treat medically. Prognosis often depends more on intrinsic disease features than on treatment choices. In this review, we examine novel therapies and scientific directions surrounding the RCC treatment problem. Reports relating chromosomal aberrations and of comparative gene expression analyses relating to RCC, are reviewed briefly. The central role of the von Hippel Lindau protein in clear cell RCC pathogenesis is evident. The limited contribution of conventional cytotoxic chemotherapy is mentioned. Some clinically applied agents whose clinical results are highlighted include 5-FU, retinoids, thalidomide, razoxane and IL-12. Features of the pathophysiology of von Hippel Lindau protein are described, with attention to potential novel therapies targeting HIF-1alpha, VEGF, TGF-beta1 and TGF-alpha pathways. Immunotherapy is being explored in many angles. Most basic are cytokine therapies incorporating new IL-2 and IFN-alpha schedules. Newer cytokine-based drugs include pegylated forms and IL-12. Allogeneic mini-transplantation has generated much interest. Tumour-associated antigens are being used to direct therapy using both identified and non-identified epitopes. A variety of tumour-cell vaccine and dendritic-cell vaccine clinical approaches are discussed. Finally, nephrectomy for known metastatic disease has been demonstrated to be helpful in retrospective and now prospective trials. Resection of metastases is also discussed. We are optimistic that the further clinical development among these novel therapies will improve the outlook for metastatic RCC.

Von Hippel-Lindau disease is a rare autosomal dominant disease with incomplete penetrance and variable expression and is characterized by diffuse haemangioblastomas of the central nervous system and viscera. The majority of the central nervous system lesions are located in the cerebellum. This report describes the successful management with epidural anaesthesia of a woman with a term gestation, von Hippel-Lindau disease and cerebellar haemangioblastoma.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder with variable penetrance. It is mainly characterized by haemangioblastomas of the retina and central nervous system. Because of physiological effects of uterine contractions, labour and spontaneous vaginal delivery increase the risk of disrupting central nervous system haemangiblastomas. We report the case of a 28-year-old woman with an history of VHL disease who had an epidural anaesthesia for labour and for Caesarean section performed because of failure to progress and of fetal distress. The overall maternal and neonatal outcomes were excellent.

von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1alpha and 2alpha, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations of the VHL tumour suppressor gene. The VHL gene product, pVHL, forms multiprotein complexes that contain elongin B, elongin C and Cul-2, and negatively regulates hypoxia-inducible mRNAs. pVHL is suspected to play a role in ubiquitination given the similarity of elongin C and Cul-2 with Skp1 and Cdc53, respectively. pVHL can also interact with fibronectin and is required for the assembly of a fibronectin matrix. Finally, pVHL, at least indirectly, plays a role in the ability of cells to exit the cell cycle. Thus, pVHL is a tumour suppressor protein that regulates angiogenesis, extracellular matrix formation and the cell cycle.

We retrospectively evaluated maternal and fetal outcomes in a series of women with von Hippel-Lindau disease. Data resulted from 56 pregnancies in 30 women. Symptoms related to von Hippel-Lindau disease occurred in 3 of 56 pregnancies. In this unselected group of patients with von Hippel-Lindau disease, most pregnancies had a favorable outcome with a 96.4% survival rate for fetuses and a 5.4 % von Hippel-Lindau-specific morbidity rate in the mothers.

The product of the von Hippel-Lindau (VHL) tumor suppressor gene, the gene inactivated in VHL disease and in sporadic clear-cell renal carcinomas, has recently been shown to have as a functional target the transcription elongation complex, elongin (also called SIII). Here it is shown that there is a tightly regulated, cell-density-dependent transport of VHL into and/or out of the nucleus. In densely grown cells, the VHL protein is predominantly in the cytoplasm, whereas in sparse cultures, most of the protein can be detected in the nucleus. We have identified a putative nuclear localization signal in the first 60 and first 28 amino acids of the human and rat VHL protein, respectively. Sequences in the C-terminal region of the VHL protein may also be required for localization to the cytosol. These findings provide the initial indication of a novel cell density-dependent pathway that is responsible for the regulation of VHL cellular localization.

Von Hippel-Lindau disease is generally considered to be a condition with very high penetrance, and individuals who live beyond the age of 60 years without showing any features of the disease, despite undoubtedly carrying the gene defect, have not previously been clearly described. The case is presented of a 65-year-old woman, who had four siblings affected with von Hippel-Lindau disease and had six children, three of whom died young with complications of von Hippel-Lindau disease. Although she is an obligate gene carrier, she has not developed any significant manifestations of the disease despite careful screening for the neurological, retinal and renal complications.

A surgical series of 59 patients with cerebellar or spinal cord hemangioblastomas or von Hippel-Lindau's (VHL) syndrome is analyzed. The presence of the tumor is easily detected by Computerized Tomography (CT) and Nuclear Magnetic Resonance (NMR), but angiography is still necessary for a correct surgical planning. The value of a sharp distinction among patients with single hemangioblastomas and the ones with Lindau's disease and VHL syndrome is stressed. In fact patients with single cerebellar or spinal hemangioblastomas have a good prognosis, while patients with disseminated hemangioblastomas have a rather poor outlook. Neuropathological studies with immunohistochemical techniques have been performed to identify the nature of the stromal cells of the hemangioblastomas: their origin from glial, endothelial and monociticphagocitic elements seems excluded.

