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This study aimed to describe the gross and histological features of multiple endocrine and non-endocrine neoplasia, including multiple PGLs found in two Boxer dogs. Additionally, the identified PGLs were immunohistochemically evaluated, and the subunits 2, 3, and 4 of the SDHD gene were screened for possible mutations. The tumors identified include aortic and carotid body PGLs, thyroid follicular-compact carcinoma, and subcutaneous lipomas. One case also had a Leydig cell tumor and adrenal cortex hyperplasia, while the other had H-type pancreatic carcinoma. Three out of 4 PGLs appeared benign, but one aortic body tumor showed malignant features with neoplastic emboli at its edge. Immunohistochemical analysis confirmed the neuroendocrine origin of all PGLs, with positive staining for Chromogranin A, NSE, and variable positivity for S100. No somatic mutations were found in exons 2, 3, and 4 of the SDHD gene in any of the evaluated PGLs. The absence of mutations in the evaluated SDHD gene subunits suggests the involvement of other genetic factors or pathways in the development of these tumors, warranting further investigation in this field. Full article

Peutz–Jeghers Syndrome (PJS) is an autosomal dominant pre-cancerous disorder caused in 80–90% of cases by germline mutations in the tumor suppressor gene STK11. We performed a genetic test of the STK11 gene in two Italian young sisters suspected of PJS, since they showed pathognomonic café au lait spots in absence of other symptoms and familiarity. Sequencing of all exons of STK11 gene and other 8 genes, suggested to be involved in hamartomatous syndromes, (PTEN, BMPR1A, SDHB, SDHD, SMAD4, AKT1, ENG, PIK3CA) led to the identification in both the probands of a novel germline silent mutation named c.597 G>A, hitting the last nucleotide of exon 4. Interestingly, genetic testing of the two probands’ parents showed that their unaffected father was carrier of this mutation. Moreover, he carried a second intronic substitution named c.465-51 T>C (rs2075606) which was not inherited by his daughters. We also observed that all the family members carrying the c.597 G>A mutation presented an aberrant splice variant of STK11 mRNA lacking exon 4. Furthermore, in silico analysis of c.465-51 T>C substitution showed that it may activate an Enhancer Splicing Element. Finally, qRT-PCR analysis of STK11 expression levels showed a slight downregulation of the wild type allele in the father and a 2-fold downregulation in the probands compared to the unaffected mother. Our results have led the hypothesis that the c.465-51 T>C intronic variant, which segregates with the wild type allele, could increase the splicing effectiveness of STK11 wild-type allele and compensate the side effect of the c.597 G>A splicing mutation, being responsible for the phenotypic variability observed within this family. This finding highlight the importance of RNA analysis in genetic testing, remarking that silent DNA variant can often be splicing variant involved in disease onset and progression. The identification of these variants has a crucial role to ensure an appropriate follow-up and cancer prevention in at-risk individuals. Full article