7428

VHL

HRCA1|RCA1|VHL1;von Hippel-Lindau tumor suppressor;VHL;von Hippel-Lindau tumor suppressor

elongin binding protein|pVHL|protein G7|von Hippel-Lindau disease tumor suppressor

3p25.3

protein-coding

tumor suppressor gene "knockout" models would predict that children who present with hemangioblastoma are likely to harbor germline mutation of the von Hippel-Lindau gene. We screened 6 pediatric patients with cerebellar hemangioblastoma for germline or somatic mutations of the von Hippel-Lindau gene. Two had prior clinical manifestations of von Hippel-Lindau disease and, as expected, had germline von Hippel-Lindau gene mutations. Four children with solitary hemangioblastoma did not have a detectable germline deletion, rearrangement, or point mutation in their von Hippel-Lindau gene, and tumor specimens in 3 of these 4 showed no somatic von Hippel-Lindau allelic loss. Solitary cerebellar hemangioblastoma in children does not predict a germline or somatic mutation in the von Hippel-Lindau tumor suppressor gene. The tumorigenesis of hemangioblastoma in younger patients may differ from that in adults, and may involve a molecular process unrelated to the von Hippel-Lindau tumor suppressor pathway.

Pheochromocytomas are frequently associated with inherited cancer syndromes suchas von Hippel-Lindau disease (VHL). Retinal angioma and hemangioblastomas of thecentral nervous system are hallmarks of VHL, but its clinical variety is remarkably broad. Pheochromocytomas as the sole or first manifestation of VHL are rare but have been observed. In this case report, the authors describe an unusual case of initial collapse, seizures, and hypertensive crisis in a child who laterwas found to have multiple extraadrenal pheochromocytomas. Molecular diagnosticsrevealed a novel point mutation in the VHL gene (VHL nt. 406 T-->G). Only 7 months after the first lesions had been removed, a new paraganglioma developed in the contralateral periadrenal region. When encountering pheochromocytomas in children, the clinician should be aware that an associated tumor syndrome might be present, and appropriate molecular screening should be initiated. Molecular genetics aid in the clinical decision-making and clinical management of individual patients with pheochromocytoma.

BACKGROUND: pediatric rhabdoid tumor of the kidney is regarded as a distinct neoplasm, whereas rhabdoid differentiation in adult renal cell carcinoma is usually found in association with conventional (clear cell) tumor, from which itis thought to evolve. OBJECTIVE: To further characterize the rhabdoid phenotype in adult renal cell carcinoma and to determine its origin by genetic analysis. DESIGN: We performed histologic, immunophenotypic, and genetic analyses on 5 cases of adult renal cell carcinoma with rhabdoid differentiation, 3 samples of adjacent conventional (clear cell) tumor, and 6 conventional (clear cell) control tumors. RESULTS: Rhabdoid tumors differed from conventional (clear cell) carcinoma as follows: (1) macroscopically, rhabdoid tumors were solid white uniform masses; (2) microscopically, they had large rhabdoid cells with abundanteosinophilic cytoplasm, reduced lipid content, and the absence of a branching vascular pattern; and (3) biologically, they had a high metastatic potential. Despite these differences, loss of chromosome 3p in both the rhabdoid and clear cell carcinoma samples from 1 patient suggested a clonal origin. An identical mutation of the VHL gene in both rhabdoid and clear cell tumor samples from 2 patients confirmed a clonal origin for the histologically distinct tumor types in those cases. CONCLUSION: Adult rhabdoid renal cell carcinoma can in some cases arise from conventional (clear cell) renal carcinoma and should be considered a clinically important form of renal cell carcinoma separate from, but analogous to, sarcomatoid change.

Renal cell carcinomas (RCCs) are rare in the pediatric population; when they occur, a significant percentage are associated with specific cytogenetic abnormalities and germline mutations. These include mutations in the von Hippel-Lindau ( VHL) gene and translocations involving the TFE3 transcription factor gene on Xp11.2. Here we report a case of a 3-year-old child with a large renal mass. Histologic examination of the tumor showed a predominantly nested growth pattern with some papillary foci. Cytogenetic analysis revealed a karyotype of t(X;1)(p11.2; p34.3), consistent with a TFE3-associated RCC. Interestingly, sequencing of the patient's VHL gene revealed a single point mutation, previously seen in a subgroup of patients with von Hippel-Lindau disease. This is the first reported case, to our knowledge, of t(X;1)-associatedRCC in a patient with concurrent VHL gene mutation.#CI- Copyright 2004 Society for pediatric Pathology

We report a novel germ-line point mutation in the von Hippel-Lindau (vhl) gene in a family with childhood occurrence of isolated pheochromocytoma. Two members of this family (the father and his son) were affected. The son had bilateral adrenal pheochromocytoma and the father had one adrenal and one extra-adrenal localization. Both patients presented cardiac arrest while exposed to surgical stress and severe hypoglycemia was registered in the son. The outcome was uneventful. A DNA sequence analysis of vhl tumor suppressor gene revealed the L163R mutation. This new mutation may be specifically associated with the von Hippel-Lindau type 2C disease phenotype. Whether this mutation is linked to the metabolic alterations developed by these patients remains to be determined.

