Neurofibromatosis‐ and schwannomatosis‐associated tumors: Approaches to genetic testing and counseling considerations

Abstract

Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor‐based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF‐ and SWN‐related tumor types, which are somewhat rare and perhaps lesser known to non‐specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre‐ and post‐test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.

Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report

“…4 , arrow). Based on the recent diagnostic criteria, the patient and his brother were diagnosed with LZTR1 -related SWN [ [11] , [12] , [13] ]. This genetic result was explained to his brother, who started his follow-up for the potential development of brain tumors.…”

“…Based on the clinical findings of multiple schwannomas and his family history, schwannoma-predisposing syndromes, particularly SWM, were suspected. To achieve a genetic diagnosis of familial SWN, whole-exome sequencing (WES) of this patient and his brother was performed [ [11] , [12] , [13] ]. Moreover, to identify transcriptome signatures associated with SWN, we performed RNA sequencing (RNA-Seq) analysis.…”

“…These three types of NF have traditionally been differentiated based on their clinical manifestations [ 6 , 9 , 10 ]. The clinical diagnostic guidelines for SWN recommend molecular testing to diagnose SWN accurately [ [11] , [12] , [13] ]. Mutations in two tumor suppressor genes, namely, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 ( SMARCB1 ) and leucine zipper-like transcription regulator 1 ( LZTR1 ), have been considered as the cause of SWN [ 1 , [11] , [12] , [13] ].…”

“…The clinical diagnostic guidelines for SWN recommend molecular testing to diagnose SWN accurately [ [11] , [12] , [13] ]. Mutations in two tumor suppressor genes, namely, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 ( SMARCB1 ) and leucine zipper-like transcription regulator 1 ( LZTR1 ), have been considered as the cause of SWN [ 1 , [11] , [12] , [13] ]. Germline mutations of the SMARCB1 or LZTR1 gene occur in 85% of familial and 40% of sporadic patients [ 1 , [11] , [12] , [13] ].…”

“…Mutations in two tumor suppressor genes, namely, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 ( SMARCB1 ) and leucine zipper-like transcription regulator 1 ( LZTR1 ), have been considered as the cause of SWN [ 1 , [11] , [12] , [13] ]. Germline mutations of the SMARCB1 or LZTR1 gene occur in 85% of familial and 40% of sporadic patients [ 1 , [11] , [12] , [13] ]. Based on a meta-analysis, malignant nerve tumors occur primarily due to the germline pathogenic variants of the SMARCB1 gene [ 14 ].…”