Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2), is a neurogenetic condition that can manifest as intracranial, spinal, ocular and cutaneous lesions (Peripheral nerve sheath tumors (PNST) throughout the neuroaxis, with vestibular schwannomas, meningiomas, and spinal ependymomas).

A patient ≤30 years of age with a vestibular schwannoma is at increased risk of having NF2.

Several Familial Tumor Syndrome of the Central Nervous systems are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors.

Leptomeningeal angiomatosis has been described with this tumour predisposition syndrome 1).

High-grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria 2).

NF2 alteration

Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe pediatric form with multiple neurological tumors is also described. In this population, an early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a family history. Cutaneous manifestations, which may precede VS or neurological tumors by several years, may contribute to an early diagnosis, but specific studies are lacking.

An observational, descriptive and multicentric study was conducted from April 2019 to April 2020 in seven academic French hospitals. They included patients ≤ 18 years old who fulfilled the Manchester diagnostic criteria or had a pathogenic mutation identified in the NF2 gene. All patients underwent a dermatological examination guided by a standardized questionnaire. 21 children were included, of whom 20 had at least one skin tumour (mean number 5 ± 4.6 [range 0-15]), which led to a diagnosis in four cases. In the other 17 cases, the diagnosis of NF2 was based on neurosensory complications (n = 10), family screening (n = 4) or ocular signs (n = 3). Before the NF2 diagnosis, 15 children had at least one “undiagnosed” cutaneous tumour that did not lead to specific management. Patients' dermatological examination also revealed < 6 non specific café au lait macules (n = 15), hypopigmented macules (n = 12) with more than 3 lesions in 4 cases, and purple reticulated macules of the trunk (n = 4).

Dermatological lesions are frequent and early in children with NF2 but rarely lead to the diagnosis. Cutaneous schwannomas are the most frequent but are often underdiagnosed. Café au lait macules are frequent, but atypical and mostly in small numbers. Multiple hypopigmented macules seem suggestive although inconsistent. The sensitivity of reticulated capillary malformation-like lesions remains to be assessed by further studies 3).

It is a genetic disorder with autosomal dominant pattern, with germline mutation of NF2/Merlin.

Mutations in the NF2 gene cause neurofibromatosis type 2. The NF2 gene provides instructions for making a protein called merlin.

Lakshiminarasimhaiah et al, has a anaesthetic management of a paediatric patient with neurofibromatosis 2 for multiple spinal and thoracic tumour decompression 4).

Patients with neurofibromatosis type II are the initial candidates for auditory midbrain implantation; the appropriate surgical approach should allow for tumor removal and electrode implantation in the same surgical setting.

Neurofibromatosis type 2 Diagnosis.

see Neurofibromatosis Type 2 Outcome.

It is a devastating disease with no well-accepted management guidelines. Better understanding of the disease process provides the basis for how or when to initiate treatment.

In neurofibromatosis type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss in vestibular schwannomas that significantly affects the quality of life of patients.

It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing 5).

Paldor et al. examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiotherapy (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2 6).

In a retrospective cohort study of the Japanese national NF2 registry between 2009 and 2013, clinical data (demographic, history, oncologic, and neurologic) of 807 patients with a diagnosis of NF2 were analyzed. The overall severity of neurologic disability was assessed using a comprehensive 25-point scoring system encompassing a wide variety of neurologic deficits. In 587 patients in whom longitudinal disability data were available, multivariate logistic regression was performed to identify risk factors for significant progression of disability.

The clinical characteristics of the Japanese NF2 population were heterogeneous. The median age of onset was 24 years (range, 1-80 years), the male:female ratio was 1:1.29, and the initial severity score was 4 (range, 0-22) out of 25 points. A family history of NF2 was present in 33% of the patients. Most frequent clinical features were bilateral cranial nerve VIII nerve sheath tumor (NST) in 87%, spinal NST in 80%, hearing loss in 65%, spinal dysfunction in 50%, intracranial meningioma in 49%, and facial paresis in 36%. The disability score progressed by ≥5 points in 6.1% of patients over the study period. Based on multivariate logistic regression analyses, the significant independent risk factors of progression (P value) included age of onset <25 years (P = 0.015), positive family history (P = 0.007), positive treatment history (P = 0.026), hearing loss (P = 0.014), facial paresis (P = 0.015), blindness (P = 0.011), and hemiparesis (P = 0.025).

