Abstract
Subependymal giant cell astrocytomas (SEGAs) are rare central nervous system tumors that are almost pathognomonic of tuberous sclerosis complex (TSC). These lesions are World Health Organization (WHO) grade-I tumors that arise in the lateral ventricles near the foramen of Monro and almost always contain detectable mutations in TSC1 or TSC2. We present three children with TSC in whom a diagnosis of SEGA was the presenting feature and who displayed a mild TSC phenotype. All patients underwent surgery for tumor resection. Following surgical resection, germline testing for TSC1 and TSC2 mutations was performed, and pathologic specimens subsequently underwent molecular analysis using chromosomal microarray and a 50-gene next-generation sequencing. There were two males and one female with an age range of 12 to 18 years. All patients had evidence of cortical tubers on brain MRI, and two had hypomelanotic macules; no other manifestations of TSC were present. None of these patients were found to have detectable germline mutations in TSC1 or TSC2. One tumor specimen contained copy-neutral loss of heterozygosity (cnLOH) of chromosome 9q34 affecting TSC1 and NOTCH1. The second specimen contained cnLOH of chromosome 16p12-13 affecting TSC2; DNA sequencing confirmed a known pathogenic mutation in TSC2 in this patient. A third specimen was cytogenetically normal but contained a missense mutation in NOTCH2 of unknown significance. These data demonstrate that SEGAs in patients with a mild TS phenotype are molecularly heterogeneous, sometimes containing genetic alterations in TSC1 or TSC2 but also containing mutations in other pathways associated with growth, development and neoplasia.