Neurofibromatosis Type 2


Article Author:
Ruchi Tiwari


Article Editor:
Achint Singh


Editors In Chief:
Jasleen Jhajj
Cliff Caudill


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 3:08:34 PM

Introduction

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors involving the central nervous system (CNS).

Etiology

NF2 is inherited as an autosomal dominant trait in some patients. The abnormal gene can be inherited from either of the parents, and the risk of passing the gene to offspring from a parent is 50%. In some patients with NF2, there is no family history and the disease is caused by a de novo mutation in the NF2 gene. NF2 is caused by mutations in the NF2 gene located in the long arm of chromosome number 22 (22q12.2). The NF2 gene encodes for the protein known as merlin, which acts as a tumor suppressor gene[1]. Merlin is found in the Schwann cells in the nervous system.

Epidemiology

The incidence of NF2 is about 1 in 25,000 to 40,000 individuals.  

Pathophysiology

Bilateral vestibular schwannomas are the hallmark feature of NF2 and present in approximately 90% to 95% of patients. Meningiomas are seen in approximately 50% of patients with NF2. 

Histopathology

Vestibular schwannomas are benign tumors involving the vestibular portion of the vestibulocochlear nerve (CN VIII). The most common location is an inferior vestibular nerve. They are well-circumscribed encapsulated tumors arising from the perineural elements of the Schwann cells. They usually cause splaying and displacement of the nerve fibers rather than engagement. Microscopically, two types of cellular architecture can be seen in these tumors: Antoni A and B[2]. Antoni A type regions have dense cellularity with closely packed elongated nuclei alternated with clear zones devoid of nuclei (Verocay bodies). Antoni B type regions are less cellular and contain more loosely arranged cells. The volume of Antoni B regions in any given tumor is variable and may be absent.

History and Physical

NF2 patients typically present with tumor-related symptoms around 20 years of age. The most common intracranial tumor associated with NF2 is vestibular schwannoma which is typically bilateral in these patients. Patients typically present with tinnitus, sensorineural hearing loss and balance problems. The cutaneous features in NF2 are less common and more subtle than NF1. The most common skin finding is an elevated plaque-like lesion which may be hyperpigmented than the surrounding skin. The other cutaneous abnormalities are subcutaneous nodules representing swelling of the nerves and cutaneous tumors which generally represent schwannomas rather than neurofibromas. Patients with meningiomas develop symptoms based on their locations and include a headache, seizures or focal neurological symptoms. NF2 patients tend to develop meningiomas earlier than those with sporadic meningiomas. Approximately 20% of children with meningiomas have NF2. Patients with intraspinal tumors present with pain, muscular weakness and paresthesia.

The clinical diagnosis of NF2 is based on the presence of any one of the following criteria[3]:

  • Bilateral vestibular schwannomas less than 70 years of age
  • Unilateral vestibular schwannoma before age 70 years and first-degree relative with NF2
  • Any two of the following: meningioma, schwannoma (non-vestibular), neurofibroma, glioma, cerebral calcification, cataract AND first-degree relative to NF2 OR unilateral vestibular schwannoma and negative LZTR1 testing
  • Multiple meningiomas and unilateral vestibular schwannoma or any two of the following: schwannoma (non-vestibular), neurofibroma, glioma, cerebral calcification, cataract
  • Constitutional or mosaic pathogenic NF2 gene mutation from the blood or by the identification of an identical mutation from two separate tumors in the same individual.

Evaluation

The detailed clinical history and family history is required from the patients suspected of having NF2. A complete physical examination should be done to look for cutaneous schwannomas or plaque-like lesions, ophthalmic examination to look for cataracts, optic nerve, among others. Contrast-enhanced MRI of the brain and entire spine is recommended to evaluate schwannomas and meningiomas.

Vestibular schwannoma has characteristic features on the MRI. They are located in the internal auditory canal which is often widened. Large tumors also extend into the cerebellopontine angle and cause the typical "ice cream cone" appearance. These lesions are hypointense on T1-weighted images and hyperintense on T2-weighted images with intense contrast enhancement. Cystic changes can be seen in large tumors. There is a poor correlation between the tumor size and degree of hearing loss.

Meningiomas are the most common extra-axial tumors in the brain. NF2 patients develop meningiomas at an earlier age, and they are often multiple. If meningiomas are seen in the pediatric age group, then a diagnosis of  NF2 should be considered. Meningiomas have typical features on the MRI. They are dural-based lesions with the isointense signal on T1-weighted images and iso to the hyperintense signal on T2-weighted images with intense enhancement along with an enhancing dural tail.

Multiple spinal tumors can also be seen in patients with NF2 including schwannomas, meningiomas, and ependymomas and can be diagnosed with MRI. Schwannomas are the most common type; they typically arise from the dorsal root with the typical appearance of dumbbell shape with the widening of the neural foramen and intense enhancement. Meningiomas are enhancing extramedullary lesions, typically seen in the cervical or thoracic region. Ependymomas are intramedullary lesions causing enlargement of the spinal cord with hemorrhage, cystic changes, and variable enhancement.

Treatment / Management

Multidisciplinary management is required in patients with NF2 including oncologists, neurologists, neuroradiologists, ophthalmologists, geneticists, and neurosurgeons. For the tumor surveillance, annual brain MRI is recommended. If there is no brain tumor seen on the initial imaging, then MRI can be done every 2 years. If the tumor is seen, then MRI should be done twice in the first year with annual follow-up after that.

Small asymptomatic vestibular schwannomas can be managed conservatively with MRI follow-up. Surgery is the primary treatment for large symptomatic vestibular schwannomas. Meningiomas are also treated surgically with radiation treatment reserved for non-surgical candidates[4]. The spinal cord ependymomas are usually low-grade tumors and can be followed clinically with surgery reserved for symptomatic patients.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is a new systemic immunotherapy for a wide range of tumors. Some studies have shown tumor regression and hearing improvement in NF2 patients treated with bevacizumab[5].

Differential Diagnosis

NF2 should be differentiated from Schwannomatosis which is another form of neurofibromatosis, however genetically distinct from both NF1 and NF2. Schwannomatosis is most frequently sporadic with 20% cases being familial. Schwannomatosis is characterized by the development of multiple schwannomas involving the peripheral nervous system without concomitant involvement of the vestibular nerves. Nonvestibular cranial nerve schwannomas are uncommon but can be seen in these patients.

Enhancing Healthcare Team Outcomes

Multidisciplinary management is required in patients with NF2 including oncologists, neurologists, neuroradiologists, ophthalmologists, geneticists, nurse practitioners, and neurosurgeons. For tumor surveillance, annual brain MRI is recommended. If there is no brain tumor seen on the initial imaging, then MRI can be done every 2 years. If the tumor is seen, then MRI should be done twice in the first year with an annual follow-up after that.

The outlook for these patients is guarded. If the tumors are detected late, then the outcomes are poor and the quality of life is reduced.


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Neurofibromatosis Type 2 - Questions

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Which of the following autosomal dominant disorders is associated with acoustic neuromas and pheochromocytomas?



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A patient has bilateral posterior fossa masses and cafe-au-lait spots. He has a family history of hearing loss at a young age. Which chromosome is most likely involved?



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What is the gene locus for merlin the protein involved with neurofibromatosis type 2?



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Posterior subcapsular cataract is associated with which of the following neurocutaneous diseases?



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Which chromosome has the gene locus responsible for NF-2?



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Which of the following are seen in patients with neurofibromatosis type 2?



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Which of the following is not found in neurofibromatosis type 2?



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Which is associated with type 2 neurofibromatosis?



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A 17 year old female presents for new patient establishment of care. She is generally healthy except for some difficulty hearing out of her left ear over the past 1 year. This is bothersome to her but she has not been alarmed by it as both her mother and her maternal grandmother went deaf over time in adulthood. She is resigned to this happening to her as well. The patient has a normal exam except for some decreased hearing in the left ear and 2 cafe au lait spots on her extremities. On which chromosome does the woman's abnormality most likely lie?



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Which of the following disease is associated with increased risk of childhood meningiomas?



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A 25-year-old male presents with sensorineural hearing loss. A contrast-enhanced MRI was performed which reveals the presence of enhancing lesions in the bilateral internal auditory canal extending into the cerebellopontine angle. What is the most likely diagnosis?



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Which of the following feature is seen in neurofibromatosis (NF)-2 and helps in the differentiation from NF-1?



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Neurofibromatosis Type 2 - References

References

Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis., Smith MJ,Bowers NL,Bulman M,Gokhale C,Wallace AJ,King AT,Lloyd SK,Rutherford SA,Hammerbeck-Ward CL,Freeman SR,Evans DG,, Neurology, 2017 Jan 3     [PubMed]
Surgical approaches to vestibular schwannomas: what the radiologist needs to know., Silk PS,Lane JI,Driscoll CL,, Radiographics : a review publication of the Radiological Society of North America, Inc, 2009 Nov     [PubMed]
Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2., Mautner VF,Nguyen R,Kutta H,Fuensterer C,Bokemeyer C,Hagel C,Friedrich RE,Panse J,, Neuro-oncology, 2010 Jan     [PubMed]
Neuropathology for the neuroradiologist: Antoni A and Antoni B tissue patterns., Wippold FJ 2nd,Lubner M,Perrin RJ,Lämmle M,Perry A,, AJNR. American journal of neuroradiology, 2007 Oct     [PubMed]
Gürsoy S,Erçal D, Genetic Evaluation of Common Neurocutaneous Syndromes. Pediatric neurology. 2018 Dec;     [PubMed]

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