DNA-based presymptomatic diagnosis for the von Hippel-Lindau disease by linkage analysis.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited condition characterized by a predisposition to the development of haemangioblastoma, renal cell carcinoma and phaeochromocytoma. The gene which, when altered, causes the disease was cloned in 1993, and maps within a series of known polymorphic loci in the 3p25-p26 region. To optimize a DNA-based presymptomatic diagnosis, we have selected six highly informative microsatellite loci, closely linked to the VHL gene. Genotyping using a multiplex-PCR approach was performed in 26 affected families including 99 asymptomatic relatives born from an affected parent. Ninety-six subjects were informative with one or more markers, 76 being informative with markers on both sides of the gene. Combination of age-related and DNA-based risk information improved the accuracy of risk assessment for 90 at-risk patients (91%) and allowed attribution of risk with a confidence limit higher than 0.98 in 79 cases (88%).

Pheochromocytoma as the first manifestation of von Hippel-Lindau disease.

BACKGROUND: von Hippel-Lindau disease is an autosomal dominant disorder characterized by the development of hemangioblastomas in the cerebellum, spinal cord, and retina, renal cell carcinoma and cysts, pancreatic cysts, and pheochromocytoma. METHODS: We have studied a series of 36 French patients affected with von Hippel-Lindau disease pheochromocytoma. Thirty (83%) of them were diagnosed as having von Hippel-Lindau disease because the disease occurred in a familial von Hippel-Lindau disease setting; six (17%) were diagnosed as having von Hippel-Lindau disease because they displayed another characteristic manifestation of that disease. RESULTS: The mean age at pheochromocytoma diagnosis was 29 +/- 14 years (5 to 62 years). Bilateral tumors were documented in 15 (42%) cases, paraganglioma was associated with adrenal pheochromocytoma in four cases, and malignant pheochromocytoma occurred in three cases. Prevalence of pheochromocytoma revealing von Hippel-Lindau disease was 20 (53%) out of 36. In six cases pheochromocytoma was the only manifestation of the disease. CONCLUSIONS: In the interest of the patients themselves and of family members who are at risk, search for von Hippel-Lindau disease must be systematic in the presence of pheochromocytoma. Basic checkup may be completed with familial inquiry, ophthalmoscopy, cerebral magnetic resonance imaging, abdominal ultrasonography, and computed tomography-scan for detection of latent lesions. In the future, after characterization of von Hippel-Lindau disease gene mutations, molecular diagnosis is going to be possible in individual patients.

Clinical and radiologic aspects of maxillonasal dysostosis (Binder syndrome).

Maxillonasal dysostosis, described by Binder in 1962, is probably more common than one would think from the small number of cases that have been published (fewer than 40). We have seen 37 cases of this syndrome over a period of 8 years. Diagnosis of the syndrome is easy because of its characteristic anomalies of the upper lip and nose: smallness of the nose, a groove under the columella, a "half-moon" appearance of the nasal apertures, absence of the nasal spine, and projection of the chin. In addition, we have observed several associated abnormalities: convergent strabismus (2 cases), mongolism (1 case), labiomaxillopalatine cleft (1 case), and, of particular note, numerous abnormalities of the cervical spine, frequently associated with mandibular prognathism. In view of the frequency of the latter abnormalities. Binder syndrome might well be called a "nasomaxillovertebral syndrome."

Craniospinal and cervicospinal malformations associated with maxillonasal dysostosis (Binder syndrome).

Craniospinal and cervicospinal malformations were found in 15 (53.5%) of 28 cases of maxillonasal dysostosis (Binder syndrome) in which a complete radiographic analysis could be done. These anomalies have not been reported previously. Analysis of the anomalies suggested a common induction factor, or, at least, a simultaneity in the development of the maxillonasal and vertebral dysplasias that characterize Binder syndrome. The following procedures are recommended: (1) examination of the cranial and cervical spine in all subjects with symptoms of Binder syndrome, and (2) regular examination of patients with spinal malformations, so that any neurologic damage may be detected early.

Therapeutic aspects of maxillonasal dysostosis (Binder syndrome).

Treatment of maxillonasal dysostosis (Binder syndrome) varies according to the age of the patient. In the newborn, respiratory and alimentary problems resulting from the anomaly may necessitate the insertion of endonasal and gastric tubes. In children, occlusal problems and orofacial dysfunctions caused by maxillonasal dysostosis should be treated as soon as possible with an orthodontic mask. Once a patient reaches adulthood, surgery may be performed. If orthodontic treatment has been successful and there is normal occlusion, the surgery may consist simply of placing the muscles of the nose and upper lip in normal; anatomic position. If occlusion is abnormal, osteotomy may be performed.

Photodynamic treatment of normal endothelial cells or glioma cells in vitro.

Photodynamic therapy is based on the interaction of a sensitizer (hematoporphyrin derivative) selectively retained by tumor cells, which becomes toxic after light exposure. We studied the influence of exogenous prostaglandins and indomethacin on photodynamic therapy of normal human endothelial cells and glioma cells. Although differing in origin and kinetic properties, endothelial cells exhibited photodynamic therapy sensitivity quite comparable to that of C6 cells. However, in contrast to studies performed using radiotherapy, exogenous prostaglandins decreased rather than protected the surviving fraction of both cell types treated by photodynamic therapy. Indomethacin, a potent inhibitor of endogenous prostaglandin synthesis, increased the surviving fraction of C6 glioma cells but not that of endothelial cells. Exogenous or endogenous prostaglandins seem to influence in vitro photodynamic therapy in a different way than does radiotherapy.

[Pheochromocytoma, first manifestation of Von Hippel-Lindau disease: a possibility to be considered]. / Phéochromocytome, première manifestation de la maladie de von Hippel-Lindau: une éventualité à connaître.

Von Hippel-Lindau (VHL) disorder is an autosomal dominant disease characterized by the almost constant development of hemangioblastomas in the central nervous system (cerebellum, spinal cord and retina). In addition, various types of tumors including renal cell carcinomas, pancreatic cysts and pheochromocytomas are frequently observed in VHL gene carriers. Linkage of the VHL locus to the RAF-1 oncogene on the short arm of chromosome 3 (3p25-26) has been recently reported. Pheochromocytoma is of particular interest because of the risk of inaugural malignant hypertensive crisis but especially because of a great degree of interfamily variability (from 0 to 92% of affected members in previously reported large kindreds). We have studied a French series of 25 pheochromocytoma (11 males, 14 females) in VHL affected patients. Twenty pheochromocytoma (80%) occurred in a familial context, whereas 5 (20%) were consistent with "apparent sporadic cases". The mean age at pheochromocytoma diagnosis was 27 years (5-55 years). Bilateral tumours have been documented in 13 cases (52%). The prevalence of pheochromocytoma revealing VHL was 14 out 25 (56%). In these cases, VHL diagnosis was considered up to 25 years later. In 6 cases (2 deceased) pheochromocytoma was the only manifestation of VHL. Thus, search for VHL must be systematic in the presence of pheochromocytoma, in the interest of the patients themselves and of potential at-risk family members (prevention of hypertensive crisis linked to latent tumours). Basic check-up (neurological and somatic examination, ophthalmoscopy, familial inquiry) may be completed with cerebral CT scan or MRI and abdominal ultrasonography followed, if positive or doubtful, by abdominal MRI or selective angiography.

[Variety of pancreatic lesions observed in von Hippel-Lindau disease. Apropos of 8 cases]. / Variété des lésions pancréatiques observées au cours de la maladie de von Hippel-Lindau. Présentation de 8 cas.

Von Hippel-Lindau's disease is a rare genetic disease, with an autosomal dominant mode of inheritance, characterised by the development of several tumours, such as haemangioblastoma of the central nervous system and retina, renal cysts or carcinoma and pheochromocytoma. Several pancreatic lesions, mainly represented by multiple cysts, are also encountered. We report here 8 cases of pancreatic involvement in patients affected with von Hippel-Lindau's disease. It consisted of multiple cysts (3 cases), serous cystadenoma (2 cases), endocrine tumour (1 case), haemangioblastoma (1 case) and ductal adenocarcinoma (1 case). Diagnosis of a rare lesion of the pancreas (multiple cysts, serous cystadenoma or vascularized tumour) in a young patient may lead to search the other lesions of von Hippel-Lindau's disease and to undergo a familial inquiry in order to propose a multidisciplinary approach for patients affected by the disease.

[Chronic ischemia of the anterior horn of the lumbar swelling of the spinal cord. Angiographic study in a subject with herniation of the T12-L1 discs]. / Ischémie chronique des cornes antérieures du renflement lombaire de la moelle. Etude angiographique chez un sujet porteur d'une hernie discale D12-L1.

On the basis of a case of almost pure involvement of the anterior horn with chronic progression in an individual with a low thoracic herniated disc (T12-L1), the hypothesis is discussed of the role of ischaemia of the lumbar swelling. Angiographic arguments (displacement of the anterior spinal axis and unusual distribution of anterior spinal afferents) perhaps make it reasonable to speak of "chronic ischaemic poliomyelitis" in the absence of pathological examination.

Integrated imaging system for stereotactic neurosurgery.

Talairach's method remains the most universal of all stereotactic methods. It makes it possible to go back to an examination left interrupted, but above all, it provides multiple lateral and coronal approaches in matters of epilepsy, radio-isotopes or photobiology. The advances achieved in modern imaging methods, notably CT and MRI, and the performance of modern computers have enabled us to devise an integrated imaging system meant to accelerate and make feasible calculations of penetrating trajectories, according to the position of the target as previously defined by CT and MRI sections, and taking into account the position of vessels given by angiography. The principal options we selected were: transfer onto video tapes of teleangiographic films and introduction of CT and MRI images obtained either from films or directly in digits on cartridges or networks. The system includes an advanced PC-type microcomputer with 8 memories of 1,024/1,024 images: 4 mega octets random access memories and a hard disc of 150 mega octets; 2 high-resolution screens to present the images, dialogue tools (alphanumeric screen, keyboard, trackball) and the usual peripherals. Our system performs three main functions: it acquires images to create or complete the patient's records; it exploits the images by calculating the parameters required for operations; it handles the records through the various peripherals of the system. Our system can retrace the proportional 3D squaring according to the CA-CP distance calculated from ventriculography or MRI, and calculates the position of the SEEG electrodes. The stereoscopic effect is obtained by means of glasses with liquid crystal obturator from two angiographic series: one orthogonal, the other 6 degrees out of phase. The daily use of this system on more than 50 patients has shown that it is accurate and reliable, irrespective of the makes of CT and MRI machines.

[The value of magnetic resonance imaging in the diagnosis of spinal cord hemangioblastoma. Apropos of 12 cases]. / Intérêt de l'imagerie par résonance magnétique dans le diagnostic des hémangioblastomes médullaires. A propos de 12 observations.

This study concerned a series of 12 patients, 4 of whom had Von Hippel-Lindau disease. Six of these patients were explored by myelography, 6 by spinal cord angiography, 8 by CT scan with contrast injection and 12 by MRI, with gadolinium injection in 8. MRI proved to be the choice examination for the diagnosis of spinal cord tumor, but gadolinium injection was necessary since it made it possible to detect the tumoral bud and its intense enhancement. The absence of gadolinium injection led us to an erroneous initial diagnosis of syringomyelia in two patients and glioma in one. Sagittal sections made it easier to evaluate the tumoral extension in patients with evidence or suspicion of Von Hippel-Lindau disease. Arteriography was indicated, as it provided a preoperative map and diagnosed punctiform lesions.

[Hemodynamic monitoring in microneurosurgical excision by sub- and retro-sinus approach in seated position in acoustic neurinoma]. / Surveillance hémodynamique au cours de l'exérèse micro-neurochirurgicale par voie sous- et rétrosinusienne en position assise du neurinome de l'acoustique.

Haemodynamic data (thermodilution Swan-Ganz catheter and radial artery cannula) were collected in 17 patients (52.4 +/- 8 yr) during retrosigmoid approach for removal of an acoustic tumour in the seated position. Measurements were made before stimulation of posterior fossa structures (period 1) and during tumour dissection along the brain stem (period 2). Significant increases in systolic, diastolic and mean blood pressures, in pulmonary capillary wedge pressure, in cardiac index and in stroke index were observed during period 2, whereas heart rate, right atrial pressure and systemic vascular resistances were unaffected. The greater the size of the tumour and the difficulties in dissection, the greater were these intraoperative haemodynamic changes. In addition, the pulmonary arterial blood temperature and the noradrenaline plasma concentrations (double isotope enzymatic assay) increased significantly during period 2. In conclusion, the prolonged microsurgical technique of acoustic tumour dissection through the retrosigmoid approach may modify left ventricular loading conditions and may lead to pulmonary oedema, even if intravascular volume expansion was minimal and ventricular function was near normal.

[Ultrastructure of cerebellar hemangioblastoma]. / Ultra-structure d'un hémangioblastome cérébelleux

Authors describe the fine structure of the border zone of a cerebellar hemangioblastoma. This electron microscopie study corroborates all the previous optic microscopic results concerning absence of a well delimited bound between hemangioblastoma and bordering cerebellar tissue. Different stages of peculiar cellular degeneration are found, and an attempt for interpretation is given. However these morphologic changes are insufficient to allow further explanation about the histogenesis of hemangioblastomas, which remains unknown.

[Bone integration within calcium phosphate ceramic by creation of posterior inter-articular lumbar spine fusions in dogs]. / Etude de l'intégration osseuse d'une céramique de phosphate de calcium par réalisation d'arthrodèses lombaires inter-articulaires postérieures chez le chien.

Following earlier experiments in which several calcium phosphate ceramics were tested, the aim of this study was to evaluate bone integration within a macroporous biphasic calcium ceramic (M.B.C.P.) in comparison to autologous bone grafts, by producing posterior lumbar spine fusions in dogs. Five dogs were used. 40 posterior lumbar joints were exposed; 38 articular surfaces were removed, 27 M.B.C.P. and 5 autologous bone grafts were implanted; 6 joints were kept free of implant for control purposes. Fixation with a metal rod was performed using Luque's method. Tetracycline was used for a double marking of bone growth. Joints were removed at 4 weeks in 1 dog, 8 weeks in two and 13 weeks in the remaining 2 dogs. Demineralized and non demineralized sections were examined. After 1 month, sections with M.B.C.P. showed early signs of mineralization of the scar tissue between the biomaterial and one of the facets of the joint. Fluoroscopy revealed an absence of bone growth in the pores at the center of the ceramic implant. After 3 months, a number of M.B.C.P. blocks had become integrated into both sides of the joint; however some microfractures in the biomaterial with discontinuity between the mineralized areas was seen. Macroporous calcium phosphate ceramic leads to revascularization allowing bone reconstruction. Similarities in the kinetics and mechanisms of bone integration between the ceramic and autologous bone grafts are demonstrated.

[Use of stereotaxic neurosurgery in the treatment of pain in cervicofacial cancers]. / Apport de la neuro-chirurgie stéréotaxique dans le traitement des algies des cancers cervico-faciaux.

Mesencephalic tractotomy employing the stereotaxic method was conducted 12 times in 11 patients with pain due to cervicofacial cancer only partially relieved by high doses of opiates. Immediate results were spectacular in 10 cases and partial on the other 2 occasions. However, relief was not permanent even in patients in whom the greatest improvement was obtained, and the usual analgesics had to be prescribed after 3 months. The operation, which requires only a short period of anesthesia, was always well supported, complications being anesthesia of one side of the body in 2 patients and convergence paralysis in two cases, one of which was transient. Mesencephalic tractotomy constitutes a new weapon for the treatment of diffuse cervicofacial cancer pain not responding to major medical treatment. Elective thermocoagulation of the Vth and IXth nerves was also successfully employed for systematized pains.

[Intraneural synovial cyst in the peroneal nerve. Case report (author's transl)]. / Kyste synovial intraneural du sciatique poplite externe. A propos d'un cas.

The authors report one case of paralysis of the peroneal nerve due to an intraneural synovial cyst, in connection with the superior tibio-fibular joint. After an anatomic work and a complete revue of the literature, etiopathogenic and diagnostic problems seem to be resolved, and this justifies their terminologic choice.

[Hamartoma of the internal auditory canal and cerebropontile space in a child. Trans-temporo-extradural excision methods]. / Hamartome du conduit auditif interne et de l'espace ponto-cérébelleux chez un enfant. Exérèse par voie temporo-extra-durale.

A progressive facial paralysis in a child of 14 years allowed the diagnosis of a hamartoma to be made. The discovery of such a benign lesion should always be followed by a search for other lesions elsewhere, i.e. to see if there is not a phacomatosis. Persistent sciatic pains which this child now has lead one to fear a second lesion, compressing a nerve root or trunk of the sciatic nerve. There is a strong possibility that this tumor of the auditory canal is only the first manifestation of a neurocristopathy.

[Value of angiography in the diagnosis of peripheral nerve tumors]. / Intérêt de l'angiographie dans le diagnostic des tumeurs des nerfs périphériques

In current practice, arteriograpy is already acknowledged, at the present time, as a method of primary importance which cannot be dispensed withfor diagnosis, prognosis and treatment. By opposition, considering pathology of the peripheric nerves, arteriography is often overlooked before chirurgical exploration though it affords the same advantages as in the remaining fields of pathology. Technically our preference goes to selective angiography by direct puncture of humeral or femoral artery. Arteriography will permit:-Visualisation of the location of the tumor close to the major vessels;-Evidence of the exact site of the efferent and afferent pedicles;-Discovery of other localisation. Mostly arteriography helps preoperatively to histological diagnosis. It must be recalled that benign neurinomas often assume a misleading aspect on the tumorography with stagnation of the contrast medium which might suggest malignancy. These benign tumors have three peculiar features: 1. Arteries are observed to stretch out around the lesion but never to narrow. 2. There is no explosive vascularisation ; hypervascularisation appears progressively, is located on the periphery of the lesion, and occupies but a part of the whole area. 3. Veins are not invaded but pushed apart and duly appear in normal timing. This peculiar aspect is quite the opposite of what can be observed in malignant tumors, which are, by far, less frequent.

[Vicious callus and unrecognized dislocations of the cervicothoracic junction]. / Cals vicieux et luxations méconnues de la jonction cervico-thoracique.

Five patients were treated after a period varying between 6 weeks and 18 months following original injury. The five lesions were similar in that they could not be reduced by conventional orthopedic measures and that they were fixed during dynamic review examinations using a brilliance amplifier.

[Is osteosynthesis justified for spinal injuries in children?]. / L'ostéosynthèse est-elle légitime en pathologie rachidienne traumatique chez l'enfant?

The legitimacy of osteosynthesis for the treatment of spinal injuries in children is analyzed as a function of results in 10 cases, 7 affecting the cervical, 2 the thoracic and one the lumbar region, six of the children being under 10 years of age. Five of these children had serious neurologic disorders, including 4 with high tetraplegia. Technical difficulties of osteosynthesis were not made easier by the poorly adapted nature of the material for infantile statures. Indications for this surgery were not only those cases not improved by orthopedic therapy: instability of lesions, the child's condition and deterioration in the neurologic state can also require initial treatment by osteosynthesis. The principal complication is postoperative cervical kyphosis, but this can be prevented by early active reeducation, the stability of the fixation dispensing with the need for external contention.