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Background  A clinical overlap exists between mosaic Neurofibromatosis Type 2 and sporadic Schwannomatosis conditions. In these cases a molecular analysis of tumors is recommended for a proper genetic diagnostics. This analysis is challenged by the fact that schwannomas in both conditions bear a somatic double inactivation of the  NF2  gene. However, SMARCB1-associated schwannomas follow a four-hit, three-step model, in which both alleles of  SMARCB1  and  NF2  genes are inactivated in the tumor, with one of the steps being always the loss of a big part of chromosome 22 involving both loci.    Case presentation  Here we report a 36-year-old woman who only presented multiple subcutaneous schwannomas on her right leg. To help discriminate between both possible diagnoses, an exhaustive molecular genetic and genomic analysis was performed on two schwannomas of the patient, consisting in cDNA and DNA sequencing, MLPA, microsatellite multiplex PCR and SNP-array analyses. The loss of a big part of chromosome 22 (22q12.1q13.33) was identified in both tumors. However, this loss involved the  NF2  but not the  SMARCB1  locus. SNP-array analysis revealed the presence of the same deletion breakpoint in both schwannomas, indicating that this alteration was actually the first  NF2  inactivating hit. In addition, a distinct  NF2  point mutation in each tumor was identified, representing independent second hits. In accordance with these results, no deletions or point mutations in the  SMARCB1  gene were identified. None of the mutations were present in the blood. Two of the patient’s children inherited chromosome 22 deleted in schwannomas of the mother, but in its wild type form.    Conclusions  These results conclusively confirm the segmental mosaic NF2 nature of the clinical phenotype presented.

Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb