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


METHODS
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.
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Spain. ecastellanos@imppc.org.
Elisabeth
E
Castellanos
Department of Dermatology, Germans Trias i Pujol Hospital (HUGTiP), Badalona, Spain. ibielsa.germanstrias@gencat.cat.
Isabel
I
Bielsa
Department of Pathology, HUGTiP, Badalona, Spain. ccarrato.germanstrias@gencat.cat.
Cristina
C
Carrato
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Spain. IRosas@imppc.org.
Imma
I
Rosas
Program on Hereditary Cancer, Catalan Institute of Onclogy (ICO), Badalona, Spain. asolanes@iconcologia.net.
Ares
A
Solanes
Department of Neurosurgery, HUGTiP, Badalona, Spain. crishp@gmail.com.
Cristina
C
Hostalot
Department of Otorrinolaringology, HUGTiP, Badalona, Spain. emilioamilibia@gmail.com.
Emilio
E
Amilibia
Department of Otorrinolaringology, HUGTiP, Badalona, Spain. 22405jpm@comb.es.
José
J
Prades
Department of Otorrinolaringology, HUGTiP, Badalona, Spain. rocaribas.germanstrias@gencat.cat.
Francesc
F
Roca-Ribas
Program on Hereditary Cancer, ICO-IDIBELL, Hospitalet de Llobregat, Spain. clazaro@iconcologia.net.
Conxi
C
Lázaro
Program on Clinical Genetics and Genetic Counseling, HUGTiP, Badalona, Spain. iblanco.germanstrias@gencat.cat.
Ignacio
I
Blanco
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Spain. eserra@imppc.org.
Eduard
E
Serra
D000328:Adult; D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D007866:Leg; D018895:Microsatellite Repeats / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D009442:Neurilemmoma / Q000175:diagnosis / Q000235:genetics*; D016518:Neurofibromatosis 2 / Q000175:diagnosis* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors