Charlotte Hammerbeck-Ward

Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis

Objective: To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. Methods: We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. Results: Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. 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. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.

Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults

Importance Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome. Objective To determine the frequency of the known heritable meningioma- or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. Design, Setting, and Participants Using the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU. Main Outcomes and Measures The type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma- and meningioma-predisposing syndromes. Results In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation. Conclusions and Relevance A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.

Hearing optimisation in neurofibromatosis type 2: A systematic review.

It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group.

Outcomes of cochlear implantation in patients with neurofibromatosis type 2

In neurofibromatosis type 2 (NF2) bilateral vestibular schwannomas (VS) or their treatment usually results in bilateral hearing loss. Cochlear implantation (CI) was traditionally not used in these patients due to concern that retrocochlear disease would render the implant ineffective. This paper describes the auditory outcomes of CI in 13 patients with NF2 and includes patients with untreated VS and patients undergoing VS removal with cochlear nerve preservation. The non-user rate was 7.7%. Of the active users, median CUNY score was 98%, median BKB score in quiet was 90% and median BKB score in noise was 68%. CI is a viable option in selected patients with NF2.

Schwannomatosis: a genetic and epidemiological study

Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

High-Grade Glioma is not a Feature of Neurofibromatosis Type 2 in the Unirradiated Patient

BACKGROUND The Manchester criteria for neurofibromatosis type 2 (NF2) include a range of tumors, and gliomas were incorporated in the original description. The gliomas are now widely accepted to be predominantly spinal cord ependymomas. OBJECTIVE To determine whether these gliomas include any cases of malignant glioma (WHO grade III and IV) through a database review. METHODS The prospective database consists of 1253 patients with NF2. 1009 are known to be alive at last follow‐up. RESULTS There was a single case of glioblastoma multiforme (GBM; World Health Organization grade IV) in the series and no WHO grade III gliomas. The GBM was in a patient who had previously undergone stereotactic radiosurgery for a vestibular schwannoma. CONCLUSION High‐grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria.

Familial unilateral vestibular schwannoma is rarely caused by inherited variants in the NF 2 gene: Familial Unilateral Vestibular Schwannoma

Unilateral vestibular schwannoma (VS) occurs with a lifetime risk of around 1 in 1,000 and is due to inactivation of the NF2 gene, either somatically or from a constitutional mutation. It has been postulated that familial occurrence of unilateral VS occurs more frequently than by chance, but no causal mechanism has been confirmed.

Intraoperative Supratentorial Extradural Hematoma Complicating Excision of a Giant Vestibular Schwannoma.

BACKGROUND A man developed a rare and unexpected contralateral intraoperative complication during a translabyrinthine resection of a large cystic vestibular schwannoma. CASE DESCRIPTION A 29-year-old man presented with progressive, low-level right-sided tinnitus and hearing loss. Magnetic resonance imaging displayed a large multicystic lesion suggestive of a vestibular schwannoma extending into the right cerebellopontine angle and distorting the midbrain. The patient subsequently underwent translabyrinthine excision of the lesion. The operation was complicated by brain swelling that obscured the operative field. Cerebrospinal fluid drainage failed to improve operative conditions, and an urgent computed tomography scan was performed, which showed a large supratentorial extradural hematoma as the cause. This extradural collection was promptly evacuated, and the patient had a good neurologic recovery postoperatively. CONCLUSIONS Although the development of postoperative extradural hematomas resulting from cerebrospinal fluid overdrainage is reported in the literature, this case is unique in that infratentorial surgery led to the development of a supratentorial hematoma.

Petrous Bone Cholesteatoma: The Manchester Experience: Presenting Author: Hannah North

Material and Methods: 50 patients (16 to 65 y.o.) with cholesteatoma have been observed in this work. 34 ears have extensive cholesteatoma with erosion of posterior bony wall of ear canal. In 12 patients cholesteatoma involves only epitympanum, in 4-hole tympanic cavity. Posterior canal wall erosion due to cholesteatoma was indentified as the primary indication for radical mastoidectomy. Most patients mentioned periodic, only 7 of thempersistent otorrhea. All patients had conductive to mixed hearing loss with ABG more than 25 dB. 34 patients were undergone CWD, 16 CWU tympanomastoidectomy with mastoid obliteration using of bone pate′ from the cortical layer of mastoid. Temporalis fascia has been used for tympanic membrane grafting and for covering of mastoid cavity filling with bone pate′. Tragal cartilage has been used in 27 patients for placement between the head of the stapes and fascia. In cases of cholesteatoma in the oval window area, ossiculoplasty is postponed for second look surgery.