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Despite increasing knowledge of disease‐causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein‐coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non‐coding spliceosomal snRNA gene RNU4‐2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4‐2 variant (NR_003137.2(RNU4‐2):n.64_65insT) in a 5‐year‐old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5‐year follow‐up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4‐2. This case illustrates the power of re‐analysis to solve previously unexplained cases even when a diagnostic genome remains negative. [ABSTRACT FROM AUTHOR]

Adipocytic tumours are among the most common mesenchymal neoplasms, and constitute a clinically, biologically and pathologically diverse group. Their wide histological spectrum and frequent morphological overlap have made classification and diagnosis challenging, with accurate classification being critical because of the considerable differences in prognosis and management between morphologically overlapping neoplasms. Ongoing advances in molecular genetics have aided significantly to our understanding of these neoplasms, with continuing evolution in classification. This review summarises the new developments in benign and malignant adipocytic neoplasms, with discussion of new entities and genetic findings, updates on the clinical and morphological spectrum, and the use of diagnostic immunohistochemistry and molecular markers in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Adipocytic tumours are among the most common mesenchymal neoplasms, and constitute a clinically, biologically and pathologically diverse group. Their wide histological spectrum and frequent morphological overlap have made classification and diagnosis challenging, with accurate classification being critical because of the considerable differences in prognosis and management between morphologically overlapping neoplasms. Ongoing advances in molecular genetics have aided significantly to our understanding of these neoplasms, with continuing evolution in classification. This review summarises the new developments in benign and malignant adipocytic neoplasms, with discussion of new entities and genetic findings, updates on the clinical and morphological spectrum, and the use of diagnostic immunohistochemistry and molecular markers in the differential diagnosis., (© 2021 John Wiley & Sons Ltd.)

Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor and dedifferentiated liposarcoma (DDL) together comprise the largest subgroup of liposarcomas, and constitute a histologic and behavioral spectrum of one disease. WDL and DDL typically occur in middle-aged to older adults, particularly within the retroperitoneum or extremities. WDL closely resembles mature adipose tissue, but typically shows fibrous septation with variable nuclear atypia and enlargement. WDL does not metastasize, but can dedifferentiate to DDL, which is associated with more aggressive clinical behavior, with a greater propensity for local recurrence and the capacity for metastasis. Although distant metastasis is rarer in DDL compared with other pleomorphic sarcomas, behavior is related to location, with a significantly worse outcome in retroperitoneal tumors. DDL typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma, and is usually a non-lipogenic sarcoma that is adjacent to WDL, occurs as a recurrence of WDL or which can arise de novo. WDL and DDL share similar background genetic aberrations; both are associated with high-level amplifications in the chromosomal 12q13-15 region, which includes the CDK4 and MDM2 cell cycle oncogenes. In addition, DDL harbor further genetic changes, particularly 6q23 and 1p32 coamplifications. While surgical excision remains the treatment mainstay with limited medical options for patients with aggressive recurrent disease or metastases, novel targeted therapies towards the gene products of chromosome 12 are being evaluated. This review summarizes the pathology of WDL and DDL, discussing morphology, immunohistochemistry, genetics and the differential diagnosis., (Copyright © 2019. Published by Elsevier Inc.)