Segmental neurofibromatosis: an uncommon variant of neurofibromatosis

It was reported that sodium thiosulfate (STS) was contributed to antivomiting effect in 20 transarterial chemotherapic patients. The antitumor sensitivity of STS (< 500 micrograms/ml) adjuncting to the ADM, MMC, CDDP and other four agens (1 x PPC/ml) individually on two tumor cells studied by MTT test in vitro and no antitumor activity of adjuvant of STS were obviously obliterated (P > 0.05) except for CDDP clinically, to comparing the adjuncting effects of STS (iv. 30 min ahead) or metochlopramidum (im. 30 min ahead) to ADM, MMC and CDDP on HCC (40 cases), the degrees of vomiting in hepatoma patient after transcatheter arterial chemoem bolization with ADM, MMC and CDDP were statisticaly analysec. It have been proven that STS was contributed to the low incidence of vomiting and superior to metocloe pramidum, without worsening of the chemotherapy of HCC. It is worth futher studying adjuvant STS to other antitumor drugs and exploring potential application of chematherapy in cancer.     

Visual function in neurofibromatosis

We performed an open-label pilot study to define analgesic efficacy, acceptability, and toxicity of transdermal fentanyl in an ambulatory population of patients with cancer pain. Our 7-day study included 35 patients, all of whom had failed a trial of an opioid analgesic conventionally used for moderate pain. Patients received either a 25 micrograms/hr or 50 micrograms/hr fentanyl transdermal patch depending on prior opioid dose. Pain was measured daily utilizing visual analogue (VAS) and categorical (CAT) scales. Hours of nighttime sleep, quality of life, toxicities, and use of rescue medication were also assessed. There was a 24%-29% reduction in mean VAS and CAT pain scores as compared with the baseline and a 25% increase in mean hours of nighttime sleep. Fifty-nine percent of those patients responding (46% of all study patients) were satisfied to very satisfied with the analgesia provided by transdermal fentanyl. Six percent of all study patients were not at all satisfied with the pain relief obtained. Toxicities were similar to those seen with other opioids. No patient developed severe sedation or respiratory depression. The 25-50 micrograms/hr patch appears to be a safe starting dosage in ambulatory patients previously receiving opioids conventionally used for moderate pain.     

Percutaneous transluminal renal angioplasty in neurofibromatosis

A 9-year-old boy with hypertension was found to have neurofibromatosis associated with stenosis of the right renal artery. Percutaneous transluminal angioplasty (PTA) was performed. Immediately post angioplasty angiography showed that the stenosis persisted, but over the next few days his blood pressure rapidly decreased and remained well controlled even when treatment was discontinued. The captopril stimulation test, performed after PTA, confirmed the return of plasma renin activity to normal values. A digital subtraction aortogram, performed 2.5 years after PTA, was unchanged. His blood pressure remained persistently normal, without anti-hypertensive agents. Based on these results, PTA is suggested as the first step in correcting renal artery stenosis due to neurofibromatosis. A complete anatomical resolution of the stenosis is probably not required since slight improvements in the renal artery lumen may be accompanied by important functional improvement.     

Mosaicism in sporadic neurofibromatosis 2 patients

More than half of neurofibromatosis 2 (NF2) patients represent de novo mutations which could have occurred at either pre-zygotic or post-zygotic stages. A post-zygotic mutation can result in mosaicism. In four sporadic NF2 patients, we found NF2 mutations in only a portion of corresponding leukocytes. In two other sporadic patients, no mutations were found in leukocytes but constitutional NF2 mutations were suggested by identical mutations in different tumors from each patient. We screened leukocyte DNA from a total of 16 inherited and 91 sporadic NF2 patients, and found NF2 mutations in 13 (81%) of the former and in 46 (51%) of the latter cases. The 30% difference in the rate of detection of mutations ( P = 0.051) might be partially explained by mosaicism in a portion of sporadic NF2 patients who carry the mutations in such a fashion that their leukocytes are unaffected. Among sporadic cases, we found mutations more frequently in patients with severe phenotypes (59%) than in patients with mild phenotypes (23%) (difference of 36%, P = 0.007). Mosaicism might be more common in the latter patient group since small populations of mutation-bearing cells can in some cases result in mild phenotypes and can also lead to difficulties in identifying mutations. No mutations were found in eight patients suspected of having NF2. Mosaicism with an extremely small population of affected cells may explain the incomplete phenotypes in some of these patients and the lack of mutations in their leukocytes. These findings suggest that mosaicism is relatively common in NF2 and may have important implications for diagnosis, prognosis and genetic counseling.     

