Neurofibromatosis type 2

• Quality of life assessment in schwannomatosis - A systematic review
• Merlin immunoreactivity fails to predict neurofibromatosis type 2 mutations in human meningiomas
• Development of a Machine Learning Algorithm for the Prediction of WHO Grade 1 Meningioma Recurrence
• Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities
• Rare case of schwannomatosis presenting with cauda equina syndrome: a case report
• Surgical Management of Peripheral Nerve Schwannomas in Non-Neurofibromatosis Type 2 Schwannomatosis
• Radiomics for Growth Prediction of Vestibular Schwannomas in Neurofibromatosis Type 2
• Pathogenic Variants and Prognosis in Meningiomas: A Systematic Review and Meta-Analysis

Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22

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 ¹⁾.

Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22. About half of patients inherit a germline mutation from a parent, and nearly 60% of de novo NF2 patients are estimated to have somatic mosaicism. The development of technical methods to detect NF2 gene mutation, including targeted deep sequencing from multiple tissues, improved the diagnostic rate of mosaic NF2. With improved understanding of genetics and pathogenesis, the diagnostic criteria for NF2 were updated to assist in identifying and diagnosing NF2 at an earlier stage. The understanding of cell signaling pathways interacting with merlin has led to the development of molecular-targeted therapies. Currently, several translational studies are searching for possible therapeutic agents targeting VEGF or VEGF receptors. Bevacizumab, an anti-VEGF monoclonal antibody, is widely used in many clinical trials aiming for hearing improvement or tumor volume control. Currently, a randomized, double-masked trial to assess bevacizumab is underway. In a randomized control trial, 12 other Japanese institutions joined the principal investigators in the clinical trial originating at Fukushima Medical University ²⁾

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 ³⁾.

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.

Neurofibromatosis type 2 complications.

see Neurofibromatosis Type 2 Outcome.

Neurofibromatosis type 2 treatment.

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 ⁴⁾.

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 ⁵⁾.

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 ⁶⁾.

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 ⁷⁾.

Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2 ⁸⁾.

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 ⁹⁾.