Victor-Felix Mautner

Diagnostic criteria for schwannomatosis

The neurofibromatoses are a diverse group of genetic conditions that share a predisposition to the development of tumors of the nerve sheath. Schwannomatosis is a recently recognized third major form of neurofibromatosis (NF) that causes multiple schwannomas without vestibular tumors diagnostic of NF2. Patients with schwannomatosis represent 2.4 to 5% of all patients requiring schwannoma resection and approximately one third of patients with schwannomatosis have anatomically localized disease with tumors limited to a single limb or segment of spine. Epidemiologic studies suggest that schwannomatosis is as common as NF2, but that familial occurrence is inexplicably rare. Patients with schwannomatosis overwhelmingly present with pain, and pain remains the primary clinical problem and indication for surgery. Diagnostic criteria for schwannomatosis are needed for both clinicians and researchers, but final diagnostic certainly will await the identification of the schwannomatosis locus itself.

Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas

Neurofibromatosis 2 (NF2) is a severe autosomal dominant disorder that predisposes to multiple tumours of the nervous system. About half of all patients are founders with clinically unaffected parents. The purpose of the present study was to examine the extent to which mosaicism is present in NF2 founders. A total of 233 NF2 founders with bilateral vestibular schwannomas (BVS) were screened by exon scanning. NF2 mutations were detected in the blood samples of 122 patients (52%). In 10 of the 122 cases, the ratio of mutant to normal alleles was obviously less than 1, suggesting mosaicism. Tumour specimens were available from 35 of the 111 subjects in whom no mutation could be detected in blood specimens. Mutational analysis by exon scanning detected typical NF2 mutations in 21 of the 35 tumours. In nine subjects, the alterations found in tumours could be confirmed to be the constitutional mutation based on finding of identical mutations in pathologically and/or anatomically distinct second tumours. In six other subjects with only a single tumour available, allelic loss of the NF2 gene was found in addition to the mutation in each tumour, suggesting that either the mutation or the deletion of the NF2 gene is probably the constitutional genetic alteration. Our results suggest that failure to find constitutional mutations in blood specimen from these 15 patients was not because of the limitation of the applied screening technique, but the lack of the mutations in their leucocytes, best explained by mosaicism. Extrapolating the rate (15/35 = 43%) of mosaicism in these 35 cases to the 111 NF2 founders with no constitutional NF2 mutations found in their blood, we inferred 48 mosaic subjects (111 × 0.429). Adding the 10 mosaic cases detected directly in blood specimens, we estimate the rate of mosaicism to be 24.8% (58/233) in our cohort of 233 NF2 founders with bilateral vestibular schwannomas.

Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety

Abstract In neurofibromatosis type 1 (NF1) spinal tumours cause neurological symptoms in about 2 % of patients. Among over 1400 patients with NF1 we saw symptomatic spinal tumours in 23 (1.6 %). MRI of the entire spinal canal was obtained in 54 patients aged 5–56 years with NF1. The number, site, morphology and signal characteristics of the spinal tumours were recorded and analysed. There were 24 patients with symptoms such as sensory impairment or paralysis; 30 patients had no neurological deficits. Of the 24 symptomatic patients, 23 (96 %) had spinal tumours, while we saw spinal tumours in 12 (40 %) of the 30 patients without neurological deficits. No spinal segment was preferred in symptomatic or asymptomatic patients. Most intraspinal extramedullary tumours were primarily extradural and intraforaminal. MRI showed intramedullary tumours in 3 patients (6 %), intraspinal extramedullary tumours in 18 (33 %) and intraforaminal tumours in 31 (57 %). Only neurological deficits in patients with NF1 should prompt further diagnostic clarification. In patients with neurological symptoms there may be a multiplicity of masses in the spinal canal, which can lead to difficulties in attaching symptoms to a certain tumour. In patients who do not satisfy the NIH criteria, it can be a helpful observation that spinal tumours in NF1 are primarily intraforaminal, extending into the spinal canal, while in NF2 they are mostly intraspinal intradural tumours.

Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions

Background Large deletions of the NF1 gene region occur in ∼5% of patients with neurofibromatosis type-1 (NF1) and are associated with particularly severe manifestations of the disease. However, until now, the genotype–phenotype relationship has not been comprehensively studied in patients harbouring large NF1 gene deletions of comparable extent (giving rise to haploinsufficiency of the same genes). Method We have performed the most comprehensive clinical/neuropsychological characterisation so far undertaken in NF1 deletion patients, involving 29 patients with precisely determined type-1 NF1 (1.4 Mb) deletions. Results Novel clinical features found to be associated with type-1 NF1 deletions included pes cavus (17% of patients), bone cysts (50%), attention deficit (73%), muscular hypotonia (45%) and speech difficulties (48%). Type-1 NF1 deletions were found to be disproportionately associated with facial dysmorphic features (90% of patients), tall stature (46%), large hands and feet (46%), scoliosis (43%), joint hyperflexibility (72%), delayed cognitive development and/or learning disabilities (93%) and mental retardation (IQ<70; 38%), as compared with the general NF1 patient population. Significantly increased frequencies (relative to the general NF1 population) of plexiform neurofibromas (76%), subcutaneous neurofibromas (76%), spinal neurofibromas (64%) and MPNSTs (21%) were also noted in the type-1 deletion patients. Further, 50% of the adult patients exhibited a very high burden of cutaneous neurofibromas (N≥1000). Conclusion These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.

Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes

Abstract Neurofibromatosis 2 (NF2) is an autosomal inherited disorder that predisposes carriers to nervous system tumors. To examine genotype-phenotype correlations in NF2, we performed mutation analyses and gadolinium-enhanced magnetic resonance imaging of the head and full spine in 59 unrelated NF2 patients. In patients with vestibular schwannomas (VSs) or identified NF2 mutations, the mild phenotype was defined as <2 other intracranial tumors and ≤ 4 spinal tumors, and the severe phenotype as either ≥ 2 other intracranial tumors or > 4 spinal tumors. Nineteen mutations were found in 20 (34%) of the patients and were distributed in 12 of the 17 exons of the NF2 gene, including intron-exon boundaries. Seven mutations were frameshift, six were nonsense, four were splice site, two were missense, and one was a 3-bp in frame deletion. The nonsense mutations included one codon 57 and two codon 262 C→T transitions in CpG dinucleotides. The frameshift and nonsense NF2 mutations occurred primarily in patients with severe phenotypes. The two missense mutations occurred in patients with mild phenotypes, and three of the four splice site mutations occurred in families with both mild and severe phenotypes. Truncating NF2 mutations are usually associated with severe phenotypes, but the association of some mutations with mild and severe phenotypes indicates that NF2 expression is influenced by stochastic, epigenetic, or environmental factors.

Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2

Bilateral vestibular schwannomas are the hallmark of neurofibromatosis type 2 (NF2), and these tumors impair hearing and frequently lead to deafness. Neurosurgical intervention, the only established treatment, often damages the vestibular nerve. We report 2 cases in which treatment with bevacizumab (for 3 months in one case and 6 months in the other) induced regression of progressive vestibular schwannomas by more than 40% and substantially improved hearing in the patient treated for 6 months. Bevacizumab therapy may thus provide an effective treatment for progressive vestibular schwannomas in patients with NF2.

MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3000. Approximately 30% of NF1 patients develop plexiform neurofibromas (PNF) which often cause severe clinical deficits. We studied the growth patterns of 256 plexiform neurofibromas (PNF) by magnetic resonance imaging (MRI) and associated disfigurement and functional deficits to determine whether there are definable growth types of these tumors. Retrospectively, we evaluated MRI scans obtained during 1997 to 2003 of 256 plexiform neurofibromas from 202 patients with NF1. Clinical investigation was carried out at the same time as the MRI scans. We identified three growth patterns: superficial in 59, displacing in 76, and invasive growth in 121 tumors. The majority (52%) of invasive PNF were found in the face, head and neck area. While superficial PNF primarily caused aesthetic problems, displacing PNF led in most cases to aesthetic problems and pain, while invasive PNF led mainly to functional deficits and disfigurement. Our study demonstrates that PNF have different growth patterns that are associated with specific clinical features. Classification of PNF may open new opportunities in clinical management, especially regarding decisions and options associated with surgical intervention.

Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1)

Background: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood. Methods: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients. Results: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with NF1 studied had BMD consistent with osteopenia, and 14 (19%) had BMD consistent with osteoporosis. High serum PTH concentration, high serum bone tartrate resistant acid phosphatase concentration, and high serum calcium concentration were associated with lower BMD among the NF1 patients. Males were more likely than females to have low BMD. The reported frequency of fractures in individuals with NF1 was much higher than in their unaffected siblings and spouses (p<0.001), and pathological fractures were reported only in NF1 patients. Conclusion: People with NF1 often have a generalised abnormality of bone metabolism. Further studies are needed to determine the biochemical and molecular basis of this abnormality.

Jaw malformations plus displacement and numerical aberrations of teeth in neurofibromatosis type 1: a descriptive analysis of 48 patients based on panoramic radiographs and oral findings

AIM The aim of this study was to analyse jaw malformations and tooth displacement in patients with neurofibromatosis type 1 (NF1). MATERIAL AND METHODS Forty-eight patients were included in the study (male or female 24 each). All fulfilled the current NIH diagnostic criteria for NF1. The age range was 2.5-66 years. The type of neurofibroma was histologically proven in surgically treated patients. Patients with disseminated cutaneous neurofibromata and those with the plexiform type were distinguished. The analysis was based on physical investigation, photographs, panoramic radiographs and dental casts. RESULTS With the emphasis on alterations of tooth position, deformities of the adjacent bones and malocclusion, the majority of these patients (26) were affected by plexiform neurofibromata. In the other 22 patients with disseminated neurofibromata, malformations of the alveolar ridge were absent and individual oral symptoms were rarely found and were mild, and in all cases were unimpaired. Numerical aberrations and retention of molars was exclusively associated with a trigeminal nerve affected by plexiform neurofibroma. Aplasia of a second lower molar was recognized in four of these plexiform-neurofibroma patients. CONCLUSION It is widely accepted that malformations of the facial skeleton are often of genetic origin. However, in this study these malformations were strongly associated with plexiform neurofibromata originating from the trigeminal nerve. Thus, in addition to presently unknown genetic factors, the pattern of skeletal malformation can be caused by tumour invasion and local destruction, e.g. the neuromuscular unit or prenatal development of the plexiform neurofibroma in the inferior alveolar nerve. It is further concluded that epidemiologic studies on the incidence and severity of NF1 in the oral and maxillofacial region have to distinguish between patients with or without plexiform neurofibroma, especially when analysing alterations and deformities of the jaws, teeth and malocclusion. Aplasia of second inferior molars is an additional (dental) finding associated with plexiform neurofibromata in NF1.

Hybrid Neurofibroma/Schwannoma is Overrepresented Among Schwannomatosis and Neurofibromatosis Patients

We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses.