The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite the clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis is not caused by germline NF2 gene mutations. Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. In contrast to patients with rhabdoid tumours, which are due to complete loss-of-function SMARCB1 mutations, individuals with schwannomatosis harbour predominantly hypomorphic SMARCB1 mutations which give rise to the synthesis of mutant proteins with residual function that do not cause rhabdoid tumours. Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. This review provides an overview of current models of tumorigenesis and mutational patterns underlying schwannomatosis that will ultimately help to explain the complex clinical presentation of this rare disease

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

Typical 22q11.2 deletion syndrome appears to confer a reduced risk of schwannoma

Purpose: The LZTR1 gene has been associated with schwannomatosis tumor predisposition and is located in a region that is deleted in the great majority (89%) of patients with 22q11.2 deletion syndrome (22q11.2DS). Since it is known that approximately 1 in 500 people in the general population will develop a sporadic schwannoma and there are no reports of the occurrence of schwannoma in 22q11.2DS, we investigated whether whole-gene deletion of LZTR1 occurs in schwannomatosis and assessed the risk of schwannoma in 22q11.2DS. Methods: We assessed the genetic testing results for LZTR1-associated schwannomatosis and the clinical phenotypes of patients with 22q11.2DS. Results: There were no reports of schwannoma in over 1,500 patients with 22q11.2DS. In addition, no patients meeting clinical diagnostic criteria for schwannomatosis had a whole-gene deletion in LZTR1. Only 1 patient in 110 with an apparently sporadic vestibular schwannoma had a constitutional whole-gene deletion of LZTR1. Conclusion: People with a large 22q11.2 deletion may have a reduced risk of developing a schwannoma compared to the general population

Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Purpose We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. Results There was no evidence for usefulness of old criteria “glioma“ or “neurofibroma.” “Ependymoma” had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. Conclusions The present study confirms important deficiencies in NF2 diagnostic criteria. The term “glioma” should be dropped and replaced by “ependymoma.” Similarly “neurofibroma” should be removed. Dropping “sibling” from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS