The patient was thought to have NF2, and this was confirmed by genetic testing. A lymphocyte DNA sample revealed a single nucleotide substitution c.169C>T in exon 2 of the NF2 gene. This mutation results in a premature truncation of the polypeptide chain and, therefore, was a pathogenic mutation. Because there was no family history of neurofibromatosis and screening of other family members was unremarkable, this was presumed to be a de novo mutation.
Audiology testing showed no hearing loss. Spinal MRI revealed a small meningioma at the T3 level 3 that was asymptomatic. The diagnosis and implications of NF2 were explained to the patient's parents, and she was referred to the medical service dealing with NF2 patients. Her right third nerve paresis gradually worsened over the ensuing 2 years.
Isolated palsies of the third, fourth, and sixth nerves have been reported infrequently in NF2 patients (2). We are unaware of any other published cases of NF2 presenting with a relapsing-remitting third nerve palsy.
There are 2 previous reports describing recurrent third nerve palsy beginning in childhood in individuals who were subsequently shown to have the magnetic resonance changes compatible with ipsilateral oculomotor nerve schwannoma (3,4). There were no other stigmata of NF2. In both cases, the ophthalmoplegic attacks were associated with focal headache and systemic symptoms, including nausea, supporting the diagnosis of OM. Thickening and enhancement of the third nerve may persist after an attack of OM, and it may be that repeated episodes of inflammatory demyelination followed by remyelination led to focal schwann cell proliferation giving the appearance of schwannoma on MRI. In contrast, in our patient, there were no clinical features to suggest an inflammatory etiology for the initial 2 episodes of third nerve palsy, and neuroimaging was normal on both occasions.
We propose a different mechanism in our case. Schwannomas develop in NF2 as a result of a mutation, which inactivates the tumor suppressor gene located on chromosome 22q12 whose 17 exons encode a 69-kDa protein product called merlin found in schwann cells (5,6). Merlin is important in the control of schwann cell metabolism, including cell-to-cell interactions and both intracellular and intercellular signaling pathways. Schwannomas, consisting of abnormal mutated schwann cells in a collagen matrix, develop when the function of the normal NF2 allele is inactivated. The mechanism of inactivation is uncertain. And in tumorigenesis, merlin dysfunction causes defects in the stability of the cell plasma membrane as it connects to the cytoskeleton, leading to cell deformation and instability (7). We speculate that merlin dysfunction in our patient compromised one or more schwann cells integral to right third nerve function before the development of a tumor detectable on MRI. This resulted in 2 episodes of acute conduction block causing a third nerve palsy, which spontaneously recovered. When NF2 presents in childhood with a mononeuropathy (e.g., facial palsy), spontaneous improvement may occur, possibly by the same phenomenon (8), with eventual progression of the cranial nerve palsy. We recognize that there are other possible explanations, including the presence of a microscopic schwannoma not detectable by MRI at the time of the initial presentation or that the initial ophthalmoplegia was unrelated to the development of the schwannoma and the diagnosis of NF2.
Our case highlights the difficulty in diagnosing NF2 in pediatric patients (9). NF2 has wide phenotypic variability, and only 18% of patients present in the first 15 years of life. Typically, adults initially develop hearing loss, tinnitus, and imbalance because of vestibular schwannomas; less than 30% of pediatric cases present this manner (9). Instead, children present with a mononeuropathy, most commonly affecting the seventh cranial nerve or rarely the peroneal nerve causing foot drop. The cranial nerve palsy may improve spontaneously and precede detection of a vestibular schwannoma by many years (8–10).
Childhood NF2 is associated with more severe disease because of associated nonsense or frame-shift mutations that lead to truncation of a protein product. This was true in our patient, where the nucleotide substitution c.169C>T resulted in a nonsense mutation of the arginine residue at position 57 (p.Arg57X) and premature termination of the polypeptide chain. This also is true of mutations in exons 1 to 5 (9). In our patient, the mutation was detected on analysis of lymphocytes, eliminating mosaicism. Mosaicism occurs with high frequency in NF2, and patient with mosaicism have tumors confined to a specific level of the neuraxis or milder of asymmetric involvement.
Using the Manchester criteria (11), the presence of bilateral vestibular schwannomas coupled with the genetic findings enabled a diagnosis of NF2 to be made in our patient (Table 1). The characteristic focal lens opacity in the form of a posterior subcapsular cataract also was consistent with this diagnosis.
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© 2012 Lippincott Williams & Wilkins, Inc.
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