Search

Background: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders.Methods: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention.Results: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues.Conclusions: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management. [ABSTRACT FROM AUTHOR]

Supratentorial ependymoma, ZFTA fusion positive, is a subtype of ependyoma with a ZFTA (C11orf95) fusion, most often involving RELA as the partner. ZFTA rearrangements were initially reported to result from intrachromosomal deletions or chromothripsis in chromosome 11 which are typically detected by chromosomal microarray analysis (CMA). We use CMA, our OncoKids NGS panel, and whole transcriptome RNA-seq to identify ZFTA fusions in pediatric brain tumors. For several tumors with ZFTA fusions detected by RNA-seq, complex copy number alterations involving chromosome 11 were not detected by CMA. To investigate the potential underlying genetic mechanisms leading to these ZFTA fusions, we performed optical genome mapping (OGM) on five supratentorial ependymomas with ZFTA fusions detected by RNA-seq. Three of 5 cases had copy neutral intra-chromosomal complex rearrangements; one had a translocation between chromosomes 4 and 11 with predominantly balanced rearrangements on the derivative chromosome 11 and only a single 880-kb copy number loss in 11q13.1; and one had intrachromosomal complex rearrangements along with two small non-contiguous deletions in 11q13.1. None met the criteria for chromothripsis. Notably, ZFTA and RELA were not within the deletion intervals. Our results indicate that not all ZFTA fusions are the results of chromothriptic events. Therefore, cases without complex copy number alterations involving chromosome 11 using CMA may require additional testing, such as OGM and RNA-seq, to reveal the underlying genetic mechanisms leading to ZFTA fusions to establish the clinical diagnosis. [ABSTRACT FROM AUTHOR]

Gangliogliomas involving the optic apparatus are rare, with only 23 cases described in the literature to our knowledge. Because of their location, they are resistant to gross total resection and command careful consideration of adjuvant treatment. Here, we review the existing literature describing these cases, along with our own additional patient. Most patients (91.3%) with optic gangliogliomas presented with progressive visual disturbances, and the majority were male (69.6%), as with gangliogliomas in general. Ophthalmological evaluation is warranted in these patients, followed by neurological imaging (preferably MRI). Screening for neurofibromatosis type 1 (NF1) is essential, as NF1 patients represent a disproportionate number of optic ganglioglioma cases (13.0%). Gross total resection should be attempted only if vision is beyond salvage, as this can be curative. Otherwise, when serviceable vision remains, subtotal resection with adjuvant radiation should be carried out when feasible. Despite treatment, the prognosis remains mixed, with roughly one-third of patients progressing. [ABSTRACT FROM AUTHOR]

Light chain deposition disease (LCDD) is a rare clinicopathologic entity first described in 1976 and is characterized by a monoclonal gammopathy resulting in nonamyloid immunoglobulin light chain tissue deposition. Only four cases of intracerebral LCDD have been previously reported, all in the setting of a known plasma cell dyscrasia or in the presence of local mature plasma cells. We present the first case of intracranial LCDD in the absence of a known plasma cell dyscrasia or local mature plasma cells. [ABSTRACT FROM AUTHOR]