Pheochromocytoma (PCC) in children is rare, genetically not well described, and often related to a poor prognosis. We detected genomic imbalances in ALL 14 tumors from children analyzed by comparative genomic hybridization. A combinatorial loss of chromatin from 3p and 11p was a common feature in 10 of 14(72%) patients, which was a result of either a loss of a total chromosome 3 and a total chromosome 11 in 6 of 10 patients, or confined deletions of their p arms in 4 of 10 patients. ALL patients exhibiting a loss of 3p and 11p carried VHL mutations. The VHL mutations were constitutive in 9 cases and somatic and restricted to tumor DNA in the remaining tumor. On the other hand, VHL mutationswere absent in 4 patients, 2 who had other familial syndromes (NF1, SDHD) and 2 with unknown etiology. Our data show that the pattern of imbalances in the tumorDNA of PCC patients strongly correlated with an underlying familial VHL mutation. Furthermore, we show that true sporadic PCC is rare in childhood. Thus, childrenwith PCC should be checked for a related predisposing gene. This would also identify familial syndrome patients requiring long-term monitoring for other syndrome-related malignancies.#CI- (c) 2006 Wiley-Liss, Inc.

Pheochromocytomas (PCCs) are rare catecholamine-producing tumors of the adrenal gland which may also occur elsewhere in the abdomen and are then called paragangliomas. A proportion of PCCs occurs in hereditary cancer syndromes, including multiple endocrine neoplasia Type 2 (MEN2), caused by mutations in theRET proto-oncogene, von Hippel-Lindau (VHL) disease, caused by VHL gene abnormalities, and the pheochromocytoma-paraganglioma (PCC-PGL) syndrome, causedby mutations in SDHB and SDHD. Since a proportion of PCCs occurs in children we hypothesized that germline mutations in RET, VHL, succinate dehydrogenase subunit B (SDHB), and subunit D (SDHD) occur more frequently in the pediatric age range.From our single-institution collection of PCCs, we have selected 10 cases that occurred in individuals up to 18 years of age at diagnosis. In these, we have performed mutation analysis on normal and tumor tissues for exons 10, 11, and 16of RET and for the entire coding sequence of VHL, SDHB, and SDHD. The 10 patients include 7 boys and 3 girls, with an average age of 15.5 years (range 9-18 years). Two patients had germline RET exon 11 mutations (C634R) and 1 patient had an R64P germline mutation in the VHL gene. In the remaining 7 patients there was one patient from a family fulfilling the clinical criteria for VHL disease. ALL tumors were benign (average follow-up: 12 years) and were located in the adrenal. From our findings we conclude that (a) a large proportion (40%) of pediatric PCCpatients is diagnosed in the context of inherited cancer syndromes, and (b) candidate gene analysis appears to be indicated to detect germline mutations.

Pheochromocytomas (PCCs) are rare catecholamine-producing tumors of the adrenal gland which may also occur elsewhere in the abdomen and are then called paragangliomas. A proportion of PCCs occurs in hereditary cancer syndromes, including multiple endocrine neoplasia Type 2 (MEN2), caused by mutations in theRET proto-oncogene, von Hippel-Lindau (VHL) disease, caused by VHL gene abnormalities, and the pheochromocytoma-paraganglioma (PCC-PGL) syndrome, causedby mutations in SDHB and SDHD. Since a proportion of PCCs occurs in children we hypothesized that germline mutations in RET, VHL, succinate dehydrogenase subunit B (SDHB), and subunit D (SDHD) occur more frequently in the pediatric age range.From our single-institution collection of PCCs, we have selected 10 cases that occurred in individuals up to 18 years of age at diagnosis. In these, we have performed mutation analysis on normal and tumor tissues for exons 10, 11, and 16of RET and for the entire coding sequence of VHL, SDHB, and SDHD. The 10 patients include 7 boys and 3 girls, with an average age of 15.5 years (range 9-18 years). Two patients had germline RET exon 11 mutations (C634R) and 1 patient had an R64P germline mutation in the VHL gene. In the remaining 7 patients there was one patient from a family fulfilling the clinical criteria for VHL disease. ALL tumors were benign (average follow-up: 12 years) and were located in the adrenal. From our findings we conclude that (a) a large proportion (40%) of pediatric PCCpatients is diagnosed in the context of inherited cancer syndromes, and (b) candidate gene analysis appears to be indicated to detect germline mutations.

