A rare case of aggressive phenotype (Wishart) of neurofibromatosis type 2

Sir,

Neurofibromatosis type 2 is a rarely seen clinical syndrome compared to neurofibromatosis type 1.¹ Based on severity as well as clinical course, neurofibromatosis type 2 is classified into two types: the less aggressive late onset Feiling-Gardner phenotype with single tumour in the central nervous system and the aggressive Wishart phenotype in young adults with multiple tumours in central as well as the peripheral nervous system.² We report a case of a 20-year-old man suffering from the aggressive Wishart phenotype.

A 20-year-old man presented with complaints of multiple painless skin-coloured swellings on the body over seven years and progressive hearing loss of left ear, hoarseness of voice, weakness as well as deformity of the right hand of six months duration. None of his family members had similar illness. Neurological examination revealed left-sided lower motor neuron type of facial palsy and contralateral hemiparesis [Figure 1a]. Right paralytic claw hand with hypothenar atrophy was noticed [Figure 1b]. Dermatological examination revealed nodules on the scalp, cheek, back and right upper limb [Figures 1c and d]. Fundoscopy showed bilateral optic disc edema with pericapillary hemorrhages [Figures 2a, b]. The audiogram showed bilateral sensorineural deafness (left > right) while indirect laryngoscopy revealed left vocal cord palsy. Axial contrast-enhanced T1 magnetic resonance imaging of the brain showed bilaterally enhancing vestibular schwannomas (right greater than left) [Figures 3a and b] and ependymomas in bilateral lateral ventricles [Figure 3c]. Sagittal contrast-enhanced T1 images revealed extra-axial lesion from C1 to C3 level with extension into neural foramina suggestive of schwannoma [Figure 3d]. Skin biopsy from a nodule on the left forearm revealed spindle cells with serpentine wavy nuclei without pleomorphism, intermixed with wire-like collagen suggestive of neurofibroma [Figure 4a] and immunohistochemistry with CD 34 showed positivity [Figure 4b]. The patient was diagnosed with neurofibromatosis type 2 as per revised Manchester criteria [Table 1]. Due to multiple tumours in the central as well as peripheral nervous system leading to an array of clinical manifestations, the patient had the more aggressive Wishart type of neurofibromatosis type 2. He was referred to a neurosurgeon for further management by gamma knife surgery of the tumours.

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Figure 1:

(a) Left sided facial paralysis. (b) Right paralytic claw hand with hypothenar atrophy (red arrow). (c) and (d) Skin colored soft nodules over arm and scalp (yellow arrows)

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Figure 2:

(a, b) Fundoscopy showing bilateral optic disc edema (green arrrows) and pericapillary hemorrhages. (yellow arrow)

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Figure 3:

(a, b) Magnetic resonance imaging- axial contrast enhanced T1 images of brain showed enhancing bilateral accoustic schwannomas, right greater than the left (yellow arrows) (2 c) Ependymomas in bilateral lateral ventricles (yellow arrows) (2 d) Sagittal contrast enhanced T1 image showing extra axial lesion at level of C1 to C3 level with extension into neural foramina suggestive of schwannoma (yellow arrow)

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Figure 4a:

Spindle cells with serpentine wavy nuclei without pleomorphism, intermixed with wire-like collagen.(H and E,×40)

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Figure 4b:

CD 34 shows fingerprints-like positivity. (IHC, CD 34)

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Neurofibromatosis is a collection of heterogeneous tumour predisposition hereditary syndromes characterised by distinctive dysplastic and neoplastic lesions mainly affecting the central and/or peripheral nervous systems. The neurofibromatosis group comprises of up to eight distinct entities, out of which three syndromes are well described: neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis. Although entities under neurofibromatosis have been described since the olden days, neurofibromatosis type 1 was first defined as a distinct nosological entity in 1882 by German pathologist von Recklinghausen when he proved the neural origin of the disease when he described two patients with multiple neurofibromas. ³ Neurofibromatosis type 2 was first described by Scottish surgeon J H Wishart in 1822. ⁴ While neurofibromatosis type 1 is caused by a defect in tumour suppressor gene neurofibromin which is located on the long arm of chromosome 17 (17q11.2), neurofibromatosis type 2 is caused by a mutation in tumour suppressor gene merlin located on the long arm of chromosome 22 (22q12.2). ¹ Merlin protein is responsible to maintain cell-to-cell connections of cytoskeleton with the plasma membrane, thereby regulating the shape and motility of the cell. ¹ Neurofibromatosis type 2 is characterised by the development of multiple neoplasms in the central and peripheral nervous system with variable clinical course. The neoplasms in order of frequency are schwannoma, meningioma, and ependymoma; hence neurofibromatosis type 2 is also known by the acronym MISME, which stands for multiple inherited schwannomas, meningiomas and ependymomas. The characteristic feature of neurofibromatosis type 2 is the presence of bilateral vestibular schwannomas leading to hearing impairment as seen in our patient. Most schwannomas are encapsulated and well-circumscribed round or oval masses consisting of spindle cells that are attached to their parent nerves without infiltration. The most commonly affected cranial nerve is the vestibulocochlear followed by the trigeminal nerve. ⁵ In neurofibromatosis type 2, apart from involving the cranial nerves, schwannomas are also the most common type of spinal tumour. A common site is a cervicothoracic region as seen in our case followed by the cauda equina where innumerable tiny schwannomas (tumorlets) may be seen. ⁶ Ependymomas are most likely to be seen in the intramedullary location of the conus medullaris or cervical region. In our case ependymoma was seen in both the lateral ventricles. Multiple meningiomas are the second pathologic hallmark of neurofibromatosis type 2. Meningioma may be found in greater than 50% of neurofibromatosis type 2 patients, most commonly in the supratentorial area. Astrocytoma may be seen but is usually low grade. Approximately 90% of patients have ocular involvement, the most common of which is early posterior sub-capsular cataract, while others are retinal hamartomas and corneal lesions. ⁷ Other ophthalmological findings may be secondary to raised intracranial pressure leading to papilledema as seen in our patient. The most common skin tumours in neurofibromatosis type 2 are schwannomas as compared to neurofibromas in neurofibromatosis type 1. ⁸ In our case, a biopsy from one of the nodules on the skin revealed a neurofibroma. Two distinct phenotypes of neurofibromatosis type 2 have been described in the literature. The lesser aggressive variant is known as the Feiling-Gardner phenotype and it generally does not have more than a single neoplasm in the central nervous system and is usually seen in patients greater than 20 years of age. On the other hand, the Wishart phenotype is the more aggressive variant presenting in patients less than 20 years of age characterised by multiple neoplasms in the brain and spine manifesting with a constellation of symptoms and signs with poor clinical prognosis. ² Young individuals with a positive family history of neurofibromatosis type 2 must be under regular yearly follow-up from as early as 10–12 years of age with magnetic resonance imaging screening until 40 years of age. ⁹ Surgery still forms the cornerstone for the management of central nervous system tumours. However stereotactic surgery and more recently anti-vascular endothelial growth factor agents like bevacizumab are increasingly being used in the management of neurofibromatosis type 2. ¹⁰ Our patient, unfortunately, belonged to the aggressive Wishart phenotype of neurofibromatosis type 2.