Bilateral vestibular schwannomas in older patients: NF2 or chance?

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant condition with high spontaneous mutation rate which predisposes to the development of multiple nerve sheath tumours (schwannomas), meningiomas and ependymoma. The cardinal feature and main diagnostic criterion for the diagnosis of NF2 remains the development of bilateral vestibular schwannoma (BVS). With increasing use of MRI screening the possibility of a 'chance' diagnosis of BVS has been mooted with a potential frequency of one in two million people in their lifetime. Until now, however, no evidence for such an event has been published. We aimed to demonstrate that chance occurrence can occur and to estimate its frequency among those with just BVS late in life. METHODS: Two vestibular schwannomas from the same patient were DNA sequenced and underwent loss of heterozygosity analysis. RESULTS: We show that a man who developed BVS, at ages 52 and 67 years developed these tumours sporadically by demonstrating that there were no molecular events in common between the two tumours. Furthermore from a database of over 1200 patients with NF2, we have estimated that ~25% of cases of BVS over 50 years and 50% over 70 years of age where no other features of NF2 are present represent a chance occurrence rather than due to an underlying mosaic or constitutional NF2 mutation. CONCLUSIONS: Patients presenting with BVS later in life should be appraised of the potential likelihood they may not have NF2 and the resultant further reduction in risks of transmission to offspring.

Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma?

Early onset of vestibular schwannoma (VS) is associated with the inherited condition neurofibromatosis type 2 (NF2). However, the majority of NF2 presents bilaterally and the proportion of early-onset apparent sporadic unilateral VS because of NF2 remains to be determined. We have determined the risk by studying NF2 risk in a population-based set of VS, looking at the mode of presentation in a large NF2 data set and the outcome of NF2 mutation analysis in 148 sporadic unilateral VS. The risk of NF2 in an apparently sporadic case of unilateral VS is small apart from in the very youngest age group (<20 years). NF2 germ line mutation testing is unlikely to reveal a mutation except <20 years as a result of the low risk and high rates of mosaicism. Germ line mutation testing is probably only justified in sporadic unilateral VS <20 years unless other features of NF2 are present. Ideally mutation testing should start with the original tumour specimen.

Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification.

BACKGROUND: Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism in the first affected generation. However, the implications of this on transmission risks have not been fully elucidated. METHODS: The expanded database of 460 families with NF2 and 704 affected individuals was analysed for mosaicism and transmission risks to offspring. RESULTS: 64 mosaic patients, with a projected mosaicism rate of 33% for sporadic classical NF2 with bilateral vestibular schwannoma at presentation and 60% for those presenting unilaterally, were identified. Offspring risks can be radically reduced on the basis of a sensitive mutation analysis of blood DNA including multiple ligation-dependent probe amplification (MLPA, which detects 15% of all mutations), but even MLPA cannot detect high levels of mosaicism. CONCLUSION: The chances of mosaicism in NF2 and the resultant risks of transmission of the mutation to offspring in a number of different clinical situations have been further delineated. The use of MLPA in this large NF2 series is also reported for the first time.

Long term performance of atrial leads.

Long term performance of 163 atrial leads implanted in 158 patients between July 1981 and June 1993 was evaluated. There were 122 DDD and 36 AAI units, with 125 (77%) polyurethane and 38 (23%) silicone leads. One hundred and nine (67%) unipolar and 54 (33%) bipolar leads were used. Patients were followed in the Pacemaker Clinic for 6 to 124 months (mean 50 +/- 39 months). Five patients were lost to follow up. Transient malfunction was observed in 18 cases (sensing 13, pacing 5) within the first 2 weeks. In 13 cases failure to sense subsided spontaneously and in 4 pacing malfunction could be corrected by reprogramming. Lead dislodgement occurred in 4 patients (2.5%), all within the first week. After the 1st month malfunction was uncommon. Between 1 and 12 months undersensing occurred in 4 (2.5%). In 3 cases it could be corrected by reprogramming. In the first year, reoperation was performed in 5 cases for lead related problems (3 dislodgements, 2 insulation failures). Beyond 12 months complications were as follows: failure to sense-8 (5%), failure to pace-3 (2%), insulation break -1 (0.6%). Majority of these problems could be managed by reprogramming. Reoperation was performed in 1 case with insulation break. The pacing mode had to be changed in 5 (3%) patients with dual chamber units who had loss of P wave sensing. During follow-up 98%, 98%, 96%, 95% and 83% of the leads were working satisfactorily at 1,2,3,4 and 9 years respectively. Thus atrial leads have excellent long term performance and an acceptable rate of late malfunction.