Supratentorial hemangioblastomas are rarely encountered tumors even in the pediatric population; an extensive review of the literature has revealed approximately 118 cases. However, only five of these occurred in infants, and three occurred during the first 2 months of life. A 5-week-old boy presented with emesis, irritability, a bulging anterior fontanelle, and a head circumference that had gradually expanded since birth. His medical and family histories were uninformative in terms of cancer or inherited diseases. Magnetic resonance imaging demonstrated a large loculated cyst with a heterogeneous contrast-enhancing 3-cm nodule, first pushing the left frontal and parietal lobes and then displacing into this region. After being exposed via a left frontoparietal craniotomy, the cyst was evacuated by a soft drain, and then the mass was totally excised. The histopathological diagnosis was a reticular variant of hemangioblastoma. Given that von Hippel-Lindau (VHL) gene mutations may be associated with hemangioblastomas, sequencing analysis of the VHL gene was performed; sequencing of the three exons of the VHL gene showed no exonic mutations. Clinical and neuroimaging follow-up of the patient have revealed an improved health status during the last 23 months. The authors reviewed the literature concerning congenital supratentorial hemangioblastomas, and they discuss the clinical and histopathological characteristics and differential diagnosis associated with such lesions.

To further study the characteristics of renal cell carcinoma (RCC) in young patients and better define their biological features, 46 RCCs of patients younger than 25 years were morphologically and immunohistochemically characterized with follow-up. Loss of heterozygosity (LOH) analysis of the von Hippel-Lindau (VHL) gene region and screening for VHL gene mutations were performed in ALL tumors. Applying the 2004 WHO classification for RCC, there were 19 Xp11.2 translocationRCCs, 9 clear cell RCCs, 17 papillary RCCs, and 1 unclassified RCC. ALL 19 Xp11.2 translocation RCCs showed moderate to strong immunoreactivity for TFE3. None hadTFEB immunoreactivity. One Xp11.2 translocation RCC had an unreported morphologywith empty or ground glass nuclei, occasional nuclear grooves, inconspicuous nucleoli and abundant mucinous material in stroma.VHL gene analysis revealed deletions at 3p25-26 in 1 clear cell RCC and 1 papillary type 2 RCC. The papillary type 2 RCC was also presented with a family history of VHL disease andfound a germline mutation G --> C on a splicing site at position 553+5. The present case widens the spectrum of microscopic features to be found in VHL-associated RCC. There were no VHL mutations in the remaining 45 RCCs. Statistical analysis of stage and outcome revealed that TFE+ pediatric RCCs weresignificantly more frequently associated with a higher pTNM pT3/pT4 stage and a poorer outcome than TFE-RCCs (P < .05). Owing to the already known aggressive behavior of these Xp11.2 translocation RCCs, patients with TFE+ pediatric RCCs should benefit from a stricter follow-up.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL.

INTRODUCTION: VHL is a genetic condition predisposing to the development of multiple and successive tumors, mainly nervous system and retinal hemangioblastomas, renal clear cell cancer, endolymphatic sac tumors (ELST), pancreatic neuroendocrine tumors and pheochromocytomas/paragangliomas. Usually diagnosed too late, they present unusually soon in relation to sporadic lesions.Expert committees guidelines for periodic clinical and image screening for thesepatients have been developed. METHODS: We analyze incidence and presentation of VHL characteristic tumors, especially the age of initial diagnosis of each tumorin order to verify the indication of early screening studies in the pediatric population. In the past 5 years, at our Familial Neuro-Oncology Program 100 VHL patients were screened following the International VHL Alliance schedule. Patient s age at every tumor's diagnosis was recorded and analyzed, specifically in the pediatric age (< 18 y). RESULTS: Ninety-four patients were diagnosed of at leasta characteristic tumor; 6 patients with VHL gene mutation have not yet developedtumors. Twenty-three patients were diagnosed of their first neoplasia at pediatric age (8-17 y, 25%): retinal hemangioblastoma (13 cases, ages 8-17), cerebellar hemangioblastoma (7 cases, ages 11-17), brainstem hemangioblastoma (5cases, ages 8-12), spinal cord hemangioblastoma (5 cases, ages 10-17), pheochromocytoma (1 case, age 11) and ELST (1 case, age 17). Eigthteen (75%) needed treatment at pediatric age. CONCLUSION: VHL neoplastic manifestations begin very early, in younger patients than sporadic presentations for those tumors, and earlier than expected in current screening schedules for these patients. In our experience, some patients have been diagnosed and required treatment before 15, the usual advised age for initial nervous system screening.In our opinion, besides ophtalmological, audiological and metanephrin screening,screening protocols for nervous system treatable tumors in VHL patients and those at risk should include periodic clinical and image studies from age 8.#FAU - De Campos, Jose M