The Japanese NF2 population has heterogeneous clinical features. Risk factors for progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurologic deficits 7).

Twenty-one NF2 patients operated on for internal auditory canal decompression in a 3-year period with a minimum follow-up of 1 year were included in this retrospective study. They presented unilateral deafness due to previous contralateral vestibular schwannoma removal in 16 patients or contralateral hearing loss due to the tumor in 5 patients. Hearing level was of class A (American Academy of Otolaryngology Head and Neck Surgery classification) in 7 patients, B in 8 patients, C in 1 patient, and D in 5 patients. Pure-tone average and speech discrimination score evaluations were performed at 6 days, 1 year, and during the follow-up. Eight patients had postoperative chemotherapy.

No case of facial nerve palsy was observed. In the early postoperative period; all patients maintained the hearing class of the preoperative period. At 1-year follow-up, all but 3 patients maintained their hearing scores; at last follow-up (mean follow-up, 23 ± 8 months; range, 12-44 months), hearing classes remained stable with only 1 patient worsening from class B to C and 1 patient improving from class D to B.

Decompression of IAC seems to be a useful procedure for hearing maintenance in NF2 patients, with very low morbidity. Ideal timing and association with chemotherapy should be evaluated in the future 8).

Ishi et al. generated induced pluripotent stem cells (iPSCs) were generated from a patient clinically diagnosed with NF2 based on multiple schwannomas, including bilateral vestibular schwannomas and meningiomas. Genetic analysis of the patient's mononuclear cells (MNCs) from peripheral blood failed to detect NF2 alteration but successfully found p.Q65X (c.193C>T) mutation in all separate tumors with three intracranial meningiomas and one intraorbital schwannoma, and confirming mosaicism diagnosis in NF2 alteration using deep sequencing. Five different clones with patient-derived iPSCs were established from MNCs in peripheral blood, which showed sufficient expression of pluripotent markers. Genetic analysis showed that one of five generated iPSC lines from MNCs had the same p.Q65X mutation as that found in NF2. There was no significant difference in the expression of genes related to NF2 between iPSC clones with the wild-type and mutant NF2. In this case, clonal expansion of mononuclear bone marrow-derived stem cells recapitulated mosaicism's genetic alteration in NF2. Patient-derived induced pluripotent stem cells (iPSCs) from mosaic NF2 would contribute to further functional research of NF2 alteration 9).

A 36-year-old male patient who presented with gait disturbance. On examination, he had clinical findings of cervical myelopathy. The patient was evaluated with an MRI of the brain and spine, which revealed multiple spinal tumors, some causing significant canal stenosis. The spinal tumors involved the cervical, thoracic, and lumbar regions. There were both intramedullary and extramedullary tumors with an extraspinal extension. The patient's MRI brain also revealed bilateral vestibular schwannomas. His family history was negative. He subsequently underwent surgery for multiple spinal lesions followed by debulking of the right-sided vestibular schwannoma. The radiological findings of both intramedullary and extramedullary spinal tumors affecting the spinal cord and extensively involving the cervical, thoracic, and lumbar regions, and the requirement of spinal and cranial surgery concurrently make this a challenging neurosurgical case 10).


Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2 11).

A 12-year-old girl presented with headache and ataxia for four months. Kawsar et al. examined and found a lump in the right side of her abdomen. On magnetic resonance imaging (MRI) of brain, a bilateral VS at the cerebellopontine (CP) angle was detected, and on computerized tomography (CT) scan and ultrasonography of her abdomen a large retroperitoneal schwannoma was revealed in the right side of her abdomen. At first, the right-sided CP angle tumour and two months later, the left-sided lesion was operated. After some days, she became mute and incontinent, and was found to have hydrocephalus on CT scan. We introduced a ventriculoperitoneal shunt. Then we operated the abdominal lump, which was histologically proven as schwannoma. The association of these three tumours is rare and untiring surgical approaches made her better. The patient recovered well except bilateral mild facial and vestibulocochlear deficit 12).

