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Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor ( CIC ) rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with CIC alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of CIC rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors.

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Steroidogenic factor 1 (encoded by the NR5A1 gene) is a critical regulator of reproduction, controlling transcription of key genes involved in sexual dimorphism. To date, NR5A1 variants have been found in individuals with a 46,XY karyotype and gonadal dysgenesis, as well as with a wide spectrum of genital anomalies and, in some patients, with adrenal insufficiency. We describe evolution of gonadal function, from the neonatal period to puberty, in a patient with a 46,XY karyotype, a disorder of sexual development, and a mutation (c.691_699dupCTGCAGCTG) in the NR5A1 gene. The patient, ascertained at birth due to ambiguous genitalia, showed normal values of plasma testosterone in the late neonatal period. Evaluation of the hormonal profile over time indicated severe tubular testicular hypofunction suggestive for a 46,XY disorder of gonadal development. A comprehensive review of published reports of 46,XY and disordered sexual development related to the NR5A1 gene confirmed the clinical and hormonal variability in patients with NR5A1 mutations. Analysis of multiple data allowed us to define the most common features associated with NR5A1 mutations. We further confirmed the indication to perform NR5A1 screening in patients with 46,XY karyotype and disordered sexual development even when Müllerian structures appear to be absent and plasma testosterone levels are within the normal range for age., (© 2014 Wiley Periodicals, Inc.)

Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Heterozygous mutations in ATP2A2, encoding the sarco-endoplasmic reticulum calcium pumping ATPase type 2, are identified as the molecular basis of DD. In this study, molecular features in a large cohort of Italian patients are reported. Molecular data were collected along with the main clinical features. Genomic DNA was used for direct sequencing of ATP2A2. The effect of selected mutations was predicted by in silico analysis or investigated by gene expression studies. 10 different ATP2A2 mutations were identified. Three mutations (c.2300A>G, c.2794G>A, c.569delAins34) have been previously described, while 7, including 2 missense (c.545G>A and c.2116G>A), 2 nonsense (c.1372G>T and c.1675C>T), 1 small deletion (c.142delA), 1 duplication (c.2935_2949dup15) and 1 splice-site mutation (c.2742-1G>A), were novel. Collected data added new variants to the ATP2A2 repertoire and confirmed that ATP2A2 mutations are scattered over the entire gene and, in most cases, private.