Neurofibromatosis type 2 a case study

A 56-year-old black male patient presented with bilateral neuronal deafuess as well as a large lump on his right forehead, Subcutaneous nodules (5 in total and not very prominent) and axillary freckles were also visible on his skin. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed intracranial masses against the skull roof (Figs I, 2), bilateral masses at the internal acoustic channels (Figs 3, 4) as well as a mass anterior to the right temporal lobe (Fig.5). Splaying of the internal acoustic channels was present suggesting acoustic neuromas (Fig. 3). Prominent enhancement was visible after intravenous contrast. The lesions at the skull roof showed much more enhancement than the lesions at the skull base (cerebello-pontine angle). Calcifications were also visible in the superior lesions. Biopsy of the lesion on the patient's forehead confirmed this lesion to be a meningioma. A diagnosis of neurofibromatosis type 2 (NF-2) was made. The patient did not receive surgery due to the advanced stage of the disease and was irradiated palliatively.He is currently being treated at oncotherapy. What made this case interesting was the late age at which this patient presented and that he was the first black patient to present with NF-2 at our hospital complex.

A 56-year-old black male patient presented with bilateral neuronal deafuess as well as a large lump on his right forehead, Subcutaneous nodules (5 in total and not very prominent) and axillary freckles were also visible on his skin.
Computed tomography (CT) and magnetic resonance imaging (MRI) revealed intracranial masses against the skull roof (Figs I, 2), bilateral masses at the internal acoustic channels (Figs 3,4) as well as a mass anterior to the right temporal lobe (Fig. 5). Splaying of the internal acoustic channels was present suggesting acoustic neuromas (Fig. 3). Prominent enhancement was visible after intravenous contrast. The lesions at the skull roof showed much more enhancement than the lesions at the skull base (cerebello-pontine angle). Calcifications were also visible in the superior lesions. Biopsy of the lesion on the patient's forehead confirmed this lesion to be a meningioma. A diagnosis of neurofibromatosis type 2 (NF-2) was made. The patient did not receive surgery due to the advanced stage of the disease and was irradiated palliatively.He is currently being treated at oncotherapy. What made this case interesting was the late age at which this patient presented and that he was the first black patient to present with NF-2 at our hospital complex.

Disease
The first probable case of NF-2 was reported in 1820 when a doctor named Wishart described a patient with multiple tumours he had examined at postmortem. Neurofibromatosis type 1 (NF-l) and NF-2     races and ethnic groups are affected equally with NF-2.' Although the genetic change causing NF-2 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. Patients present before the age of 55 years. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF-2. While NF-2 is quite variable in severity from person to person, family stud-ies have shown some intrafarnilial consistency in age of onset. 2.3 Diagnosis in children is often difficult because of the absence of central nervous system (eNS) involvement at young age.' .4 The severity of the disease ranges from appearance in childhood with large numbers of crippling and fatal tumours, to mild cases with slow-growing and fewer tumours appearing later in life. This seems to be related to the difference in the NF2 gene. Data suggest that there are two types of NF-2 genes, one with later onset and bilateral vestibular schwannomas as the only usual feature and the other with earlier onset and multiple other tumours." Vestibular schwannomas are the most common and well-recognised feature of NF-2 leading to significant morbidity. 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 NF-2 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 cause a variety of symptoms and eNS deficits.' Posterior subcapsular or so-called 'juvenile cataracts' can predate eNS 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 mayor may not be visually significant.' The most common ocular abnormalities are posterior subcapsular or capsular, cortical or mixed lens opacities.' The diagnosis ofNF2 in the paediatric age group requires a high degree of suspicion and should be considered in children with multiple eNS or skin tumours without cafe-au-lait spots or Lisch nodules," Presenting symptoms include hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions. Individuals at risk for NF-2 should be screened carefully for early signs of hearing loss, motor or sensory changes, and visual deficits. Deafness is sometimes accompanied by tinnitus.' Rare clinical findings are muscle weakness or wasting, seizures, vertigo, numbness and tingling.' Differentiating clinically between the relatively common NF-l and the rare NF-2 is occasionally problematic. Patients with NF-2 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 NF-I.
Neither axillary nor inguinal freckles are common occurrences in NF-2.
Malignant transformation of benign growths is almost unheard of in NF-2, unlike NF-I. However, individuals with either NF-l or NF-2 can develop multiple subcutaneous lesions that may be clinically indistinguishable. In NF-2 these lesions would most often be defined histologically as schwannomas or neurilemomas, while in NF-l these would be defined histologically as neurofibromas. Subcutaneous neurofibromas are occasional findings in NF-2. A mix-ture between the two occurs in very rare cases.' The growth of tumours in NF-2 is unpredictable and growth rates are extremely variable.Y" Most are slow-growing and can cause minimal problems for years, while others may lead to increasing problems over a few weeks.

Genetics
NF-2 is the result of an abnormal gene on chromosome 22 at Q12 (NF2), with a resulting defect in the production of the tumour-suppressor protein schwannomin, also called Merlin. Like other tumour-suppressor genes (such as p53 and Rb), the normal function of NF2 is to act as a brake on cell growth and division, ensuring that cells do not divide uncontrollably, as they do in tumours. The exact molecular function of NF2 in the cell is still unknown. Schwannomin is a 595 amino acid protein. With only single amino acid abnormality, the disease is mild, whereas frame shift deletions or insertion and nonsense mutations causing truncation of schwannomin cause more severe disease.Y" NF-2 is an autosomal-dominant genetic trait, meaning it affects both genders equally and that each child of an affected parent has a 50% chance~f inheriting the gene. Half of affected individuals have NF-2 as a result of a new (de novo) gene mutation.
The estimated incidence ofNF-2 is 1 in 37 000 per year, with about onethird of affected individuals representing first cases in the family as a result of new dominant mutations. I I Approximately 1 000 patients in the entire United States are affected.' There are no statistic data available for South Africa.

Diagnosis
Plain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumours that may occur in NF-2. In general, MR! is the preferred technique for monitoring individuals with NF-2 who have symptoms of spinal cord lesions.I MR! remains the mainstay for diagnosis and screening of CNS and spinal cord tumours. At-risk individuals may be monitored for CNS tumours beginning in their teens, with annual MR!s of the head done through their late 50s. MR! of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MR! imaging of the spinal cord is probably not indicated for asymptomatic affected or at-risk individu-alS. 12 nomas, syrinx associated with tumour; and (ii) intramedullaryspinal cord ependymomas." The presence of multiple and different pathologic types of spinal tumours is highly suggestive of NF-2. 13 Clear molecular diagnosis may help to modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation." The diagnosis ofNF-2 is still based largely on clinical criteria.
The updated NIH Consensus Development Conference criteria for confirmed or definite NF-2 differ from the original criteria only slightly and include individuals with: 1. Bilateral vestibular schwannomas visualised by MR imaging, or 2. A parent, sibling, or child with NF-2, plus (i) unilateral vestibular schwannoma detected before the age of 30 years, or (ii) any 2 of the following: meningioma, glioma, schwannorna, or juvenile posterior subcapsular lenticular opacity?" In practice, these clinical criteria may be too rigid and may exclude individuals who should be evaluated for NF-2. The evaluation for NF-2 should never represent a single point in time, but should include long-term follow-up. If no further tumours develop during a 5 -lO-year period or if NF-2 molecular testing becomes more reliable for exclusion, then screening for possible NF-2 can be relaxed. It is recommended that a distinction be made between a 'confirmed' and a 'presumptive' diagnosis of NF-2. Individuals with multiple NF-2 manifestations and no bilateral vestibular schwannomas classified as presumptive NF-2 may represent developing NF-2, in which other NF-2 features have not yet manifested, or NF-2 mosaicism. It is often difficult to distinguish between NF-2 mosaicism and 'definite' NF-2. 4 Other groups of individuals to be considered at risk for NF-2 and examined further include those with a family history of NF-2, persons younger than 30 years who have a unilateral vestibular schwannoma or meningioma, and those with multiple spinal tumours. In addition, individuals who have the following clinical features should be evaluated for NF-2: 1. A unilateral vestibular schwannoma plus anyone of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.
3. Multiple meningiomas plus 1 or more of the following: glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.A highquality MR! should be performed to rule out bilateral vestibular schwannomas definitively,' Peripheral tumours in NF-2 are usually schwannomas and not neurofibromas. Both schwannomas and neurofibromas may be useful diagnostic adjuncts in the paediatric and adolescent age groups, when severe NF-2 phenotypes typically manifest.' Cerebral calcifications have sometimes been suggested as a diagnostic feature of NF-2. There are no convincing data to justify their inclusion, as they represent relatively nonspecific findings. In addition, CT scans that routinely detect calcification are now not the investigation of choice in NF-2. 4 Now that the gene for NF-2 has been identified, analysis for diseasecausing mutations can be offered in some clinical settings. Detection rates for molecular-based testing are approximately 65%; therefore, such testing is of limited use in making the diagnosis of NF-2. However, in a patient with suspected NF-2 who is stillyoung, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be helpful.":" Predictive diagnosis by linkage analysis using markers flanking the NF2 gene is now possible in the vast majority of families with 2 or more living affected individuals.' Once a mutation has been identified in an affected individual, a 100% specific test is then available for that family. However, mutation detection is time-consuming and expensive and may not reveal the causative mutatien.":" Currently these tests are not available in South Africa.