A Clinical Study of Type 2 Neurofibromatosis

Transcription

1 Quarterly Journal of Medicine, New Series 84, No. 304, pp , August 1992 A Clinical Study of Type 2 Neurofibromatosis DGR EVANS t, SM HUSON*, D DONNAI, W NEARY, V BLAIR, V NEWTONt and R HARRIS From the ^Department of Medical Genetics, St Mary's Hospital, Manchester, *Department of Medical Genetics, Churchill Hospital, Oxford, ^Centre for Audiology, Education of the Deaf and Speech Pathology, University of Manchester, %CRC Department of Cancer Genetics, Peterson Institute for Cancer Research, Christie Hospital Manchester, and CRC Paediatric and Familial Cancer Research Group, Christie Hospital, Manchester Accepted 12 June 1992 SUMMARY The clinical features, age at onset of symptoms and survival of 150 patients with type 2 neurofibromatosis were studied. The mean age at onset was years (n 110) and no patients presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas and spinal tumours. In 100 patients studied personally by the authors 44 per cent presented with deafness and this was unilateral in the majority (35/44). Deafness was accompanied by tinnitus in a further 10 per cent and muscle weakness or wasting was the first symptom in 12 per cent. Less common presenting symptoms were seizures (8 per cent), vertigo (8 per cent) numbness and tingling (2 per cent) and blindness (1 per cent). Eleven patients were diagnosed asymptomatically through screening. Cafe au lait spots occurred in 43 per cent (n = 43) but only one case had six. Skin tumours were detected in 68 per cent (68/100) and 38 per cent (34/90) had an identifiable lens opacity or cataract. The mean age at death in 40 cases was years and all but one death was a result of a complication of neurofibromatosis. There are marked inter-family differences in disease severity and tumour susceptibility. INTRODUCTION Neurofibromatosis type 2 is an autosomal dominant disorder characterized by the development of bilateral vestibular schwannomas. Until recently neurofibromatosis type 1 and type 2 were frequently classified as one disease, often leading to inappropriate genetic counselling and advice about screening for disease complications. The first probable case report of neurofibromatosis type 2 was that of Wishart in 1820 [1]. This patient had multiple intracranial tumours with no reported cutaneous features and was, therefore, quite different to those patients reported by von Recklinghausen in 1882 [2], whose principal features were Address correspondence to Dr DGR Evans, Department of Medical Genetics, St Mary's Hospital, Manchester M13 0JH, UK. Oxford University Press 1992

2 604 DGR Evans and others nodular skin lesions with no intracranial tumours. Following von Recklinghausen's report, however, authors reported cases of neurofibromatosis type 1 with intracranial tumours and neurofibromatosis type 2 with cutaneous features [3,4]. The two conditions became lumped together and referred to as von Recklinghausen disease, or multiple neurofibromatosis. In reporting a large family with neurofibromatosis in 1930, Gardner and Frazier [5] suggested that bilateral acoustic neuromas represented a separate central form of von Recklinghausen neurofibromatosis. However, subsequent reports did not follow this suggested subclassification. In their large study of neurofibromatosis in 1956, Crowe et al. [6] did not distinguish between the two forms. They reported that 5 per cent of patients with what they called multiple neurofibromatosis had acoustic neuromas. In retrospect it is clear these patients had neurofibromatosis type 2. A follow-up study of Gardner and Frazier's family in 1971 [7] again concluded that the disorder was distinct from that described by von Recklinghausen, and suggested that it should be called central neurofibromatosis. The division of the two types of neurofibromatosis then became widely accepted [8, 9]. Subsequent studies of large populations of patients with type 1 disease have shown no increased incidence of acoustic neuroma [10, 11]. They have also shown the quite different natural history of neurofibromatosis type 1, in which various complications affect all of the main body systems and occur at random, even within families. The National Institute of Health Consensus Statement on neurofibromatosis in 1987 [12] gave clear guidelines on nomenclature, recommending the use of neurofibromatosis type 1 rather than peripheral or von Recklinghausen neurofibromatosis and type 2 rather than central or bilateral acoustic neurofibromatosis. In the same year the mapping of the gene for neurofibromatosis type 1 to chromosome 17 [13, 14] and that for type 2 to chromosome 22 [15, 16] confirmed the clinical impression of two distinct diseases. A further nomenclature change with regard to neurofibromatosis type 2 was made at the recent National Institute of Health Consensus Conference (Dec 1991) on 'acoustic neuroma'. The tumours are histologically schwannomas of the vestibular branch of the eighth cranial nerve. The conference recommended replacing the term acoustic neuroma with vestibular schwannoma. Recent studies of neurofibromatosis type 2 have drawn attention to new disease features, namely lens opacities [17] and a specific type of cutaneous tumour [18]. Neither of these have been assessed in a large series of patients nor has their use in screening at-risk relatives been assessed. It has also been suggested that there may be at least two distinct forms of neurofibromatosis type 2 [19]. One has early onset, rapid course and multiple other tumours in addition to bilateral vestibular schwannomas (Wishart type). The other has late onset, a more benign course and usually just bilateral vestibular schwannomas (Gardner type). In affected individuals with bilateral vestibular schwannomas, the problem is whether or when to operate. In the study of Young et al. [20], affected individuals who had not had surgery survived longer than those who did. Improved surgical technique led the NIH consensus conference on neurofibromatosis to recommend early surgery for vestibular schwannoma in 1987 [12]. Experience has not been as successful as for unilateral tumours and the consensus conference on neurofibromatosis in 1990 suggested that watchful waiting may be more appropriate for tumours without serious symptoms. Our interest in neurofibromatosis type 2 has developed from the setting up of a neurofibromatosis register in the North West Regional Health Authority in 1988 and through our endeavours to clone the neurofibromatosis type 2 gene. The need for a large study of this condition to determine natural history further, look at the newly recognized features and address the question of clinical heterogeneity became obvious. We report here

3 A clinical study of type 2 neurofibromatosis 605 the clinicalfindingsof our nationwide UK study of neurofibromatosis type 2. The detailed genetic analysis and surgical aspects of the study are reported in detail elsewhere [21, 22]. PATIENTS AND METHODS The study was carried out from May 1989 until January It began with a prevalence study in the North Western Regional Health Authority of England and then extended throughout the UK. Patients were ascertained by contacting neurosurgeons, ENT surgeons, neurologists, paediatricians, dermatologists and geneticists throughout the UK. In the North Western Region case identification was augmented by using the North West Regional Cancer Registry. All individuals and families fulfilling the diagnostic criteria for neurofibromatosis [12] (Table 1) were entered into the study. In addition to known cases of bilateral vestibular schwannoma, any cases of unilateral vestibular schwannoma with spinal tumour or meningioma, multiple meningioma and multiple spinal tumours were studied. Affected individuals and their first-degree relatives where possible were visited at home after appropriate permission had been granted by the involved clinician. A detailed questionnaire was then filled in with the patient and at-risk relatives. This concentrated on features leading to deafness, the age at which it occurred and whether it was unilateral or bilateral at presentation. Other allied symptoms such as tinnitus, vertigo, problems with balance and speech were then addressed. Any possible unrelated cause of deafness such as administration of aminoglycosides, exposure to noise and infections such as measles and mumps was also determined. Problems with weakness, wasting, numbness, tingling, headaches and general questions about non-neurological symptoms were also included. The individual was then examined clinically with special emphasis on skin, nervous system and eyes. Slit lamp examination was possible in the later stages of the study. Patients and families were placed in diagnostic groups as suggested by Eldridge and others [ 19] on the basis of their age at onset and whether meningioma and spinal tumours were present. RESULTS A total of 155 patients were enterd into the study. Patients with multiple meningiomas or multiple spinal tumours without vestibular schwannoma and with no skin or eye manifestations were excluded. Because of the relatively rigid diagnostic criteria only five patients originally referred as affected were removed from the study. The first patient had multiple spinal schwannomata but no skin signs, no cataract and no intracranial tumours on CT scan; his family history was also negative. The second patient had a unilateral vestibular TABLE 1. Diagnostic criteria for neurofibromatosis type 2 Bilateral vestibular schwannomas or family history of neurofibromatosis type 2 plus (1) Unilateral acoustic or (2) Any two of: meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities. Additional criteria (2) Also cerebral calcification Unilateral acoustic +(2) Multiple meningioma (2 or more) + unilateral acoustic or any 2 of: glioma, neurofibroma, schwannoma, cataract, cerebral calcification.

4 606 DGR Evans and others schwannoma and no other features of neurofibromatosis type 2, but was thought to have a family history of at least 2 close relatives with vestibular schwannoma. After examination of hospital records no clear evidence of acoustic tumour was documented in his deceased relatives, and he was therefore also excluded from the study. The mother of two children was thought to have died with acoustic and spinal tumours, but search of her hospital records revealed only features of neurofibromatosis type 1 and the two children on review clearly also had type 1 disease. A final patient aged 60 with multiple meningiomata was excluded as she had no other feature of neurofibromatosis type 2. Full clinical details were available for 120 of the 150 patients fulfilling the diagnostic criteria for neurofibromatosis type 2, and 100 were personally studied by the authors. One family in which two individuals had meningiomas, spinal and skin tumours and two isolated patients with a unilateral vestibular schwannoma and three and four meningiomas, respectively were included, as was one isolated patient with multiple unilateral vestibular schwannomas and a trigeminal neuroma. These latter cases, although not fulfilling the strict NIH diagnostic criteria outlined in Table 1, were considered to be affected as they did not have features consistent with simple isolated autosomal dominant multiple spinal tumours or multiple meningiomas. The full details of the 120 patients in terms of their diagnostic criteria and presence of central nervous system tumours is presented in Table 2. Of the 150 patients 110 are alive; the mean age at death in the remaining 40 was years (range 16-67). When the North West regional cases were compared with those from the rest of the UK, there was no suggestion of ascertainment bias in the latter group. Therefore, apart from in looking at disease prevalence the group is considered as a whole. PREVALENCE In the North West Region, where 100 per cent ascertainment was likely, 19 living cases were identified in a study population of 4.01 x This represented a diagnostic prevalence of 1 in TABLE 2. Diagnostic criteria, mean age at onset and clinical subtype in 120 cases with NF2. Families and sporadic cases were subdivided into Gardner or Wishart types (see text). The diagnostic criteria for every individual are shown Diagnostic criteria Gardner type Wishart type All cases Bilateral VS 46 (28.3)* 4(11.25) Bilateral VS+cranial meningiomas 5 (24.2) 19(19.1) Bilateral VS +spinal tumours 0 9 (14.4) Bilateral VS+meningioma and spinals 0 19(18.7) Family history + unilateral VS 2 (20.45) 1(11) Family history + cranial meningiomas 1(29) 3(29) Family history + spinal tumours 1(11) 0 Family history + meningioma + unilateral VS 1(8) 1(3) Family history + meningioma + spinal tumour 1(6) 0 Family history + cataract + peripheral tumour 1(19) 0 Family history + cranial schwannoma 1(42) 0 Unilateral VS meningiomas 0 2(35) Family history + cerebral calcification 1(8) 0 + peripheral tumour Meningiomas, spinal tumours + peripherals 0 2(13) 50 (27) 24 (20) (17.3) 4 (29.5) VS, vestibular schwannoma * Numbers in parentheses are years.

5 A clinical study of type 2 neurofibromatosis Birth incidence has also been calculated from our data, the calculation being presented in detail elsewhere [21]; the birth incidence is estimated to be 1 in NATURAL HISTORY The major disease features that allowed a diagnosis of neurofibromatosis type 2 to be made in the 120 cases for which we have full clinical details are shown in Table 2. A summary of age at presentaton and other disease features is shown in Table 3. First Manifestation of Neurofibromatosis Type 2 We have included only the 100 cases studied personally, so that we could be sure of the first attributable symptom. Skin lumps or cataract was excluded as these were usually asymptomatic. Deafness was the first symptom in 44 (44 per cent) and this was unilateral in 35 patients. Tinnitus which may have been accompanied by some deafness was the first perceived problem in 10 patients (10 per cent). Vertigo or loss of balance was the first symptom in 8 patients (8 per cent). Symptoms attributable to other nervous system tumours were the presenting feature in the remainder. Twelve patients presented with muscular weakness or wasting (12 per cent), 8 (8 per cent) with seizures and four (4 per cent) with nerve root pain. Blindness (one patient) and numbness and tingling (two patients) were less common features. Eleven patients (11 per cent) were diagnosed asymptomatically (although six are now symptomatic with deafness or balance problems). These cases were detected on screening first-degree relatives of known cases with brain stem evoked responses and cranial CT or MRI scans. Age at Onset Mean age at first symptom («=110) was years (range 2-52) and at diagnosis of neurofibromatosis type 2, years (range 5-66). The age distribution of onset of TABLE 3. Age at onset, death and frequency of tumour types for each clinical subgroup and for neurofibromatosis type 2 as a whole Clinical subgroup Gardner Wishart All cases Number of cases Number of families Isolated cases Age at onset (years) Age at death (years) (n = 5) (n = 20) 22.2 Meningiomas (%) Spinal tumours (%) Skin tumours (%) > 10 skin tumours (%) Cafe au lait (%) Cataracts (%) Astrocytoma (%) Ependymoma (%) Optic sheath meningioma (%)

6 608 DGR Evans and others 0 S Age ^H age at first symptom FIG. 1. Age of onset in 120 patients with neurofibromatosis type 2. symptoms is shown in Fig. 1. Mean age at onset of deafness was years (range 4-50) in 87 patients, although two obligate gene carriers with other complications have no evidence of deafness or vestibular schwannoma on scan at the ages of 52 and 61 years. Eleven patients (10 per cent) presented with features before the age of 10 years; only four of these were due to vestibular schwannoma (deafness 4 years, facial palsy 3, 7, 8 years). Another patient developed deafness at 3 years although this was due to a cerebellopontine angle meningioma. Three patients presented with fits (meningioma 5,6 years, cerebral calcification 8 years), one with unilateral blindness and amblyopia (optic sheath meningioma, aged 5 years), one with intractable headache (meningioma, aged 2 years), and one with foot drop (aged 6 years). Course of the disease Mean age at death in 40 cases was years. Mean actuarial survival from diagnosis was 15 years which gave a mean age at death of years if mean age at diagnosis was used. Mean actuarial survival in 150 cases was 62 years; however, over 40 per cent would be expected to have died by 50 years and all cases by 70 years. A survival curve is shown in Fig. 2. % ally* O I % alive with NF2 FIG. 2. Survival curve from actuarial data on 150 patients with neurofibromatosis type 2 (110 living).

7 Effect of Gender on Disease A clinical study of type 2 neurofibromatosis 609 The mean age at onset of symptoms in 51 women with neurofibromatosis type 2 was years and at diagnosis years. In 59 men the ages for onset and diagnosis were and years respectively. Age at onset of deafness was 24.1 years in women («= 40) and 24.3 years in men in = 47). There was, therefore, no clear difference in disease course between men and women. Effect of Pregnancy There was no instance of death or need for urgent intervention in pregnancy in women in our series. At least two women reported an increase in symptoms during or soon after pregnancy, but these did not require intervention. In one case symptoms such as tinnitus resolved after the pregnancy. Several women who were symptomatic before pregnancy went through up to four pregnancies without recourse to surgery. MORBIDITY AND MORTALITY Many patients have a progressively deteriorating disease course with loss of hearing, ambulatory ability and often sight. They may require enormous physical and mental support from their families or require admission to an institution. Fifteen per cent of patients were effectively wheelchair and bed-bound when examined. During the course of this 2-year study eight patients have died. Surgical procedures, although still the mainstay of treatment, may add to morbidity. In 113 vestibular schwannoma operations performed on this series, hearing was preserved in less than 10 per cent and some degree of facial nerve disfunction was present in over 70 per cent post-operatively. Loss of facial nerve function led to effective blindness in one patient as she already had bilateral loss of corneal reflexes from trigeminal nerve involvement. HETEROGENEITY One of the major factors determining the natural history of neurofibromatosis type 2 was the course of the disease known to occur in the family if they were not the first case. The condition appears to breed relatively true in families, with late age at onset and vestibular schwannomas only in many patients with minimal skin signs if any, and a more severe form with spinal tumours, meningiomas and more profound skin signs with early onset in others. There is no evidence from this study for a separate sporadic form of neurofibromatosis type 2, as familial cases are found even in the most severe categories. A recent report suggested the subdivision of neurofibromatasis type 2 into three categories [19]: the 'Gardner' type [5], being the late onset variety, with early onset in the 'Wishart' type [1] and general meningiomatosis in the 'Lee Abbott' type [23]. In Tables 2 and 3 we have subdivided the families and sporadic cases into thefirsttwo groupings but could notfindsufficient evidence for the third. Meningiomas and spinal tumours may still occur at a young age in families with the Gardner type of disease. Late onset is unusual in families with severe disease (Wishart type) and many of these may be due to new mutation as the reproductivefitnessis reduced. There are, however, cases which appear to fall between the two groups and classification is often artificial, particularly in new mutations, when there are no further relatives to compare with.

8 610 DGR Evans and others CLINICAL FEATURES Peripheral Features Cafe au lait spots Examination of the skin in the 100 patients personally studied revealed that only 43 (43 per cent) had cafe au lait patches. Ofthese24had one patch, 11 had two, four had three and three had four patches. Only one patient had six cafe au lait patches. Axillary and groin freckling was not convincingly found in any patient. Skin tumours Evidence of skin tumour was found in 68 patients (68 per cent) and varied in number from 1 to 27. Only 10 patients (10 per cent) had more than 10 skin tumours; the average number in those that manifested skin lumps was 5.8. The tumours appeared clinically to be of three different types. The first and least common was similar to the intradermal papillary skin neurofibroma with violaceous colouring occurring in neurofibromatosis type 1; these were present in 27 per cent of patients. The second type comprised subcutaneous well circumscribed, often spherical, tumours (Fig. 3). These appear to be occurring on peripheral nerves and the thickened nerve could often be palpated at either end of the tumour, the skin being mobile and separate from the tumour. The final type, first described by Martuza and Eldridge [18], were discrete, well circumscribed, slightly raised, roughened, areas of skin often pigmented and accompanied by excess hair. The second and third types were the most numerous, present in 43 per cent and 48 per cent of patients, respectively. Some patients had a predilection for one type and not the others, but in some patients all three types were present. The overall incidences of the skin tumours were: type 1, 75 of 372 (20 per cent); type 2,122 of 372 (33 per cent); and type 3,175 of 372 (47 per cent). No patient in this study had any areolar neurofibromas and there was no convincing evidence of a plexiform neurofibroma. One case did however have an extracranial meningioma which had infiltrated the face and appeared clinically indistinguishable from a plexiform tumour. Eye findings Cataracts were specifically sought. Ninety patients were examined ophthalmo- FIG. 3. Type 2 or deep skin lumps, well defined and palpable separate from the skin. The thickened peripheral nerve was felt at either end of the lump on the forearm. The hand and fingers are also a common site as here.

9 A clinical study of type 2 neurofibromatosis 611 logically and 55 underwent slit lamp examination. Thirty-four patients (38 per cent) have been identified as having lens opacities. Only 4 have required slit lamp examination to visualize them, but 60 per cent (33/55) of those having slit lamp examination have had opacities identified. Fifteen cases had been identified as having cataracts in childhood, of which 4 cases had minimal vision in the affected eye probably from birth. The ophthalmic findings are the subject of a separate more detailed study, but it appears that a congenital polar cataract also occurs in addition to the presenile posterior lenticular opacities previously noted [17]. In addition to this, one case at 50 per cent risk had a cataract associated with hyperplastic persistent primary vitreous, and another had anisometropic amblyopia being blind in one eye without a cataract. A further 4 cases at 50 per cent risk were identified as having polar cataracts but were not included as affected as they had not yet developed other features. Lisch nodules were found in only 2/55 cases who had slit lamp examination, these exhibited one nodule each. Neurological Features Vestibular schwannoma related All cases with established vestibular schwannoma (Fig. 4) had problems with balance. Thirteen of 60 individuals complained of underwater disorientation while swimming, but six had never been swimming and many others had not FIG. 4. MRI scan with gadolinium enhancement showing bilateral vestibular schwannomas in the cerebellopontine angles.

10 612 DGR Evans and others attempted to do so after onset of their problems. Forty of 92 patients complained of vertigo and 46 of 92 of having moderate or severe headaches. Twenty-five of 92 felt that their condition interfered with their speech. On examination 67 of 92 had a positive test for poor balance such as the Unterberger or Romberg test. Thirty-six of 92 had nystagmus, but only 10 of 92 manifested cerebellar signs. Other tumours Meningiomas and spinal tumours were particularly common in this study (Table 3). The majority were symptomatic and not incidental findings. Every division of the cranial nerves except olfactory was involved with a schwannoma or meningioma in at least one patient. The results of primary or secondary involvement of the cranial nerves are presented in Fig. 5 (post-operative complications and eighth nerve are not included). Astrocytoma (5 of 120), ependymoma (3 of 120), and optic nerve meningioma (5 of 120) occurred more frequently than expected in the study population. The astrocytomas and ependymomas were low grade and affected the lower brain stem or upper cervical cord, although one astrocytoma had spread to involve the entire medulla of the spine. Optic sheath meningioma was bilateral in two of five patients and resulted in complete blindness in one case. Peripheral neuropathy Many patients with advanced neurofibromatosis type 2 were severely debilitated by poor balance and generalized wasting. Three of 100 patients had good evidence of a mixed peripheral motor and sensory neuropathy, with glove and stocking loss and peripheral weakness accompanied by fasciculation. This was confirmed with nerve conduction studies and electromyography. Three further patients had an asymmetrical sensory motor neuropathy but had not undergone conduction studies or myography. Four other patients had developed sudden onset wasting of a muscle group with no obvious antecedent cause. Two were said to have had polio although there was no confirmatory evidence for this. None of the patients could be confirmed as having a tumour to initiate the problem. Intelligence Only five of the 100 patients examined had experienced any learning difficulties and none had required special schooling. The majority had achieved O-level examination passes and many had gone on to higher education. Professions included a doctor, a dentist, a lawyer and several company directors. I number of cases FIG. 5. Cranial nerve involvement in 100 patients with neurofibromatosis type 2 (excluding eighth nerve).

11 GENETICS A clinical study of type 2 neurofibromatosis 613 The pedigrees were consistent with autosomal dominant inheritance. There were many cases of male to male transmission and if only offspring of affected cases over 20 years were included nearly 50 per cent had developed neurofibromatosis type 2. New mutation was common, with 50 percent of patients having no feature of the disease present in their parents. There were no clear cases of non-penetrance, with all patients becoming symptomatic before 55 years of age. Expression was mild in some families, with no easily identifiable features in the skin or eyes and symptoms from vestibular schwannoma or meningioma not appearing until the forties or fifties in 11 per cent of cases. Maternal Gene Effect The mean age at onset of symptoms was years in 36 patients inheriting the neurofibromatosis type 2 gene from their mother and 24.5 years in 20 patients who inherited the gene from their father (p = 0.03). Anticipation We are gathering evidence on the apparent worsening of disease course and age at onset with each successive generation. DISCUSSION This is the first population based study of neurofibromatosis type 2 and is now the largest individual study of the condition. The condition was previously thought to be extremely rare [8], but this study has shown a diagnostic prevalence of 1 in , which equates to a birth incidence of 1 in [21]. The condition has been confirmed as being autosomal dominant and 50 per cent of cases are likely to represent new mutations. Within families, the natural history of neurofibromatosis type 2 is relatively consistent, although there is marked interfamily variation. It may be premature to firmly separate neurofibromatosis type 2 on clinical grounds alone, even in a study of this size, but this report adds to the evidence of this subdivision existing, especially with the survival curve showing a distinct double hump. The difficulty in classifying some cases suggests a spectrum of severity, although the groupings are certainly important for genetic counselling. It is unlikely that this clinical heterogeneity represents different genetic loci for neurofibromatosis type 2, but rather different mutations in the same gene. Firm subclassification on clinical grounds should, therefore, wait for supporting evidence from mutation studies. There is no evidence to support the theory that there is a separate severe sporadic type of neurofibromatosis type 2. A separate report [21] shows a probable worsening of the gene expression when inherited from the mother, and this has also been reported before [8]. It is not the manifestations in a family that change, but rather the age at onset and disease course becoming worse when the gene is maternally inherited. The worsening of the disease in each successive generation, first noted in 1930 [5] makes neurofibromatosis type 2 another candidate gene for anticipation. Recent molecular evidence from myotonic dystrophy [25] and fragile X syndrome make gene modification by an insertion which becomes larger a possible mechanism for neurofibromatosis type 2 as well. Although the majority of our cases satisfied the NIH criteria for neurofibromatosis type 2 there were some who did not, but who clearly had the disease. Four of our cases had

