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INTRODUCTION

ESSENTIALS OF DIAGNOSIS

  • Bilateral vestibular schwannomas.

  • Multiple meningiomas, ependymomas, and rarely astrocytomas.

  • Posterior subcapsular lenticular opacities.

  • Spinal tumors.

  • Skin tumors or lesions.

GENERAL CONSIDERATIONS

Neurofibromatosis type 2 (NF2; OMIM Entry 607379) is the official name for the syndrome whose hallmark is bilateral vestibular schwannomas (VSs) (Figure 65–1). NF2 replaces a variety of synonyms that have been associated with this entity: central neurofibromatosis, bilateral acoustic neurofibromatosis, cranial neuromatosis, central schwannomatosis, neurofibromatosis universalis, familial bilateral acoustic neuroma syndrome, familial bilateral acoustic neurofibromas, Wishart–Gardner–Eldridge syndrome, neuromatosis, and neurofibrosarcomatosis. The first known description of the clinical course and postmortem findings of NF2, almost 2 centuries ago, was of a patient who developed bilateral deafness, had intractable headaches and vomiting, and died at age 21 years.

Figure 65–1

MRI scan with gadolinium, demonstrating bilateral VS.

NF2 has long been confused with classic von Recklinghausen syndrome. In 1987, a consensus panel of the National Institutes of Health officially differentiated the clinical manifestations associated with classic von Recklinghausen syndrome or peripheral neurofibromatosis from those of a predominantly intracranial subtype or central neurofibromatosis. The 2 syndromes were designated NF1 and NF2, respectively. Molecular genetic investigations confirmed this clinical differentiation: the gene responsible for NF1 was located near the proximal long arm of chromosome 17q11.2, whereas the gene responsible for NF2 was located on chromosome 22q12.2.

NF2 is much rarer than NF1, with an incidence estimated between 1:33,000 and 1:60,000. Inheritance of NF2 is autosomal-dominant and gene penetrance is above 95%. NF2 most frequently presents in the second and third decades of life. VSs represent approximately 8% of intracranial tumors and account for approximately 80% of the tumors found in the cerebellopontine angle. Most cases of VS occur sporadically, are unilateral, and present in the fifth decade. Patients with NF2 have bilateral VSs and represent 2% to 4% of patients with VSs.

The identification of the gene responsible for NF2 in 1993 has significantly advanced our understanding of the molecular pathology, as well as the factors responsible for the clinical heterogeneity among patients with NF2. The NF2 gene encodes for the protein merlin or schwannomin; it has been shown to have homology to the ezrin–radixin–moesin family of genes, which function as membrane-organizing proteins. These proteins have a basic function indigenous to all cells, which are postulated to link cytoskeletal proteins to the plasma membrane. It has been proposed to represent a recessive tumor suppressor, whose deletion or inactivation alters the abundance, localization, and turnover of cell-surface receptors, thus initiating tumorigenesis. Understanding the function of merlin in tumor formation will lead to the development of novel therapies that may eventually alleviate the suffering associated with NF2.

PATHOGENESIS

NF2 results from the inheritance of a mutation in merlin (or schwannomin) protein on chromosome ...

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