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

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Abstract

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.

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Authors and Affiliations

  1. Institute of Human Genetics, University of Ulm, 89081, Ulm, Germany

    Hildegard Kehrer-Sawatzki, Anna Summerer & Eleonora Schäfer

  2. Department of Neurology, University Hospital Hamburg Eppendorf, 20246, Hamburg, Germany

    Lan Kluwe, Said Farschtschi & Victor-Felix Mautner

  3. Department of Oral and Maxillofacial Surgery, University Hospital Hamburg Eppendorf, 20246, Hamburg, Germany

    Reinhard E. Friedrich

  4. KBO- Children Clinical Center Munich, 81377, Munich, Germany

    Ute Wahlländer

  5. Department of Neurosurgery, University of Würzburg, 97080, Würzburg, Germany

    Cordula Matthies

  6. Department of Neurosurgery, University Hospital Tübingen, 72076, Tübingen, Germany

    Isabel Gugel

  7. Department of Neuropathology, University Hospital Hamburg Eppendorf, 20246, Hamburg, Germany

    Christian Hagel

  8. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

    David N. Cooper

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  1. Hildegard Kehrer-Sawatzki
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  2. Lan Kluwe
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Correspondence to Hildegard Kehrer-Sawatzki.

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Kehrer-Sawatzki, H., Kluwe, L., Friedrich, R.E. et al. Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas. Hum Genet 137, 543–552 (2018). https://doi.org/10.1007/s00439-018-1909-9

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