12 614 DGR Evans and others meningiomas as the sole CNS manifestation of their condition. It is extremely unlikely they did not have the disease as one was an obligate gene carrier, two were parents and the fourth was an offspring of affected cases with bilateral vestibular schwannomas. Vestibular schwannomas do not therefore reach full penetrance in cases even into the sixties. The absence of bilateral tumours should not dissuade a clinician from diagnosing neurofibromatosis type 2 in an individual with no family history, particularly if a unilateral tumour is associated with meningiomas or spinal tumours. This could represent a somatic mutation if all the manifestations are on one side. As 50 per cent of cases are new mutations some provision needs to be made for them in the diagnostic criteria. Likewise, at present a patient with multiple meningiomas and spinal and peripheral tumours would not satisfy the diagnostic criteria: currently the diagnosis can only be made without a family history when bilateral vestibular schwannomas are present. As vestibular schwannomas do not reach full penetrance and are often found some years after meningiomas and spinal tumours a change to the criteria is necessary. As a result of this study we suggest the additional criteria shown in Table 1. We found little overlap between neurofibromatosis types 1 and 2. Confusion is only likely to occur in a new mutation who presents relatively early with skin features. One at-risk relative in our series had six cafe au lait patches, but with plaque-like peripheral tumours of neurofibromatosis type 2. Neurofibromatosis types 1 and 2 have been described to co-occur in at least one patient [26]. This was clearly due to transmission of the separate genes from each parent differently affected by each condition. A further patient fulfilled the diagnostic criteria for both conditions [27], and was thought to represent a case of neurofibromatosis type 1 with bilateral vestibular schwannomas. Although vestibular schwannomas have been said to occur in excess in neurofibromatosis type 1 [ 10], there has been no recent evidence that they do so [21]. A more logical explanation is that this patient exhibited the extreme expression of the neurofibromatosis type 2 gene. Only with mutation studies of the two genes will alternative possibilities, such as new dominant mutation of both genes or the possibility of a different gene locus causing a variant form of neurofibromatosis, be elucidated [22], While these tests are not available a sensible evaluation of difficult cases with not too rigid adherence to the NIH criteria is probably wise. A child with a few skin signs should alert the clinician to the possibility of neurofibromatosis type 2. The child should be followed up with the possibility of meningiomas, spinal and acoustic tumours in mind. Previous reports of neurofibromatosis type 2 have concentrated on large families [5, 7, 8, 28-30], or have covered mainly neurosurgical aspects [31-33]. Even relatively early reports [5, 34] alluded to the paucity of peripheral features in patients with bilateral acoustic tumours. The only report to look in detail at skin findings [8], found that 13 of 31 patients (42 per cent) had cafe au lait patches. None had more than five patches, although 61 per cent had evidence of patches and/or skin tumours. These findings, although limited to familial cases, are very similar to our incidences of 43 per cent for cafe au lait patches and 68 per cent for skin tumours. There was no evidence in our study of a plexiform neurofibroma and, where histological examination of skin lesions was performed, fibrous and mast cell elements were not usually present. The majority were simple schwannomas, particularly those occurring deep to the skin on peripheral nerves. Malignant transformation was not found in any of our 150 patients nor in 137 from a previous study and review of published cases [8]. The importance of the eye in diagnosis was first suggested in 1986 [35]. Since then presenile posterior capsular lenticular opacity has been shown to occur in around 80 per cent of affected individuals (29 of 35) [17]. The relatively low level (38 percent) in our study probably reflects the fact that 35 of 90 patients are still awaiting slit lamp examination. However, in many cases the lesions were obvious on ophthalmoscopy and this alone is likely to identify an

13 A clinical study of type 2 neurofibromatosis 615 opacity in around 50 per cent of those affected. Lisch nodules were not seen in our series, although they were reported to occur in one patient with neurofibromatosis type 2 [36]. Cataracts may be present at a very early age and were probably congenital in four patients in our study. These cataracts are probably different in origin to the posterior capsular variety and more work is in progress to confirm this. In view of a recent report of retinal hamartomas in patients with neurofibromatosis type 2 [37] and the presence of other eye disease in patients in this study, a detailed ophthalmic assessment at birth or soon after is necessary. This may prevent loss of vision in a condition where this may be at a particularly high premium. Problems arising from the tumours themselves are very variable. Most patients die from complications of the disease and many become severely handicapped. Loss of balance is a major problem, even in those who have had acoustic tumours excised. Patients tend to become increasingly housebound and communication can be a real problem. Deafness is the normal outcome, although this may not be complete even in the sixties. Visual problems may occur due to papilloedema, frontal tumours, optic sheath meningiomas, or corneal disease following bilateral post-operative facial palsy. Spinal tumours may cause severe muscular weakness and add enormously to the individual's debility. Swimming difficulties and near drowning has an anecdotal association with neurofibromatosis type 2 [20]. There is now good evidence that underwater disorientation is a problem and that affected people should be discouraged from diving or going under water. It would perhaps be too harsh to advise against swimming altogether as this may be a good therapeutic aid. The development of tumours in an individual is age related, as can be seen in Table 2. The vestibular schwannomas may not be the first to appear: presentation in the first decade is more likely to be due to spinal tumour or meningioma than acoustic tumour. Spinal tumours particularly tend to occur in the first and second decades if at all. We have found a much higher incidence (53 per cent) of meningiomas and spinal tumours than other studies [8] and this may well represent better imaging techniques such as MRI with gadolinium enhancement. Tumours may also occur on all the cranial nerves and facial neuromas may mimic vestibular schwannoma unless the nerves are adequately visualized [38]. Careful evaluation of the cranial nerves is worthwhile in all patients. Although the facial nerve appeared to be affected less often than might be expected, all patients in whom it had been affected during surgery were excluded. Although there has been a concern that vestibular schwannomas may grow rapidly in pregnant women [39], the only woman in that report with neurofibromatosis type 2 had no problems in five pregnancies. There has also been a feeling that men fare better than women [40], perhaps because of some oestrogenic effect. There is really no evidence to support either of these contentions from this study. Symptoms and diagnosis in men occurred, on average, just earlier than in women (by 0.47 year, 0.19 year respectively) and deafness occurred only marginally earlier in women (0.25 year). These differences are not significant. It may be that the time at which women are likely to embark on pregnancy is around the time of peak onset of neurofibromatosis type 2. Since the individual will have closer medical supervision, a perceived increase in problems in women is, therefore, not surprising. No women in this study or previous studies [28] experienced any serious worsening during pregnancy, and the disease itself is not a contraindication to pregnancy. There have been at least two reports of a generalized neuropathy affecting patients with neurofibromatosis type 2 [41, 42]. Three of our 100 patients exhibited a distal symmetrical sensory motor neuropathy, confirmed by nerve conduction studies and electromyography. A further seven patients had either mixed (n = 3), or isolated motor neuropathy (n = 4) not confirmed as being due to tumour. Generalized and isolated neuropathy appears to be a

14 616 DGR Evans and others relatively common feature of neurofibromatosis type 2, although similar features may result from the multiple spinal and intracranial tumours that occur in the condition. Intracranial calcification has already been reported in one of our patients [43] and appears to be a real manifestation of the condition [9, 44]. An extracranial meningioma which mimicked a plexiform tumour on the face also occurred in our series. This has also been reported before [45], and is likely to be a rare complication affecting around 1 per cent of patients. There is no evidence to suggest that mental function is impaired due to inheritance of neurofibromatosis type 2. This compares with neurofibromatosis type 1, in which moderate or severe retardation occurs in up to 3 per cent of patents, with mild retardation or learning difficulties in a further 30 per cent [46]. Patient Care Those diagnosed as having neurofibromatosis type 2 should have regular monitoring at specialist centres as the timing and type of surgery, particularly for vestibular schwannoma, is critical [22]. A spinal MRI scan should be performed before surgery as asymptomatic spinal tumours can lead to serious problems during intubation. Regular neurological examinations and scans, if appropriate from signs and symptoms, should be performed at least annually, depending on the severity of the condition in the individual. If vestibular schwannomas are not present on both sides brain stem evoked responses should be measured annually. Where tumours are known to be present annual MRI scanning to assess growth is probably required. The patient should be warned about the problems of disorientation when swimming. There is no clear indication that women should be advised against oral contraception or pregnancy on health grounds. The patient and their family should be referred for genetic counselling, so that assessment and screening of at-risk relatives can be arranged. At-risk Management At-risk people include those with a unilateral vestibular schwannoma or meningioma under the age of 30, those with multiple spinal tumours, and those with minimal skin signs, as well as those with a family history of neurofibromatosis type 2. All those at 50 per cent risk should have a detailed ophthalmological examination at birth or soon after. Annual review for a general neurological examination and ophthalmoscopy alone until the age of 10 years is advised. This gives the patient and family a point of contact, and will mean that any symptomatic tumours are identified early. Audiological examination should commence at 10 years and should include brain stem evoked responses [40]. Annual clinical and audiological screening should continue until 30 years of age or until the risk has been sufficiently reduced by linkage analysis or mutation studies. Cranial CT scans should be avoided in view of the potential risk of radiation. MRI scans should be arranged if the patient is symptomatic or has an abnormal audiological screen. In addition MRI could be arranged at the age of years to enable better counselling with reference to reproductive decisions and at 30 years to act as a probable exclusion test. Ophthalmic screening with slit lamp examination should be performed at least 5-yearly. After 30 years screening will depend on how severely the family has been affected. In severe cases it may be possible to reassure an individual with a normal audiological screen, MRI scan with gadolinium enhancement, slit lamp examination and skin examination, that they have not inherited the gene. In less severe families it is probably necessary to continue screening until at least 5 years after the latest onset of symptoms in the family.

15 A clinical study of type 2 neurofibromatpsis 617 The cloning of the neurofibromatosis type 2 gene will not only help in determining who in families known to be affected has inherited the gene, but also in identification of cases who do not fulfil the current clinical diagnostic criteria. As the gene appears to behave as a tumour suppressor [47] there is a realistic hope that its cloning will also lead to developing more effective treatment for sporadic vestibular schwannoma and meningioma and that gene therapy may be able to prevent the development of these devastating tumours in affected families. ACKNOWLEDGEMENTS We are grateful for the enormous help supplied by clinicians throughout the UK who have supplied details of patients. We should particularly like to thank Mr TT King for supplying 19 cases and the Neurosurgical and ENT Units at the Manchester Royal Infirmary for their help in ensuring good ascertainment. REFERENCES 1. WishartJH. Case of tumours in the skull, dura mater, and brain. Edinburgh Med SurgJ 1982; 18: Von Recklinghausen F. Uber die multiplen Fibroma der Haut und lhre Beziehung zu den multiplen Neuromen. Berlin: A. Hirschwald, Henschen F. Zur Histologie und Pathogcnese der Kleinhirnbrucken-Winkeltumoren. Arch Psychiatr 1915; 56: Cushing H. Tumours of the nervus acusticus and the syndrome of the cerebello-pontine angle. Philadelphia, WB Saunders, Gardner WJ, Frazier CH. Bilateral acoustic neurofibromas: A clinical study and field survey of a family of five generations with bilateral deafness in thirty eight members. Arch Neurol Psychiatr 1930; 23: Crowe FW, Schull WJ, Neal JV. A clinical, pathological and genetic study of multiple neurofibromatosis. Springfield, Illinois: Charles C. Thomas, Young PF, Eldridge R, Nager GT, Deland FH, McNew J. Hereditary bilateral acoustic neuroma (central neurofibromatosis). Birth Defects OAS 1971; 7: Kanter WR, Eldridge R, Fabricant R, Allen JC, Koerber T. Central neurofibromatosis with bilateral acoustic neuroma: Genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology 1980; 30: Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981; 305: Riccardi VM, Eichner JE. Neurofibromatosis: phenotype, history and pathogenesis. Baltimore, John Hopkins University Press, Huson SM, Harper PS, Compston DAS. Von Recklinghausen neurofibromatosis; a clinical population based study in south east Wales. Brain 1986; 111: National Institutes of Health Consensus Development Conference Statement on Neurofibromatosis. Neurofibromatosis Res Newsl 1987; 3: Seizinger BR, Rouleau GA, Ozelius LG el al. Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell 1987; 49: Barker D, Wright E, Nguyen K et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 1987; 236: Seizinger BR, Martuza RL, Gusella JF. Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 1986; 322: Rouleau G, Seizinger BR, Ozelius LG et al. Genetic linkage analysis of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature 1987; 329: Kaiser-Kupfer MI, Freidlin V, Datiles MB el al. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol 1989; 107: Martuza RL, Eldridge R. Neurofibromatosis 2. N Engl J Med 1988; 318: Eldridge R, Parry DM, Kaiser-Kupfer MI. Clinical heterogeneity and natural history based on 39