A 59-year-old woman with von Hippel-Lindau disease developed erythrocytosis and a recurrent intracranial hemangioblastoma. Radioimmunoassay showed an elevated level of erythropoietin in her serum. Cyst fluid from the tumor also contained erythropoietin, concentrated a thousandfold relative to the serum level. Production of erythropoietin by hemangioblastomas may explain the erythrocytosis present in some patients with von Hippel-Lindau disease.

von Hippel-Lindau disease is a multi-system disorder characterized by hemangioblastic lesions of the central nervous system and visceral organs. Angiomatosis retinae is often the first observable manifestation of von Hippel-Lindau disease. Optometry may be the initial point of entry into the health care system for the von Hippel-Lindau patient. As such, the eye care practitioner should be aware of the diffuse nature of the disease and initiate the search for silent, possibly lethal, lesions associated with the disease. Management may involve consultation with a neurosurgeon, internist, and retinal specialist. The presentation and clinical course of a young man with von Hippel-Lindau disease is presented.

The neurocutaneous diseases are a loosely bound group of clinical entities that were initially considered to have dysplastic and/or neoplastic changes of the nervous system and skin, though other organ systems are frequently involved. During the last several decades a variety of additional diseases have been included in this disease category despite their not having any known cutaneous abnormality. The major neurocutaneous syndromes are considered in this review.

The authors report a case of Hippel's angiomatosis successfully treated with contact beta irradiation. The area of the multiplex retinal angioma and the accompanying retinal detachment was irradiated with a 106Ru/106Rh radioactive applicator. Hemodynamic changes due to irradiation were followed up in the ipsilateral ophthalmic artery with transcranial Doppler sonography. Scarring was also demonstrated by fluorescein angiography and A- and B-scan ultrasonography. Irradiation caused the narrowing and later the occlusion of the precapillaries and capillaries (i.e. the resistance vessels) and that of the shunts inside the angioma; consequently, vascular resistance increased. Transcranial Doppler sonographic recordings showed a decrease in blood flow velocity as compared to pathologically increased blood flow velocity in angiomas, and a gradual increase in vascular resistance which was lower before treatment.

Von Hippel-Lindau disease (VHLD) is a rare disorder known to occur with pheochromocytoma. We report a case with this association and also with pancreatic apudoma. We believe that this is the fifth reported case of this triad, which represents an overlap in the multiple endocrine neoplasia (MEN) classification. Many recent reports of overlap of MEN syndromes challenge the validity of this classification. New understanding of the embryologic origin of cells of endocrine organs has led to the elucidation of the APUD (amine precursor uptake and decarboxylation)-neuroendocrine system. Integration of the APUD system may be important to understanding the pathogenesis of the MEN-like syndromes as well as their relationship to the neurocutaneous syndromes. Any endocrine tumor or neurocutaneous syndrome should be evaluated to exclude a spectrum of possible associations.

An unfamiliar concept, the presence of centripetal flow in the subretinal space, is proposed as explaining the maculopathy of Coats's and von Hippel-Lindau's syndromes. If this flow exists, our recognition of it will contribute to understanding the etiology of other posterior-pole disorders, and possibly to their treatment as well. The obvious and important posterior-pole disorder to which this is applicable is macular degeneration, especially diskiform macular degeneration. Laser treatments designed to reduce the amount of peripheral retinal biologic waste production should reduce the work load of the macular disposal system, thereby prolonging its useful life.

A 30-year-old man was found to have juxtapapillary exophytic capillary hemangioma complicated by circinate maculopathy and peripapillary exudative retinal detachment. The diagnosis was made from the appearance of the tumor and confirmed by fluorescein angiography. The presence of intermittent hematuria associated with a cystic kidney supported the diagnosis of von- Hippel-Lindau disease. subsequently, and attempt to treat the vascular lesion by yellow krypton (586 nm) laser photocoagulation failed to arrest the progression of the exudative retinal detachment, which finally became total.

Thirty-seven cases of von Hippel-Lindau syndrome are reported. The urinary tract was studied in 23 patients; 15 of them had the renal lesions. Eight of these 15 patients had renal cell carcinoma, which was bilateral in six. Because 80 percent of these patients are seen initially by neurologists or ophthalmologists, the potential for the development of renal cell carcinoma in these patients, the familial nature of the disorder, and the need for early urologic investigations and subsequent close follow-up are emphasized.

Von Hippel-Lindau disease is a hereditary neoplastic syndrome that generally manifests in early adulthood but does present occasionally in adolescence. In the past, diagnosis and management of this disorder fell within the domain of internists and surgeons. Because pediatricians are now seeing older patients, they must learn to recognize the various components of this disorder. Additionally, they must be able to assure appropriate medical evaluation and follow-up and also arrange for genetic counseling. Pediatricians already attuned to the benefits of preventive medicine should find themselves uniquely qualified to provide the level of care that this disease requires.