Diagnosing neurofibromatosis type I in children

Neurofibromatosis is the single most common genetic disease of the neurologic system. Because neurofibromatosis type 1 (NF-1) is often diagnosed early in life, it is essential that health care providers deepen their understanding of this common genetic disorder. Children who meet particular criteria, as formulated by the National Institutes of Health, must be worked-up for NF-1 in order to initiate appropriate treatment implementation and evaluation. This article provides a review of the literature regarding the pathophysiology, clinical manifestations, and plan of treatment related to NF-1, specifically as it affects children. Clear guidelines for health care providers in primary care are outlined.     

Meningiomas and neurofibromatosis for the oncologist

The goal of this review is to understand meningioma, one of the most frequent primary intracranial tumors, from an oncologic and neurosurgical point of view. The epidemiology, pathogenesis, cytogenetics, and molecular genetics are presented. The operative therapeutic possibilities, the recurrence rates in relation to the intracranial tumor localization, and the place of adjunctive therapies is discussed. Although the emphasis of this review is on developments in the past year, some historical references are provided.     

NF1 (neurofibromatosis type 1)

Several distinct Ras GTPase activating proteins (GAPs) from mammals, including Ras GAP of 120 kDa (GAP1) and NF1, stimulate the intrinsic GTPase activity of normal Ras, but not oncogenic Ras mutants (Trahey and McCormick, 1987). That is the reason why normal Ras remains predominantly in the inactive GDP-bound form (D-Ras), whereas oncogenic Ras remains constitutively in the active GTP-bound form (T-Ras). NF1 is a tumor suppressor of 2818 amino acids whose disruption or deletion causes brain tumors called neurofibromatosis type 1 by elevating the T-Ras level. T-Ras activates several distinct oncogenic effectors, including Ser/Thr kinase Raf, GAP1, P1-3 kinase, PKC-zeta and Ra1 GDS. Interestingly, the binding of T-Ras to either GAPs or these oncogenic effectors requires the same effector domain I (residues 32-40) of T-Ras molecule. In other words, these GAPs and effectors compete for binding to T-Ras. Using a series of N- and C-terminal deletion mutants of NF1, we identified a 78 amino acid fragment (NF78, residues 1441-1518) as the minimum GAP domain, and a 56 amino acid fragment (NF 56, residues 1441-1496) as the minimum Ras-binding domain. Furthermore, we identified the Raf fragment of 81 amino acids (Raf81, residues, 51-131) as the minimum Ras-binding domain with a high affinity. We found that (i) these NF1 fragments and Raf81 compete for binding to T-Ras, and that (ii) over-expression of these NF1 or Raf fragments strongly suppresses the malignant transformation caused by oncogenic Ras mutants. Thus, these agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors that represent more than 30% of all human carcinomas including neurofibromatosis type 1.     

Bilateral acoustic neurinomas (neurofibromatosis 2)

Type 2 neurofibromatosis is a rare genetic condition, with an autosomal (dominant) inheritance and a prevalence of 1/50.000 inhabitants, characterized by bilateral acoustic neuromas. We present here a 16-year-old patient with a greater growth of the right-sided neuroma. A review of the literature, regarding incidence, clinical presentation, diagnostic clues and treatment is also included.     

Aneurysm of the major vessels in neurofibromatosis

The case of a patient who presented with a ruptured aneurysm of the brachial artery and type I neurofibromatosis is presented. Angiography revealed a ruptured aneurysm of the brachial artery in the middle of the upper arm. Repair of the artery with autogenous vein grafting was impossible due to the extremely brittle brachial artery and accompanying veins. The blood supply distal to the aneurysm was secured by collaterals, and the aneurysm, including a relatively long portion of the brachial artery and veins adjacent to the aneurysm, was resected. The patient died of massive hemorrhage from the subclavian artery of the involved side 9 days postoperatively. Histological and immunohistological examinations of the tissues involved in the ruptured aneurysm were conducted. The resected brachial artery and veins were surrounded by hypertrophied tissue which tested positive for S-100 protein and negative for desmin and action. These findings suggest that the origin of the proliferating tissue was not mesodermal dysplasia, but neurofibroma occurring near or in the vessels. A ruptured aneurysm in a patient with neurofibromatosis should not be treated with reconstruction of the vessels. The treatment of choice is surgical or endovascular occlusion of the vessels involved.     