16 618 DGR Evans and others individuals in 9 families and 16 sporadic cases. Proceedings of the Eighth International Congress on Human Genetics. Am J Hum Genet 1991; 49: Young DF, Eldridge R, Gardner WJ. Bilateral acoustic neuroma in a large kindred. JAMA 1970; 214: Evans DGR, Huson SM, Donnai D et al. A genetic study of type 2 neurofibromatosis in the north west of England and the UK: I prevalence, mutation rate, fitness and confirmation of maternal transmission effect on severity. J Med Genet 1992; In Press. 22. Evans DGR, Ramsden R, Huson SM, Harris R, Lye R, King TT. Type 2 neurofibromatosis: the need for supraregional care? J Laryngol Otol 1992; In Press. 23. Lee DK, Abbott ML. Familial central nervous system neoplasia. Arch Neurol 1969; 20: Mayfrank L, Wullich B, Wolff G, Finke J, Gouzoulis E, Gilsbach JM. Neurofibromatosis 2: a clinically and genetically heterogeneous disease? report on 10 sporadic cases. Clin Genet 1990; 38: Harley HG, Brook DJ, Rundle SA et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 1992; 355: Sadeh M, Martinovits G, Goldhammer Y. Occurrence of both neurofibromatosis 1 and 2 in the same individual with a rapidly progressive course. Neurology 1989; 39: Michels VV, Whisnant JP, Garrity JA, Miller GM. Neurofibromatosis type 1 with bilateral acoustic neuromas. Neurofibromatosis 1989; 2: Wertelecki W, Rouleau GA, Superneau DW et al. Neurofibromatosis 2: Clinical and DNA linkage studies of a large kindred. N Engl J Med 1988; 319: Huson SM, Thrush DC. Central neurofibromatosis. Q J Med 1985; 55: Moyes PD. Case report and technical note. Familial bilateral acoustic neuroma affecting 14 members from 4 generations. J Neurosurg 1968; 29: Glasscock ME, McKennan KX, Levine SC. Acoustic neuroma surgery: the results of hearing conservation surgery. Laryngoscope 1987; 97: Hitselberger WE, Hughes RL. Bilateral acoustic tumours and neurofibromatosis. Arch Otolaryngol 1968; 88: Martuza RL, Ojemann RG. Bilateral acoustic neuromas: Clinical aspects, pathogenesis and treatment. Neurosurgery 1982; 10: Henneberg, Koch M. Ueber centrale Neurofibromatose und die geschwulste des kleinhirn Bruckenwinkels (Acusticusneurome). Arch Psychiatr 1902; 23: Pearson-Webb MA, Kaiser-Kupfer Ml, Eldridge R. Eye findings in bilateral acoustic (central) neurofibromatosis: association with presenile lens opacity and cataracts but absence of lisch nodules. N Engl J Med 1986; 315: Charles SJ, Moore AT, Yates JRW, Ferguson-Smith MA. Lisch nodules in neurofibromatosis type 2. Arch Ophthalmol 1989; 107: Good WV, Erodsky MC, Edwards MS, Hoyt WF. Bilateral retinal hamartomas in neurofibromatosis type 2. Br J Ophthalmol 1991; 75: KingTT, Morrison AW. Primary facial nerve tumours within the skull. J Neurosurg 1990; 72: Allen J, Eldridge R, Koerber T. Acoustic neuroma in the last months of pregnancy. Am J Obstet Gynecol 1974; 119: N1H Conference statement. Neurofibromatosis 1 (von Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). Ann Intern Med 1990; 113: Thomas PK, King RHM, Chiang TR, Scaravilli F, Sharma AK, Downie AW. Neurofibromatous neuropathy. Muscle Nerve 1990; 13: Mori M, Morisaki S, Hazama R et al. A family of von Recklinghausen's neurofibromatosis complicated by mononeuritis multiplex, bilateral acoustic neuromas, and falx and spinal meningiomas. No To Shinkei 1985; 37: Clarke A, Church W, Gardner-Medwin D, Sengupta R. Intracranial calcification and seizures: a case of central neurofibromatosis. Dev Med Child Neurol 1990; 32: Arts WFM, van Dongen KJ. Intracranial calcified deposits in neurofibromatosis. J Neurol Neurosurg Pschiat 1986; 49: Friedman CD, Costantino PD, Teitelbaum B, Berktold RE, Sisson GA. Primary extracranial meningiomas of the head and neck. Laryngoscope 1990; 100: Huson SM, Compston DAS, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II Guidelines for genetic counselling. J Med Genet 1989; 26: Seizinger BR, Rouleau G, Ozelius LJ et al. Common pathogenetic mechanism for three tumour types in bilateral acoustic neurofibromatosis. Science 1987; 236: