Neurofibromatosis 2 (bilateral acoustic schwannomas). What is it? A review of literature and an update.

CE Desouza, RD Nagpal 
 International Hearing Foundation, Bombay, Maharashtra.

Correspondence Address:
C E Desouza
International Hearing Foundation, Bombay, Maharashtra.

Full Text

::   The status of neurofibromatosis 2 (nif2) before the first hihcd conference.

Robert Smith is credited with first describing a patient with what he called “multiple skin neurogenic tumours”[1]. However, it was Friedrich von Recklinghausen's description in 1882, which made the disease a recognised entity[2]. Von Recklinghausen's disease was initially thought to present in three patterns[3].

1. a predominantly peripheral type;

2. a predominantly central type in which the occurrence of bilateral acoustic schwannoma was a characteristic feature; and

3. a mixture of peripheral and central types.

Improved understanding of this condition led to the formulation of a new classification, based primarily on Genetic[4],[5] and somatic[6],[7] differences, at the National Institutes for Health Consensus Development Conference in 1988. This classifies the conditions as Neurofibromatosis 1 (NF1, previously known as peripheral von Recklinghausen's disease) and Neurofibromatosis 2 (NF2, previously known as central von Recklinghausen's disease or bilateral acoustic neurofibromatosis).

::   What are the neurofibromatoses?

The neurofibromatoses belong to the group of neurocutaneous syndromes, the other common ones being the Sturgeweber syndrome, Von Hippel-Linday syndrome and the tuberous sclerosis complex. The neurofibromatoses have been considered to be “neurocristopathies", a term used to describe syndromes thought to arise from dysontogenesis of neural crest tissue. Kanter et al[9] find this concept useful to explain otherwise perplexing associations such as pigmentary skin changes, peripheral nerve tumors and endocrine abnormalities occurring simultaneously. This concept can explain the common manifestations seen in NF1 and NF2 despite the fact that they arise from disorders associated with different chromosomes. The characteristics of NIF11 and NF2 are listed in [Table:1].

The two neurofibromatoses, NFl and NF2, despite their common names and superficial similarities are indeed different disorders. Patients with neurofibromatosis tend to develop cranial & tumours and dyspiasias of astrocytic and neuronal origin (e.g. astrocytoma, glioma, neurofibroma, hamartoma) while patients with NF 2 develop tumours of the lining of the brain (schwannomas, meningiomas and ependymomas).

::   Genetic origin of nf2

Neurofibromatosis 1 and 2 are hereditary autosomal disorders presenting without skip generations. However, the family history is positive in only about 50% of cases[10],[11]. In the others, spontaneous mutation is believed to have occurred.

Rouleau et al[4], established that the defective gene causing neurofibromatosis 2 is located on chromosome 22 and is therefore, distinct from NFl which is caused by a defective gene located near the centromere of chromosome 17 [12]. In an earlier report, Seizinger et al[5] linked the loss of chromosome 22 to the tumorigenesis of acoustic neuromas. An inherited mutation of chromosome 22 may be recessive at cellular level but becomes expressed when a second event occurs[13].

One mutation (inherited) is on one copy of chromosome 22 but is small and cannot be detected by standard karyotyping techniques. The second event affects the other (previously normal) copy of chromosome 22. This can take place through processes like point mutation, transolocation or chromosome loss. The exact process and the various mechanisms involved are not clear. One of the substances thought to be involved is glial growth factor. Increased glial growth factor like activity is found in acoustic schwannomas, with a subsequent increase in cell growth. It is thought that tumour cells secrete this substance in an autocrine fashion, leading to further growth.

The clinical features of NF2 presumably arise from mutations in DNA and are manifested through general biologic mechanisms. These mechanisms include those of derivatives of the embryonic neural crest, schwann cell neuron interactions bone formation, melanin regulation, oncogenes and antioncogenes, nerve growth factor and its receptor and mast cell biology.

Two animal models are emerging for the evaluation of the neurofibromatoses. Marine biologists have identified schools of damsel fish with pigmented skin tumours resembling neurofibromas[14]. The fish with these tumours swim along corals making researchers[15] think that the disease is a horizontally transmitted disease. Researchers[16] at the National Cancer Institute tried replicating the paresis associated with human T- lymphocyte virus 1 in Caribbean populations by transgenically inserting its tat protein gene into mice. The mice developed neurofibromas instead of paralysis. The neurofibromas were situated in the skin. They also developed nerve tumours of the brain. This disease was then transmitted to next generations in an autosomal dominant manner. It is hoped that the isolation of human genes responsible for causing the neurofibromatoses will result in improved animal model systems.

Sadeh et al[17] reported a patient who presented with both NFl and NF2 simultaneously, with a rapidly progressive course. The father was a documented case of NF1 and the mother had NF2, indicating that both NFl and NF2 can be transmitted together and manifest equally in the same person without exclusion of the other. The neurofibromatoses "breed true"; for example a patient with a family history of NF2 has a risk of developing only NF2. It is extremely unlikely that such a patient will develop NF1. The same holds true for NF1.

::   Age of onset of symptoms in nf2

Costantino et a1[18] state that the symptoms in NF2 usually first manifest in the 2nd decade, with the earliest complaint being a hearing loss. Martuza and Ojeman[19] report a more fulminant course in young patients of NF2 and a higher incidence of multiple central nervous system tumours in these patients.

::   The influence of gender in nf2

Nager's [20] report showed a female preponderance. However, Martins and Benitez[21] found no evidence of sex preponderance. Kasantikul et al [22] noted that acoustic schwannomas were larger in females than in males. Miller and Hall [23] noted that neurofibromatoses inherited from the mother were more severe than those inherited from the father. Reports in literature [9],[24],[25] have described cytaneous neurofibromas and central neurofibromas as first appearing or enlarging during pregnancy. Regression of both following delivery has also been documented[9],[24]. Counselling women afflicted with this disease is important as the risk of pregnancy causing an exacerbation of theses lesions is real; this is also accompanied by the risk of genetic transmission of NF2 to the child.

::   Suspecting nf2 clinically

Most authors[19],[26] agree that acoustic schwannomas in patients of documented NF2 grow slowly. Malis[27] describes unequal and disproportionally rapid rates of growth of different tumours in the same patient. He also describes detecting bilateral acoustic schwannomas in a symptomatic patients.

The possibility of NF2 should be entertained in any patient who presents with multiple neurogenic tumours in the absence of any other etiology, or with either a meningioma of the posterior fossa or an acoustic schwannoma before 30 years of age[18]. There should be a high index of suspicion when there is involvement of separate and distinct compartments of the central nervous system, spinal column and cranial nerves[28]. Patients presenting with bilateral acoustic schwannomas may or may not present with the peripheral stigmata associated with the neurofibromatoses[29]. However, the peripheral stigmata in NF2 are much more mild as compared to those in NF1.

::   Audiological investigations

Pure tone audiometry must be part of any evaluation for NF2. When patients with NF2 present early, pure tone audiogram will usually demonstrate as asymmetrical sensorineural hearing loss[30]. In the late stages patients may present with profound sensorineural hearing loss bilaterally. Brainstem evoked response audiometry (BERA) has been proved to have great predictive powers for acoustic schwannomas[31],[32]. Results have been found to be abnormal in 95% to 100% of patients with tumours confirmed by radiographic imaging, surgery or both. Patients with neurofibromatosis 2 were found to have reversed amplitude ratios of waves I and V, prolonged interpeak latencies from wave I to wave V, and absent wave forms beyond waves I or II or BERA testing.

Radiological imaging in NF2

::   Management strategies in nf2

::   Alternative non-surgical management for nf2

::   Summing up on nf2

References