Neurofibromatosis type 2 (NF2): A clinical and molecular review

Medical Genetics Research Group, Regional Genetics Service and National Molecular Genetics Reference Laboratory, Central Manchester Foundation Trust, St Mary's Hospital, Manchester M130JH, UK.
Orphanet Journal of Rare Diseases (Impact Factor: 3.36). 07/2009; 4(1):16. DOI: 10.1186/1750-1172-4-16
Source: PubMed


Neurofibromatosis type 2 (NF2) is a tumour-prone disorder characterised by the development of multiple schwannomas and meningiomas. Prevalence (initially estimated at 1: 200,000) is around 1 in 60,000. Affected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness. The majority of patients present with hearing loss, which is usually unilateral at onset and may be accompanied or preceded by tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease. The other main tumours are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas). Ophthalmic features are also prominent and include reduced visual acuity and cataract. About 70% of NF2 patients have skin tumours (intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular tumours). Neurofibromatosis type 2 is a dominantly inherited tumour predisposition syndrome 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. Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common. A strategy for detection of the latter is vital for a sensitive analysis. Diagnosis is based on clinical and neuroimaging studies. Presymptomatic genetic testing is an integral part of the management of NF2 families. Prenatal diagnosis and pre-implantation genetic diagnosis is possible. The main differential diagnosis of NF2 is schwannomatosis. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management although watchful waiting with careful surveillance and occasionally radiation treatment have a role. Prognosis is adversely affected by early age at onset, a higher number of meningiomas and having a truncating mutation. In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating condition.

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Available from: Dafydd Gareth Evans, Oct 06, 2015
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    • "Les mutations localisées au niveau des sites d'e ´pissage entraıˆnent un phénotype assez variable. Cette observation rappelle enfin que l'espérance de vie est réduite dans cette affection (estimée a ` 15 ans après le diagnostic avant 1990) [1], même si elle est meilleure en cas de prise en charge dans un centre spécialisé [10] "
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is a rare dominantly inherited disease. Its clinical presentation can be completely different in children and adults and early diagnosis is often difficult. The NF2 gene molecular analysis can help for diagnosis, but its result can be negative in case of NF2 mosaicism. We report the case of a 43-year-old man who had developed a severe phenotype with bilateral vestibular schwannomas at 19years of age. His son presented a retinal hamartoma with loss of vision in his right eye at 2months of age. At 9years of age, asymptomatic schwannomas of the cranial nerves were discovered: cranial nerves X (left), XI (left), and VIII (bilateral). Partial constitutional NF2 deletion (from exons 2-7) was detected in his son. The deletion was not detectable in the DNA blood of his father and we strongly suspect a mosaic form of NF2. Ophthalmological manifestations can be the initial sign of NF2 in childhood. These features must be actively sought during the first year of life in individuals at risk of NF2. NF2 mosaicism is often described as a mild form of NF2 with a very low risk of transmission to the carrier's children. We show that NF2 mosaicism can sometimes develop severe NF2 symptoms and we confirm that the transmission risk to the offspring depends on the proportion of zygotes carrying the mutation. NF2 remains a life-limiting and life-spoiling condition. Early diagnosis is necessary to prevent complications and the follow-up of NF2 patients must be organized throughout life in specialty centers. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Archives de Pédiatrie 11/2014; 21(11):1233-40. DOI:10.1016/j.arcped.2014.08.031 · 0.41 Impact Factor
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    • "Molecular biology of NF-2 NF-2 mutations are found in 93% of patients in the second generation [10]. Around 50% inherit the mutation, the remainder being de novo mutations. "
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    ABSTRACT: The systemic treatment of patients with neurofibromatosis type 2 associated tumours is challenging, as these patients often have prolonged survival but with the inevitable propensity for their disease to cause symptoms, and no effective therapies other than local treatments such as surgery. Understanding the molecular mechanisms driving NF-2 pathogenesis holds promise for the potential use of targeted therapy. Initial studies of agents such as bevacizumab (angiogenesis inhibitor) and lapatinib (epidermal growth factor and ErbB2 inhibitor) have indicated benefit for selected patients. As the biology of NF-2 is dependent on multiple interlinked downstream signalling pathways, targeting multiple pathways may be more effective than single agents. Phase zero trials, adaptive phase II or small multi-arm trials, are likely the way forward in this rare disease. Ideally, well-tolerated targeted therapy would appear to be the most promising approach for patients with NF-2, given the natural history of this disease.
    Cancer Treatment Reviews 08/2014; 40(7). DOI:10.1016/j.ctrv.2014.05.004 · 7.59 Impact Factor
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    • "Both gastroenteropancreatic neuroendocrine tumors (GEP NET) and neurofibromatosis type 2 (NF2) are fairly rare diseases [1,2]. GEP NET have occasionally been described in association with neurofibromatosis type 1 (NF1) [3], whereas an association with NF2 has never been reported. "
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    ABSTRACT: Background Gastroenteropancreatic neuroendocrine tumors have occasionally been described in association with neurofibromatosis type 1, whereas an association with neurofibromatosis type 2 has never been reported. Case presentation This report refers to an Italian 69 year old woman with neurofibromatosis type 2 and a pancreatic gastrinoma. In the past she had encephalic meningiomas, a tongue schwannoma and bilateral acoustic neurinomas. She presented with weight loss and a long-term history of diarrhea, responsive to proton pump inhibitors. 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). After secretin stimulation testing, the plasma gastrin level rose to 3789 pg/ml. The abdomen magnetic resonance imaging and gallium68-DOTATOC positron emission tomography scan demonstrated the presence of a 1.2 x 2 cm lesion in the pancreatic head and a liver metastatis. 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. The genetic test for multiple endocrine neoplasia type 1 syndrome mutation was negative. Conclusion This report focuses on the first case of coexistence of gastrinoma with neurofibromatosis type 2. Although the clinical relevance of this association remains to be determined, our case report will surely give cause for due consideration.
    BMC Gastroenterology 06/2014; 14(1):110. DOI:10.1186/1471-230X-14-110 · 2.37 Impact Factor
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