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Neurofibromatosis type 2

Neurofibromatosis Type II (or "MISME Syndrome", for "Multiple Inherited Schwannomas, Meningiomas, and Ependymomas") is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant brain tumours in the region of the cranial nerve VIII, which is the auditory nerve that transmits sensory information from the inner ear to the brain. Most people with this condition also experience problems in their eyes. NF II is caused by mutations of a gene which probably influences the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. more...

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There is no therapy for the underlying disorder of cell function caused by the genetic mutation.

Causes

Incidence, Mode of transmission, Epidemiology

NF II is an inheritable disorder with an autosomal dominant mode of transmission. Incidence of the disease is about 1 in 35,000. There is a broad clinical spectrum known, but all patients checked have been found to have the same mutation of a gene on chromosome 22. It is suspected that statistically, one half of cases are inherited, and one half are the result of new, de novo mutations.

Pathogenesis, Molecular Biology and pathophysiological relations

NF II is caused by a defect in the gene that normally gives rise to a product called "Merlin" or "Schwannomin", located on chromosome 22 band q11-13.1. This peptide is thought to have a tumor-suppressive function. The NF II gene is presumed to result in either a failure to synthesize Merlin, or the production of a defective peptide that lacks the normal tumor suppressive effect. The Schwannomin-peptide consists of 595 amino acids. Comparison of Schwannomin with other proteins shows similarities to proteins that connect the cytoskeleton to the cell membrane. Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.

Pathology

The so called acoustic neuroma of NF II is in fact a Schwannoma of the nervus vestibularis. The wrong term is used despite better knowledge in the whole scientific and medical literature. The vestibular Schwannomas grow slowly at the inner entrance of the internal auditory meatus (meatus acousticus internus). They derive from the nerve sheaths of the upper part of the nervus vestibularis in the region between the central and peripheral myelin (Obersteiner-Redlich-Zone) within the area of the porus acousticus, 1 cm from the brainstem.

Genotype-Phenotype-Correlation

Many patients with NF II were included in studies which were designed to compare disease type and progression with exact determination of the associated mutation. The goal of such comparisons of genotype and phenotype is to determine whether specific mutations cause respective combinations of symptoms. This would be extremely valuable for the prediction of disease progression and planning of therapy even at children age. The results of such studies are the following:

In most cases the mutation in the NF II gene causes shortened peptides.
There are no mutational hot-spots.
Patients with Frameshiftmutation- or Nonsense mutations suffer poor prognosis.
Patients with Missense mutations have a better prognosis.
In cases with Mutations in the splice-acceptor-region there is no good correlation to determine.
Point mutations may have only minor effects.
Cases are published in which exactly the same mutation is associated with clearly different outcome.

These results suggest, that probably other factors (Environment, other mutations) will determine the clinical outcome.

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Leprosy and neurofibromatosis 2: What is common?
From International Journal of Leprosy and Other Mycobacterial Diseases, 9/1/01 by Dogra, Sunil

TO THE EDITOR:

The neurofibromatoses are a heterogeneous set of genetic disorders having clinical manifestations that involve the skin, the nervous system or both. Although this condition is unrelated to leprosy, common clinical as well as histological features have aroused the interest of clinicians in the field of leprosy. Leprosy in association with von Recklinghausen neurofibromatosis (NFl) has been reported previously (2, 3, 8, 9), but to the best of our knowledge, the association of leprosy with neurofibromatosis 2 (NF2) has not been reported in the past. We wish to share our interesting observations of histoid leprosy occurring in a patient with NF2.

CASE REPORT

A 36-year-old male patient presented to us with complaints of progressive sensory loss over the hands and feet for a duration of 3 years. He also noticed multiple papulonodular lesions over his body and deafness for the last 6 months. There was no symptom suggestive of leprosy reaction in the past. The patient had not received any treatment for his complaints previously. One examination, multiple skin-colored to erythematous papulonodular lesions were seen over the face, trunk and extremities, varying in size from 0.5 cm to 1.5 cm. The nodules were waxy, firm, nontender and were present over apparently normal-looking skin. In addition there was diffuse infiltration of the face and ears (Fig. 1) and thickening of the peripheral nerve trunks involving ulnar and common peroneal (lateral popliteal) nerves bilaterally with glove-and-- stocking type of anesthesia.

A clinical diagnosis of histoid leprosy was made which was confirmed by histopathology. A biopsy of one of the nodules on histopathological examination showed numerous spindle-shaped histiocytes forming interlacing bands and whorls in the dermis. Numerous acid-fast bacilli were seen that were slightly longer than normal along with few foamy histocytes. Slit-skin smear examination from the nodules and the earlobes demonstrated a bacterial index (BI) of 5+. Routine hematological, biochemical and radiological investigations were within normal limits. Initially, the deafness was thought to be due to ear pathology secondary to leprosy, but on suspicion of associated vertigo, brain stem-evoked response audiometry (BERA) was done, which suggested a retrocochlear pathology. On further investigations, a magnetic resonance imaging (MRI) scan (Fig. 2) revealed a welldefined, approximately 2 x 2.5 cm heterogeneous mass lesion in both CP angles with a well-defined intracanalicular component of the lesion on both sides, features suggestive of bilateral acoustic schwannomas. There was another cystic lesion along the posterior part of the cervicomedullary junction with an enhancing nodule anteriorly, suggestive of ependymoma. Orbits, basal ganglia, thalami, sella and corpus callosum were normal. All of these radiological findings confirmed the diagnosis of NF2, which was probably responsible for the vertigo and deafness in the patient.

DISCUSSION

The co-existence of leprosy and neurofibromatosis in the same patient is interesting in that Schwann cells are involved in the pathogenesis of both and masquerade each other clinically. Cutaneous and subcutaneous neurofibromas may be mistaken for nodules of lepromatous leprosy (1). Peripheral nerve trunk thickening in neurofibromatosis has been recognized as a clinical differential diagnosis of leprosy (5, 6), but such clinical attention is not shared by tumors of NF2 arising in the central nervous system. The literature reveals contradictory findings about the affection of the audiovestibular system in leprosy. There are reports of high incidence of hearing loss (10) and vestibular hypofunction (7). Mann, et al. (4) in a case control study concluded that leprosy selectively affects the cochlear end organs without affecting the vestibular functions. Bilateral vestibular schwannomas, the hallmark of NF2, can mimic audiovestibular involvement of leprosy as in our case. This case is reported to alert clinicians that audiovestibular symptoms in leprosy may not always be related to the primary disease. Although the frequency of central neurofibromatosis (NF2) is much less compared to NFl, a high index of suspicion should be kept in a leprosy patient who has vestibular symptoms associated with sensorineural deafness.

REFERENCES

1. DHARMENDRA. A case of leprosy wrongly diagnosed as neurofibroma. Lepr. India 24 (1925) 160-163.

2. GANAPATI, R., DES PANDE, D. H. and CHULAWALA, R. G. Leprosy with subcutaneous neurofibromatosis; a case report. Bombay Hosptial J. 18 (1976) 34-36.

3. GHOSH, S. and KUDU, S. K. Neurofibroma and leprosy. Indian J. Dermatol. 15 (1970) 79-82.

4. MANN, S. B. S., KUMAR, B., YANDE, R., KAUR, S., KAUR, J. and MEHRA, Y. N. Eighth nerve evaluation in leprosy. Indian J. Lepr. 59 (1987) 20-25.

5. NAIK, R. P. C., SRINIVAS, C. R. and RAO, R. V. Thickening of peripheral nerves in neurofibromatosis. Indian J. Lepr. 57 (1985) 876-878.

6. RAO, M. V., THAPPA, D. M., D'SOUZA, M. and RATNAKAR, C. Neurofibromatosis with pure neuritic leprosy. J. Dermatol. 24 (1997) 799-800.

7. SINGH, T. P., AGARWAL, S. K., BAJAJ, A. K., SINGH, R. K. and SINGH, M. M. Evaluation of audiovestibular status in leprosy. Indian J. Lepr. 56 (1984) 24-29.

8. Swier, T. R. Neurofibromatosis and leprosy. J. Neurol. Neurosurg. Psychiatry 34 (1971) 742-749.

9. THOMAS, J., WILSON, N. C., PARIMALAM, S. and AUGUSTINE, S. M. Multiple neurofibromatosis with histoid leprosy. (Letter) Int. J. Lepr. 57 (1989) 695-696.

10. USDMANOV, R. K. [Ear status in leprosy.] (Abstract) Int. J. Lepr. 37 (1969) 431.

-Sunil Dogra, M.D., D.N.B.

Ranju Rai, M.D.

Inderjeet Kaur, M.D., M.N.A.M.S.

Bhushan Kumar, M.D., M.N.A.M.S.

Department of Dermatology, Venereology and Leprology

Postgraduate Institute of Medical Education and Research

Chandigarh 160 012, India

Reprint requests to Dr. Kaur at the above address or FAX 91-172-744-401; e-mail: kaur_inderjeet@yahoo.com

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