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Neurofibromatosis Type 2

Neurofibromatosis type 2 is an autosomal dominant genetic disease that stems from mutations in the NF2 gene located on chromosome 22. The hallmark of this condition is a predisposition to various tumors of the nervous system and the skin, with symptoms usually starting in adolescence and early adulthood. Bilateral schwannomas of vestibular nerves producing bilateral hearing loss are a highly specific finding, whereas meningiomas and ependymomas of the spine, neuropathies, and ocular disturbances from cataracts or retinal hamartomas are other typical features. The diagnosis rests on clinical criteria and genetic studies.


Presentation

The clinical presentation of neurofibromatosis type 2 is comprised of several crucial elements [1] [2] [3] [4] [5] [6]:

  • Nervous system tumors - Schwannomas are the most common tumor type identified in patients suffering from this condition and they predominantly develop in vestibular nerves [1] [2] [3]. For this reason, early-onset bilateral hearing loss and possible deafness in adolescents (accompanied by tinnitus and deficits in maintaining balance) is a cardinal characteristic of neurofibromatosis type 2 [2] [3]. Schwannomas, but also meningiomas, ependymomas, and astrocytomas, may also be seen in other parts of the nervous system, such as the spinal cord, the cranial nerves, and the peripheral nervous system [1] [2] [3]. In rare cases, vestibular tumors can compress the brain stem and induce hydrocephalus [1]. One of the additional traits of neurofibromatosis related to the nervous system are neuropathies that often develop (without a connection to the tumors), mainly manifesting as palsies of the facial or oculomotor nerve, whereas peripheral signs of a foot drop or wrist drop are encountered as well [1] [6].
  • Ocular deficits - Although findings related to the vestibular system are a very important feature of neurofibromatosis, eye symptoms often precede hearing loss and are often the first sign of this rare condition [1] [3]. Subcapsular lens opacities that may progress into cataracts, retinal hamartomas, and epiretinal membranes can be noticed in the affected population [1].
  • Skin lesions - Schwannomas can also develop on the skin, either subcutaneously or intradermally [3]. In addition, the appearance of slightly raised and well-circumscribed hyperpigmented plaques commonly indicates neurofibromatosis [3].
Aspiration
  • Pancreatic endoscopic ultrasound with fine needle aspiration revealed cytomorphologic features suggestive of pancreatic gastrinoma. Brain magnetic resonance showed a pituitary microadenoma. There was no evidence of hyperparathyroidism.[ncbi.nlm.nih.gov]
  • 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[emedicine.medscape.com]
Pelvic Mass
  • Here we report the case of a 30-year-old woman with a history of neurofibromatosis type 2 (NF2) who presented with an incidentally discovered pelvic mass on an ultrasound.[ncbi.nlm.nih.gov]
Hip Pain
  • A 9-year-old female with neurofibromatosis type 2 (NF-2) presented with right hip pain and severe weakness of bilateral legs for 3 months.[ncbi.nlm.nih.gov]
Ulcer
  • The patient ultimately underwent a distal gastrectomy for a partially obstructing submucosal antral mass, associated with an overlying ulcer. Histopathologic examination showed the mass to be a PS.[ncbi.nlm.nih.gov]
  • Upper gastrointestinal endoscopy revealed peptic ulcer of the duodenal bulb. Blood tests were normal, except for the elevation of plasma gastrin (1031 pg/ml; reference value 108) and chromogranin A (337 U/L; reference value 36).[ncbi.nlm.nih.gov]
  • If facial nerve damage coexists with loss of corneal sensation from damage to the trigeminal nerve then the eye becomes exceptionally vulnerable to corneal ulceration and blindness.[ojrd.biomedcentral.com]
Purpura
  • Three grade 3 adverse events, hypertension (n 2) and immune-mediated thrombocytopenic purpura (n 1), were possibly related to bevacizumab.[ncbi.nlm.nih.gov]
Retinal Lesion
  • The purpose of this study was to describe a subset of severely affected patients with neurofibromatosis type 2 (NF2), multiple central nervous system tumors, and characteristic retinal lesions.[ncbi.nlm.nih.gov]
  • METHODS: Nine NF2 patients from the neurofibromatosis outpatient reference center of the Federal University of Minas Gerais, in Brazil, were submitted to a complete anamnesis and a detailed ophthalmic evaluation, including SD-OCT, to detect retinal lesions[ncbi.nlm.nih.gov]
Bilateral Proptosis
  • A 12-year-old girl with a family history of NF2 was examined because of bilateral proptosis. Visual acuities were light perception RE and 20/40 LE.[ncbi.nlm.nih.gov]
Hearing Impairment
  • In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely.[ncbi.nlm.nih.gov]
  • Fifteen patients had progressive hearing impairment, and 7 ears were totally deaf. Computed tomography and magnetic resonance imaging were used for preoperative and postoperative evaluation.[ncbi.nlm.nih.gov]
  • impairment Depending on the extent and severity of your symptoms, more frequent tests may sometimes be required.[web.archive.org]
  • Scoliosis resource listing Hearing impairment resource listing Clinical trials open through the National Institutes of Health for NF1 and NF2 NF Network is an international website with links to information in various countries and languages.[med.umich.edu]
  • With NF1, the risk of hearing impairments is not increased appreciably. Discuss indications for surgery, as appropriate.[pediatrics.aappublications.org]
Neck Mass
  • A 16-year-old girl presented with gait disturbance and a palpable neck mass, which had been present for 2 years. MRI revealed an intramedullary lesion within the upper cervical spinal cord, which was removed surgically.[ncbi.nlm.nih.gov]
  • One of these patients, the daughter of one of the other individuals, presented with a large neck mass, but no surgically treatable findings associated with the external growth of the meningioma.[ncbi.nlm.nih.gov]
  • Right neck mass in a patient with neurofibromatosis type 2. Facial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with neurofibromatosis type 2.[emedicine.medscape.com]
Headache
  • The acute effect of the treatment was alopecia and mild headache. Subsequent follow-up confirmed clinical improvement. This is the first reported case of clinical experience with tomotherapy in the management of NF2.[ncbi.nlm.nih.gov]
  • Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache.[ncbi.nlm.nih.gov]
  • NF2 is characterized by tumors on the eighth cranial nerve, which can lead to hearing loss, headaches, loss of facial control, and problems with balance and walking.[weillcornellbrainandspine.org]
  • We offer psychological assessment and interventions for children with neurological conditions such as epilepsy, chronic headaches, tics, and neuromuscular conditions.[cpft.nhs.uk]
  • NF2 Symptoms Symptoms depend on the exact location and size of the tumor and may include: Hearing loss Tinnitus (ringing in ears) Poor balance Headaches Pain or numbness in the face Visual problems such as double or blurry vision Weakness or tingling[neurosciences.uvahealth.com]

Workup

The diagnostic workup of patients must include a thorough patient history and a detailed physical examination. The physician should obtain as much information as possible regarding the onset of complaints, their progression, as well as severity, while a complete neurological and skin examination is crucial for raising clinical suspicion [2] [3]. The findings of bilateral hearing loss in adolescence with cutaneous lesions and neuropathy can be sufficient to make a presumptive diagnosis based on clinical grounds. Despite the fact that autosomal dominant pattern of inheritance is established (meaning that a proper family history is of great benefit) [4], up to 50% of cases develop de novo mutations [2] [3]. For this reason, the presence of a bilateral vestibular schwannoma (regardless of the family history) is considered to be the main criteria for neurofibromatosis type 2 [3] [5]. Alternatively, a clinical diagnosis is reached when unilateral vestibular tumors or two lesions typically associated with this condition are supported by either a positive family history or the appearance of multiple meningiomas [3] [4]. To confirm central nervous system tumors, magnetic resonance imaging (MRI) is the cornerstone and high-resolution T1 weighted, contrast-enhanced images are optimal for visualizing vestibular schwannomas [3]. By using mutational analysis of the NF2 gene located on chromosome 22, genetic studies can be employed to make a definitive diagnosis [1].

Brain Edema
  • It was found that with an increase in tumor volume, brain edema and with the tumor location at the skull base, meningiomas are more likely to be symptomatic.[ncbi.nlm.nih.gov]

Treatment

  • Evidence for disease-specific medical treatment options is increasing, nevertheless most patients will benefit from multimodal treatment including surgery during their lifetime.[ncbi.nlm.nih.gov]
  • Time to tumor progression increased threefold from 4.2 months before treatment to 12 months. Hearing was stable under treatment. The safety of everolimus was manageable.[ncbi.nlm.nih.gov]
  • This treatment doesn't involve the use of an actual knife – it uses a tightly focused beam of gamma radiation to shrink a tumour. As with surgical removal, this treatment carries some risks.[web.archive.org]
  • Your treatment centre should be able to recommend a hearing therapist or another healthcare professional qualified to teach lip reading. Treating other problems NF2 can also cause several other health problems that require different treatments.[nhs.uk]
  • The median annual growth rate before treatment was significantly higher than after 1 year of treatment (138 vs. 36 %, n 5, p 0.043). We noted one hearing improvement over the course of 1 year under treatment (hearing response rate was 14 %).[ncbi.nlm.nih.gov]

Prognosis

  • We emphasized the role of radiology in the early diagnosis of this inherited disorder in order to provide a better prognosis.[ncbi.nlm.nih.gov]
  • In contrast to meningiomas in adults, childhood ones have a poorer prognosis because of their high growth potential and tendency to recur. Meningiomas are often associated with neurofibromatosis type 2 (NF2) which is an autosomal-dominant disorder.[ncbi.nlm.nih.gov]
  • NF2 patients with multiple tumours at diagnosis may not be treatable with surgery alone and, as a result, presentation with such a disease in childhood results in poor prognosis.[ncbi.nlm.nih.gov]
  • Multidisciplinary treatment consisting of total surgical removal and adjuvant radiotherapy should be considered due to poor prognosis of this abnormality.[ncbi.nlm.nih.gov]
  • NF2 has a substantial effect on life expectancy and individuals with a constitutional truncating mutation have the worst prognosis.[ncbi.nlm.nih.gov]

Etiology

  • Little is understood about the etiology and underlying mechanisms. To our knowledge, macrodactyly has not previously been associated with neurofibromatosis type 2.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort.[ncbi.nlm.nih.gov]
  • Etiology NF2 is caused by mutations in the NF2 gene on chromosome 22. More than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation.[orpha.net]
  • To identify the etiology of peripheral neuropathy in patients with NF2. To identify serum biomarkers of NF2 disease progression.[clinicaltrials.gov]
  • Synonym(s): bilateral acoustic neurofibromatosis; formerly central NF Epidemiology Incidence Birth incidence: 1/33,000 to 40,000 Prevalence 1/60,000 Etiology and Pathophysiology Protein product of affected gene is called “merlin” or “schwannomin”: Merlin[unboundmedicine.com]

Epidemiology

  • Brain Tumour Research Network, Royal Manchester Children's Hospital, Manchester, UK. 2 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3 National Drug Evidence Centre (NDEC), Centre for Epidemiology[ncbi.nlm.nih.gov]
  • Summary Epidemiology Prevalence (initially estimated at 1: 200,000) is around 1 in 60,000. Clinical description Affected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness.[orpha.net]
  • Synonym(s): bilateral acoustic neurofibromatosis; formerly central NF Epidemiology Incidence Birth incidence: 1/33,000 to 40,000 Prevalence 1/60,000 Etiology and Pathophysiology Protein product of affected gene is called “merlin” or “schwannomin”: Merlin[unboundmedicine.com]
  • The opening chapters cover general principles, including epidemiology, pathogenesis, tumor stem cells, supportive care, complications of therapy, and quality of life.[books.google.com]
Sex distribution
Age distribution

Pathophysiology

  • Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice[ncbi.nlm.nih.gov]
  • Offers the most comprehensive content available on retina, balancing the latest scientific research and clinical correlations, covering everything you need to know on retinal diagnosis, treatment, development, structure, function, and pathophysiology.[books.google.com]
  • Comprehensively updated to reflect everything you need to know regarding retinal diagnosis, treatment, development, structure, function, and pathophysiology, this monumental ophthalmology reference work equips you with expert answers to virtually any[books.google.com]
  • Synonym(s): bilateral acoustic neurofibromatosis; formerly central NF Epidemiology Incidence Birth incidence: 1/33,000 to 40,000 Prevalence 1/60,000 Etiology and Pathophysiology Protein product of affected gene is called “merlin” or “schwannomin”: Merlin[unboundmedicine.com]
  • The pathophysiology of neurofibromatosis (type 1) consists of the NF1 gene protein. This protein is a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation.[en.wikipedia.org]

Prevention

  • If there is a tumor inside the cranium, the disease in the brain must be treated first to prevent the occurrence of cerebral hernia or hemorrhage.[ncbi.nlm.nih.gov]
  • BACKGROUND: In neurofibromatosis type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss that significantly affects the quality of life of patients.[ncbi.nlm.nih.gov]
  • Large tumor volumes do not prevent good outcome. Positive preconditions are short ipsilateral and short bilateral deafness periods and high number of auditory electrodes.[ncbi.nlm.nih.gov]
  • Haber Springer Science & Business Media, ٢٠‏/٠٧‏/٢٠١٠ - 227 من الصفحات Advances in genetics are transforming estimates of an individual’s risk of developing cancer and approaches to prevention and management of cancer in those who may have increased susceptibility[books.google.com]
  • However, in some cases, surgery may be required to prevent potentially serious complications, such as a tumour growing so large there's a risk it may damage your brain.[nhs.uk]

References

Article

  1. Evans DG. Neurofibromatosis 2. 1998 Oct 14 [Updated 2011 Aug 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol. 2013;115:957-967.
  3. Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet. 2009;373(9679):1974-1986.
  4. Evans DGR, Huson SM, Donnai D, et al. A genetic study of type 22 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992;29:841–46.
  5. Evans DGR, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. 2000;37:897–904.
  6. Evans DGR, Birch JM, Ramsden RT. Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child. 1999;81:496–99.

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Last updated: 2019-06-28 10:17