Pheochromocytoma associated with von Hippel-Lindau disease in a Pakistani family

The aim was to study the presentation, disease characteristics, operative outcome, and prognosis in patients with familial Pheochromocytoma associated with von Hippel-Lindau [VHL] disease. There were six patients belonging to two generations of a single family who developed features of VHL over a period of 13 years and were treated at our institute. Patients' characteristics, that is, age, gender, presenting complaints and clinical signs, laboratory and biochemical evaluation, and the presence of associated conditions was gathered from medical records. The preoperative and postoperative radiological imaging and histopathological results were also collected. Out of six cases, five were male, and one was female. The mean age at first presentation was 25 years [16-40]. All patients presented with uncontrolled hypertension and were found to have Pheochromocytoma on workup. Three patients had unilateral adrenal tumor, and three had bilateral disease. None of the patients had extra-adrenal Pheochromocytoma. All patients were managed with adrenalectomy and had benign pathology. Two patients subsequently had craniotomy for excision of cerebellar hemangioma, and one patient had bilateral partial nephrectomy at the time of adrenalectomy. There was no peri- post-operative mortality and all patients are being followed by the surgeon[s] and endocrinologist. Pheochromocytoma can be a part of familial conditions including VHL. Other associated features should be suspected, investigated, and treated in these patients that can influence patients' clinical course and prognosis. Family members should also be screened to achieve early diagnosis

Fundamentos moleculares de la enfermedad de von Hippel Lindau / Molecular bases of von Hipperl Lindau's disease

La enfermedad de von Hippel Lindau es una rara entidad genética que se caracteriza por la predisposición al cáncer, especialmente angiomas de la retina, hemangioblastomas del sistema nervioso central y carcinoma renal de células claras. Los productos del gen presentan un mecanismo de acción peculiar, pues está relacionado con los procesos de adaptación del organismo a la hipoxia. En este trabajo se presenta una panorámica actualizada de esta enfermedad, con énfasis en los aspectos moleculares

The von Hippel Lindau's disease is uncommon genetic entity characterized by a predisposition to cancer, specially the retina angiomas, hemangioblastomas of central nervous system and the clear cells renal carcinoma. Gene products have a typical action mechanism since it is related to organism adaptation processes to hypoxia. In present paper an updated panorama of this disease emphasizing in molecular processes

Verteporfin photodynamic therapy of retinal capillary hemangioblastoma in von Hippel-Lindau disease.

An 18-year-old boy presented to us with bilateral retinal hemangioblastoma and von Hippel-Lindau disease with history of cerebral capillary hemangioblastoma and embryonic cell carcinoma of left testes. The vision in the right eye was already lost with development of secondary closed angle glaucoma, optic atrophy with subsequent development of bullous keratopathy. The multiple retinal angiomatous lesions in the seeing left eye were treated with various modalities like triple freeze thaw cryopexy, focal lasers and transpupillary thermo therapy in multiple sittings over a period of almost 20 years since detection. One particular angiomatous lesion in the left eye was showing resistance to all the above mentioned modalities and was finally successfully treated with verteporfin and photodynamic therapy to achieve complete regression without any post-treatment complication and with a sustained 20/20 vision till a follow-up of 15 months.

Enfermedad de von Hippel Lindau en una familia chilena: diagnóstico clínico y genético / Von Hippel Lindau disease: report of an affected family

Von Hippel Lindau disease is a hereditary syndrome characterized by the appearance of benign and malignant tumors in different organs. Its incidence is 1 case per 36000 born alive. We report a family with the disease. The index case was a male with a bilateral pheochromocytoma and cerebelar and retinal hemagioblastomas that had a sudden death due to a cerebrovascular accident at the age of 52 years. One sibling had central nervous system and retinal hemangioblastomas and other was operated for an unilateral pheochromocytoma. Both siblings had the R167Q VHL mutation of the syndrome. Other family members did not have the mutation.

Abordagem cirúrgica dos hemangioblastomas intramedulares / Manejo quirúrgico de los hemangioblastomas intramedulares / Surgical management of intramedullary hemangioblastomas

OBJETIVO: descrever uma experiência e as técnicas para abordagem destas lesões com ênfase nos aspectos microcirúrgicos. MÉTODOS: foram relatados nove casos consecutivos de pacientes submetidos à ressecção de lesões intramedulares operados entre 2000 e 2008. A escala funcional de McCormick foi usada para avaliar o status funcional dos pacientes RESULTADOS: a idade dos pacientes variou de 13 a 45 anos (média de 27,1 anos). Quatro (44,4 por cento) pacientes eram homens e cinco (55,5 por cento), mulheres. Dois pacientes tinham a doença de von Hippel-Lindau, com outros hemangioblastomas associados. Conforme a localização, sete (77,7 por cento) pacientes tinham lesões na região cervical (dois deles com tumores na transição crânio-cervical) e dois (22,2 por cento) tinham lesões na região torácica. Todos os pacientes tiveram ressecção total das lesões, sendo que três apresentaram leve piora clínica no pós-operatório imediato. Após seis meses do procedimento cirúrgico, dois pacientes apresentaram melhora clínica, enquanto sete mantinham-se funcionalmente iguais ao período pré-operatório. CONCLUSÕES: o conhecimento anatômico e de técnicas microcirúrgicas adequadas permite a ressecação total destas lesões sem agregar morbidade adicional.

OBJECTIVES: to report an experience and to present a surgical technique to achieve total resection and cure. METHODS: nine consecutive cases of intramedullary haemangioblastomas, operated between 2000 and 2008 are presented. The functional scale proposed by McCormick was used to evaluate the patients' neurological status. RESULTS: age at presentation varied from 13 to 45 (average 27.1) years. Four (44.4 percent) patients were male and five (55.5 percent), female. Two patients had an associated von Hippel-Lindau disease, with others haemangioblastomas. According to the site of presentation, seven (77.7 percent) were localized at the cervical region (including two at the cervico-medullary junction), and two (22.2 percent) at the thoracic level. Total resection was achieved in all cases. Three patients had some functional worsening immediately after surgical procedure. After six months, there were no patients with functional worsening comparing with the pre-operative status and two patients had clinical improvement. CONCLUSIONS: adequate knowledge of anatomy and the correct use of microsurgical techniques allowed total resection of these tumors with minimal morbidity and maximum functional recovery.

OBJETIVOS: describir una experiencia y las técnicas para abordaje de esas lesiones, enfatizando los aspectos microquirúrgicos. MÉTODOS: fueron relatados nueve casos consecutivos de pacientes sometidos a resección de lesiones intramedulares, operados entre 2000 y 2008. La escala funcional de McCormick fue usada para la evaluación del status funcional de los pacientes RESULTADOS: la edad de los pacientes varió de 13 a 45 anos (media de 27,1). Cuatro (44,4 por ciento) pacientes eran hombres y cinco (55,5 por ciento), mujeres. Dos pacientes eran portadores del enfermedad de von Hippel-Lindau, con otros hemangioblastomas asociados. Conforme la localización, siete (77,7 por ciento) pacientes tenían lesiones en la región cervical (dos con tumores en la transición cráneo-cervical) y dos (22,2 por ciento) tenían lesiones en la región torácica. Todos los pacientes tuvieron resección total de los tumores, siendo que tres tuvieron deterioración clínica leve en el post-operatorio inmediato. Después de seis meses del procedimiento quirúrgico, dos pacientes presentaron mejoras clínicas, mientras seis se mantuvieron funcionalmente iguales al periodo pre-operatorio. CONCLUSIONES: el conocimiento anatómico y de técnicas microquirúrgicas adecuadas permite la resección total de estos tumores sin agregar morbididad adicional.

Improved Detection of Germline Mutations in Korean VHL Patients by Multiple Ligation-dependent Probe Amplification Analysis

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the development of tumors in the eye, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis, associated with germline mutations in the VHL gene. We used sequentially sequencing method and multiple ligation-dependent probe amplification (MLPA) analysis and detected germline mutations in the VHL in 15/15 (100%) of VHL patients fulfilling the clinical criteria. Of the 15 distinct mutations detected, large deletions were detected in 5/15 (33.3%) patients, including 4/15 (26.7%) partial deletions and 1/15 (6.6%) deletion of the entire VHL gene by MLPA and the remainder were point mutations detected by sequencing method, of which five mutations were novel. Using MLPA analysis, we detected large deletions including both partial deletions and complete gene deletion, which has not been reported in Korean VHL patients. In conclusion, sequential application of sequencing method and MLPA analysis might make possible to identify germline mutations in most patients with VHL.

Hemangioblastomas aparentemente esporádicos e doença de von Hippel-Lindau não suspeita / Apparently sporadic hemangioblastomas and not suspected von Hippel-Lindau disease

Objetivo: Apresentar os achados associados à doença de von Hippel-Lindau em pacientes portadores de hemangioblastoma do sistema nervoso central, aparentemente esporádico, submetidos a rastreamento (screening)em um centro neurocirúrgico de referência.Métodos:Na base de dados do Instituto Nacional de Neurologia e Neurocirurgia da Cidade do México foram identificados todos os pacientes com diagnóstico histológico confirmado de hemangioblastomado sistema nervoso central entre janeiro de 1980 e agosto de 2000.Os arquivos médicos, radiológicos e patológicos desses pacientes foram revisados retrospectivamente. Destes, 25 pacientes assintomáticos concordaram em submeter-se ao rastreamento, por meio de exame físico, ultra-sonografia e tomografia axial computadorizada de abdômen,ressonância magnética cranioespinhal e exame oftalmológico.Resultados: 32 por cento dos pacientes apresentaram policistose, 16 por cento, hemangioblastomas múltiplos e 12 por cento, carcinomas viscerais. Segundo os critérios de Neumann, logrou-se estabelecer o diagnóstico clínico da doença de von Hippel-Lindau em 60 por cento dos casos. Conclusão:A presença de lesões assintomáticas nos portadores da doença de von Hippel-Lindau assinala a falta de sensibilidade do exame clínico, fazendo-se necessário o rastreamento de todo paciente portador de hemangioblastomas do sistema nervoso central.

Huge pancreas helps diagnosis in von Hippel-Lindau disease.

We describe five patients diagnosed with von Hippel-Lindau disease who complained of abdominal distension, pain and discomfort for a long time. All patients underwent ultrasonography, CT scan and MRI, which showed huge pancreas filled with multiple cysts. Additionally, extrapancreatic findings such as cerebellar hemangioblastoma (3 patients), retinal hemangioblastoma (2), renal cell carcinoma (3), renal adenoma (1), renal cysts (4), and splenic cyst (1) helped to reach the right diagnosis. One patient who had no known associated pathology had a family history of von Hippel-Lindau disease. Pancreatic cysts detected on imaging may be a clue to the diagnosis of von Hippel-Lindau disease. In all patients with multiple pancreatic cysts, this disease should be included in the differential diagnosis.

Visceral manifestations of von Hippel-Lindau disease: value of ultrasound and CT imaging.

Visceral manifestations of von Hippel-Lindau disease (VHLD) are generally asymptomatic and their early detection is of considerable help in the management. This communication documents the usefulness of imaging studies in detecting visceral manifestations in two cases of VHLD.

Diagnóstico molecular da doença de Von Hippel-Lindau (VHL) em famílias brasileiras: estudo ampliado / Molecular diagnosis of the disease of Von Hippel-Lindau (VHL) in Brazilian families: study extended

A doença de von Hippel-Lindau (VHL) é uma doença hereditária multissistêmica, causada por mutação no gene VHL que predispõe o portador a manifestações benignas e malignas em diversos órgãos. O início dos sintomas pode ocorrer a partir dos primeiros anos de vida e inclui entre outros, angioma de retina, hemangioblastoma de sistema nervoso central (SNC), feocromocitoma, carcinoma renal do tipo células claras e cistos múltiplos renais, pancreáticos, hepáticos e de epidídimo. O diagnóstico clínico baseia-se em critérios que consideram a história familial e a apresentação clínica das lesões. Muitas vezes o diagnóstico é dificultado ou retardado até que estes critérios sejam preenchidos. O aconselhamento genético e avanços dos métodos de diagnóstico e de tratamento vêm mudando o curso desta enfermidade com a diminuição da morbidade e da mortalidade, contribuindo para a melhoria da qualidade de vida das famílias afetadas por esse mal e para o entendimento da doença. O diagnóstico molecular da doença baseia-se na aplicação de técnicas de biologia molecular que visam a detecção de mutações germinativas no gene VHL. O teste genético em pacientes com VHL permite avaliar a amplitude do fenótipo da doença baseado no estudo de outras famílias com a mesma mutação... Neste estudo, foram analisadas 100 indivíduos, sendo 83 indivíduos pertencentes a 20 famílias com diagnóstico de VHL; sete indivíduos pertencentes a duas famílias em que VHL era um diagnóstico diferencial; oito pacientes com tumores relacionados a VHL aparentemente esporádicos, além de dois familiares de uma paciente com hemangioblastoma aparentemente esporádico na qual foi identificada mutação germinativa no gene VHL. A taxa de 100% de detecção de mutação foi alcançada no estudo das 20 famílias com VHL através da combinação das técnicas de seqüenciamento direto e de Southern-blot quantitativo...(AU)

von Hippei-Lindau (VHL) disease [MIN 193300] is a heritable monogenetic disorder transmitted in a autosomal dominant pattern that predisposes affected individuais to the development to many typical lesions, including retina! angiomas, hemangioblastomas of the central nervous system, multiple cysts of the kidneys and pancreas, pheochromocytoma (PHE), renal cell carcinoma (RCC), and pancreatic tumors. The molecular basis of the disease is the presence of germline mutations in the VHL tumor suppressor gene. A total of 17 consecutive families with VHL (15 from Brazil, one from Portugal, and one from Equator) and three Brazilian VHL patients without family history were included in this study. Genetic counseling with signed informed consent was offered to ali participants. The mutation detection strategy consisted in direct sequencing of the coding regions of the VHL gene and quantitative Southern-blotting. We identify germline mutations in ali probands, giving rise to a 1 00°/o mutation detection rate. These consisted in 16-point mutations (9 missense, 3 frameshift, 1 in-frame deletion, 2 splice defect, 1 non-sense), 3 partia! deletions and 1 complete deletion of the VHL gene. As observed in other studies, mutations in the codon 167 confer a high risk for PHE and RCC, and mutations that predicted a truncated protein were related to VHL type 1. Twelve families (60°/o) could be characterized as having a high risk to renal carcinoma based on the family occurrence or characteristics of the mutations. Three out four families with large deletions had a high incidence of HB of the SNC. Also, we observed a tendency of the germline point mutations to concentrate among exons 1 and 2 of the VHL gene, including boundaries (87.5°/o). In addition, eight novel VHL gene mutations and two polymorphisms (one novel) are described. We concluded that the combination of direct sequencing and quantitative Southern-blotting represented a good strategy for germline mutation detection in the VHL gene and can be considered the gold standard when 1 00°/o mutation detection is needed. This preliminary study suggests that VHL families in Brazil, which are mostly of Portuguese origin, may have unique features in respect to VHL mutations and risk of malignancies, and this may be considered in the approach of genetic counseling and screening for patients of Portuguese descendents (AU)

Aspectos clínico-radiográficos del síndrome de Sturge-Weber: presentación de un caso / Clinical and radiographic aspects of Sturge-Weber syndrome

El síndrome de Sturge-Weber se caracteriza por una angiomatosis córticocerebral, nevo facial o mancha en "vino de oporto", calficicaciones cerebrales, epilepsia, afecciones oculares y retraso mental. Presente en ambos sexos por igual, de forma infrecuente y aparentemente sin influencia hereditaria. A nivel bucal se pueden observar lesiones angiomatosas capilares siguiendo el recorrido trigeminal. Las características radiográficas patognomónicas a nivel cerebral son áreas opacas, doblemente contorneadas simiilares a rieles de un tren, siguiendo las circunvalaciones cerebrales. La TAC, IRM, agiografía y la medicina nuclear son elementos de diagnóstico por imágenes utilizados en la actualidad

Hemangioblastomas: achados clínicos, epidemiológicos e anatomopatológicos em 14 casos / Haemangioblastomas: clinical, epidemiological and pathological findings in 14 cases

Relatamos os achados clínicos, epidemiológicos e anatomopatológicos de 14 casos de hemangioblastoma. Sessenta e quatro por cento ocorreram em pacientes do sexo masculino, com idades variando de 16 a 60 anos, com média de 34,4 anos. Nove localizaram-se no cerebelo. Os sintomas mais comuns foram cefaléia (n=7) e tontura (n=7), com período médio de evolução de 70 dias. O diagnóstico de síndrome de von Hippel-Lindau (vHL) foi feito em 3 pacientes. Onze pacientes foram submetidos a ressecção cirúrgica total e 3 a exérese parcial. Evidenciou-se recidiva em 28 ppor cento dos casos, em 3 anos de acompanhamento. Os pacientes com vHL apresentaram recidiva em 66 por cento dos casos. Estes achados aproximam-se dos encontrados na literatura, enfatizando a morbidade deste tumor quando associado à vHL.

Hemangioblastoma de localización multiple supra e infratentorial: primer caso en Venezuela / Multiple supratentorial and infratentorial hemangioblastoma: first case at Venezuela

Presentamos un caso inusual de hemangioblastomas supre e infratentoriales de diferente histología. Se describen las características y los estudios neuroradiológicos que permitieron identificar esta necesidad de considerar esta patología como uno de los diagnósticos diferenciales en los procesos tumorales del Sistema Nervioso Central

Doença de von Hippel Lindau / Hippel-Lindau disease

Os autores apresentam um caso de angiomatose retínica e discutem a necessidade de serem feitos exames diagnósticos o mais breve possível