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King AT, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SM, Pathmanaban ON, Rodriguez-Valero M, Thomas OM, Laitt RD, Stivaros S, Kellett M, Evans DG. High-Grade Glioma is not a Feature of Neurofibromatosis Type 2 in the Unirradiated Patient. Neurosurgery. 2017 Jul 21. doi: 10.1093/neuros/nyx374. [Epub ahead of print] PubMed PMID: 28973691.
Legoupil S, Bessis D, Picard F, Mallet S, Mazereeuw J, Phan A, Dupin-Deguine D, Kalamarides M; Research Group of the French Society of Paediatric Dermatology, Chiaverini C. Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study. Orphanet J Rare Dis. 2022 Jun 21;17(1):242. doi: 10.1186/s13023-022-02379-6. PMID: 35729665.
Lakshiminarasimhaiah G, Jagannatha AT, Pai KR, Varma RG, Hegde AS. Anaesthetic management of a child with neurofibromatosis type 2 for multiple tumour decompressions. J Clin Diagn Res. 2013 Dec;7(12):3004-5. doi: 10.7860/JCDR/2013/6881.3828. Epub 2013 Dec 15. PubMed PMID: 24551709.
Lloyd SKW, King AT, Rutherford SA, Hammerbeck-Ward CL, Freeman SRM, Mawman DJ, O'Driscoll M, Evans DG. Hearing optimisation in neurofibromatosis type 2: A systematic review. Clin Otolaryngol. 2017 Apr 1. doi: 10.1111/coa.12882. [Epub ahead of print] PubMed PMID: 28371358.
Paldor I, Abbadi S, Bonne N, Ye X, Rodriguez FJ, Rowshanshad D, Itzoe M, Vigilar V, Giovannini M, Brem H, Blakeley JO, Tyler BM. The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma. J Neurooncol. 2017 Jul 22. doi: 10.1007/s11060-017-2567-9. [Epub ahead of print] PubMed PMID: 28735458.
Iwatate K, Yokoo T, Iwatate E, Ichikawa M, Sato T, Fujii M, Sakuma J, Saito K. Population Characteristics and Progressive Disability in Neurofibromatosis Type 2. World Neurosurg. 2017 Oct;106:653-660. doi: 10.1016/j.wneu.2017.07.036. Epub 2017 Jul 16. PubMed PMID: 28720529.
Bernardeschi D, Peyre M, Collin M, Smail M, Sterkers O, Kalamarides M. Internal Auditory Canal Decompression for Hearing Maintenance in Neurofibromatosis Type 2 Patients. Neurosurgery. 2016 Sep;79(3):370-7. doi: 10.1227/NEU.0000000000001125. PubMed PMID: 26579965.
Ishi Y, Era T, Yuzawa S, Okamoto M, Sawaya R, Motegi H, Yamaguchi S, Terasaka S, Houkin K, Fujimura M. Analysis of induced pluripotent stem cell clones derived from a patient with mosaic neurofibromatosis type 2. Am J Med Genet A. 2022 Feb 18. doi: 10.1002/ajmg.a.62700. Epub ahead of print. PMID: 35178855.
Banerjee S, Agarwal A. Neurofibromatosis Type Two: A Case With Both Intracranial and Spinal Lesions. Cureus. 2021 Dec 20;13(12):e20535. doi: 10.7759/cureus.20535. PMID: 35103122; PMCID: PMC8768891.
Tao XG, Hou ZG, Hao SY, Zhang JT, Liu BY. Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2. Chin Med J (Engl). 2017 Apr 5;130(7):872-873. doi: 10.4103/0366-6999.202732. PubMed PMID: 28345553; PubMed Central PMCID: PMC5381323.
Kawsar KA, Haque MR, Chowdhury FH. Abdominal schwannoma in a case of neurofibromatosis type 2: A report of a rare combination. Asian J Neurosurg. 2017 Jan-Mar;12(1):89-91. doi: 10.4103/1793-5482.145347. PubMed PMID: 28413544; PubMed Central PMCID: PMC5379816.
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