eMedicine Specialties > Neurology > Pediatric Neurology

Neurofibromatosis, Type 2

Author: Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Contributor Information and Disclosures

Updated: Dec 10, 2008

Introduction

Background

Central neurofibromatosis or neurofibromatosis type 2 (NF2) is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts with a paucity of cutaneous features, which are seen more consistently in neurofibromatosis type 1 (NF1). Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system involvement at a young age.

Pathophysiology

The manifestations of NF2 result from mutations in (or rarely deletion of) the NF2 gene located on the long arm of chromosome 22. The gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems. Half of affected individuals have NF2 as a result of a new (de novo) gene mutation.

Frequency

International

The estimated incidence of NF2 is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new dominant mutations.

Mortality/Morbidity

• Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the number one presenting symptom, eventually bilateral deafness would be expected in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and occasionally facial nerve palsy.
• Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding and may be asymptomatic or may cause a variety of symptoms and CNS deficits.
• Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead to dysphagia, esophageal dysmotility, hoarseness, or aspiration. On the other hand, nonvestibular schwannomas in patients with NF2 tend to be more indolent and grow slowly over time, which can complicate treatment decision-making since possible options include surgery, radiation therapy, or watchful waiting.¹
• Posterior subcapsular or so-called juvenile cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.
• Sensory motor polyneuropathy is seen in some individuals with NF2 who may or may not have identifiable tumors along the length of the peripheral nerve(s) of interest.

Race

All races and ethnic groups are affected equally with NF2.

Sex

Males and females are affected equally with this autosomal dominantly inherited condition.

Age

Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate the clinical picture, resulting in under or late diagnosis.

Clinical

History

Clinical diagnosis of NF2 requires that an individual present with at least 1 of the 3 situations described below. As approximately half of affected persons represent new gene changes, family history is often negative and makes diagnosis all the more difficult.

• Bilateral eighth nerve masses visualized on MRI using thin cuts, with and without gadolinium and on both axial and coronal views
• First-degree relative with documented NF2 for an individual with a unilateral eighth nerve mass imaged as already described
• First-degree relative with documented NF2 for an individual with at least 2 of the following findings:
  • Meningioma
  • Glioma
  • Schwannoma
  • Juvenile cataract

Physical

Unlike NF1, which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied by few external signs.

• Presenting symptoms include hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions. Individuals at risk for NF2 should be screened carefully for early signs of hearing loss, motor or sensory changes, and visual deficits.
• Cranial nerve palsies may stem from compression of adjacent nerves secondary to an expanding vestibular schwannoma or directly from nonvestibular cranial nerve schwannomas.
• Differentiating clinically between the relatively common NF1 and the rare NF2 is occasionally problematic. Patients with NF2 almost never have a large number of cafe-au-lait spots (although rarely 6 or more may be seen), whereas cafe-au-lait spots are numerous and ubiquitous in NF1. Neither axillary nor inguinal freckles are common occurrences in NF2.
• Malignant transformation of benign growths is almost unheard of in NF2, unlike NF1. However, individuals with either NF1 or NF2 can develop multiple subcutaneous lesions that may be clinically indistinguishable (see Media files 1-4). In NF2 these lesions most often would be defined histologically as schwannomas or neurilemomas, while in NF1 these would be defined histologically as neurofibromas. Subcutaneous neurofibromas are occasional findings in NF2.
• Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1.
• Finally, although individuals with either NF1 or NF2 can develop dumbbell-shaped spinal cord tumors, schwannomas are common in NF2, whereas neurofibromas are seen primarily in NF1.

Causes

• NF2 is inherited as an autosomal dominant condition resulting from decreased production of the protein merlin, which has a putative tumor suppressor function. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit signs of the condition.
• Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with other proteins to promote cellular adhesion and responses via the growth factor receptor.² Understanding these interactions may eventually lead to more effective targeted treatment strategies since the benign nature of NF2 lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.
• The NF2 gene has been localized to the long arm of chromosome 22; numerous mutations in this gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.

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