Atypical aortic coarctations in type I neurofibromatosis

AIM: Quantification of haemodynamics of the peripapillary choroid in and the assessment of possible differences between normal subjects (N), ocular hypertensive (OHT), primary open angle (POAG), and normal pressure glaucoma (NPG) patients. METHODS: Video fluorescein angiograms (Rodenstock SLO 101) were made in 22 N subjects, 12 OHT, 48 POAG, and 46 NPG patients. The angiographically derived dye build up curves were described by means of an exponential model. One of the model parameters is the time constant tau theoretically reflecting local blood refreshment time; the blood refreshment time tau is the time needed to replace the blood volume in the choriocapillaris, inversely proportional to the local choroidal blood flow. Other variables are maximal fluorescence (Fdt) and time of first fluorescence (t0). Mean variable values were calculated for disc area and circular areas around the disc. RESULTS: Fdt of the disc was significantly lower in the POAG and NPG patients. There was no statistical difference in t0 between the study groups. The choroidal blood refreshment time was significantly longer in NPG patients and to a lesser extent in the POAG patients compared with the normal controls. The slowest choroidal blood refreshment can be found in the NPG group. The median choroidal blood refreshment times (25th-75th percentile) in the controls, OHT, POAG, and NPG patients were 4.1 (3.7-4.5), 4.4 (3.7-6.4), 5.8 (4.3-6.8), and 7.1 (5.5-9.3) seconds respectively. CONCLUSIONS: With the help of parametrisation of dye curves, using a one compartmental model, choroidal haemodynamics can be quantified. The blood refreshment time of the peripapillary choriocapillaris was found to be significantly prolonged especially in NPG patients; this may indicate slower choroidal haemodynamics in NPG patients.     

Learning disability subtypes in children with neurofibromatosis

A high incidence of learning disabilities (LD) has been reported in children with neurofibromatosis Type 1 (NF-1), and many children affected with this disease are thought to have a form of LD that is characterized by selective visuospatial and motor deficits. However, the evidence is subject to sampling biases and is limited by the clinical-inferential methods used to classify children into LD subtypes. In the present study, objective statistical methods were used to categorize LD in 105 children with NF-1 between the ages of 6 and 18 years. A cluster analysis of achievement test scores yielded 10 groups; 6 of which met our criterion for academic deficiency. An analysis of neuropsychological data for 72 children with academic deficiencies with complete neuropsychological data yielded three groups: a neuropsychologically normal group (n = 28), a group with general academic deficiencies (n = 34), and a group with visuospatial-construction deficiencies (n = 10). The low incidence of visuospatial-constructional deficits and the absence of cases involving pure linguistic deficits is notable.     

NF2 gene in neurofibromatosis type 2 patients

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that predisposes to nervous system tumors. The schwannomin (also termed merlin) protein encoded by the NF2 gene shows a close relationship to the family of cytoskeleton-to-membrane proteins linkers ERM (ezrin-radixin-moesin proteins). Even though penetrance of the disease is >95% and no genetic heterogeneity has been described, point mutations in the NF2 gene have been observed in only 34-66% of the screened NF2 patients, depending on the series. In order to generate tools that would enable an exhaustive alteration screening for the NF2 gene, we have deduced its entire genomic sequence. This knowledge has provided the delineation of a mutation screening strategy which, when applied to a series of 19 NF2 patients, has revealed a high recurrence of large deletions in the gene and has raised the efficiency of mutation detection in NF2 patients to 84% of the cases in this series. The remaining three patients who express two functional NF2 alleles are all sporadic cases, an observation compatible with the presence of mosaicism for NF2 mutation.     

Mutations in von Recklinghausen neurofibromatosis: an hypothesis

Von Recklinghausen neurofibromatosis or neurofibromatosis type I (NF1) is a relatively frequent (1/3,000 livebirths) autosomal dominant condition. Some unusual aspects are noted in this disorder: new mutations are frequent and almost all are of paternal origin without parental age effect. The recurrence of NF1 among children of healthy parents is rare as opposed to other dominant disorders. I propose that in NF1 (1) new mutations occur often in somatic cells or in late germinal cells, however, they occur very rarely in early germinal cells leading to germinal mosaicism and (2) the individual with somatic mosaicism presents symptoms of the disease. Therefore, an NF1 patient with an apparent new mutation is often a somatic mosaic for the mutation and if the mosaic is also present in germinal cells some of his children will be affected. This hypothesis may explain the unusual aspects of mutation in NF1.     

Cognitive control in adolescents with neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by partial loss of growth control that affects the central nervous system. NF1 has been consistently associated with cognitive dysfunction, although there is no consensus on the cognitive profile in NF1 or on brain-cognition relationships. To clarify the pattern of cognitive dysfunction, performance of 16 NF1 patients and 16 age- and sex-matched controls (mean age = 14.5 years, SD = 1.3) was compared on computerized tasks measuring perception, executive functioning (inhibitory control, cognitive flexibility, and working memory), and motor control. A further aim of this study was to contrast performance on tasks or task parts requiring varying levels of cognitive control to find out whether this could explain potential difficulties experienced by this population in different cognitive domains or at different stages of information processing. Repeated measures analyses of variance showed that group differences, indicating poorer performance of NF1 patients, varied as a function of the level of cognitive control required. Evidence was also found for more basic motor skill problems in NF1 patients. Furthermore, NF1 patients were generally slower than controls. Results are discussed in the context of what is known about brain-cognition relationships in NF1. (PsycINFO Database Record (c) 2010 APA, all rights reserved)