Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity.

BackgroundDifferently expressed circular RNAs (circRNAs) have been reported to play a considerable role in tumor behavior; however, the expression profile and biological function of circRNAs in papillary thyroid carcinoma (PTC) remains unknown. Thus, the study was aimed to characterize the circRNA expression profile to comprehensively understand the biological behavior of PTC.MethodsWe investigated the expression profile of circRNAs using circRNA microarray in three pairs of PTC and adjacent normal tissues. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate eight candidate circRNAs in 40 paired PTC tumors and adjacent normal samples. Next, we employed a bioinformatics tool to identify putative miRNA and circRNA-associated downstream genes, followed by constructing a network map of circRNA-miRNA-mRNA interactions and exploring the potential role of the candidate circRNAs.ResultsIn total, 206 up- and 177 downregulated circRNAs were identified in PTC tissues (fold change >1.5; P < 0.05). The expression levels of eight candidate circRNAs confirmed by qRT-PCR were significantly different between the PTC and normal samples. The downstream genes of candidate circRNAs participated in various biological processes and signaling pathways. The most up and downregulated circRNAs were hsa_circRNA_007148 and hsa_circRNA_047771. The lower expression level of hsa_circRNA_047771 was associated BRAFV600 mutation, lymph node metastasis (LNM), as well as with advanced TNM stage (all P < 0.05). The higher expression level of hsa_circRNA_007148 was significantly correlated with LNM (P < 0.05). The areas under receiver operating curve were 0.876 (95% CI [0.78–0.94]) for hsa_circRNA_047771 and 0.846 (95% CI [0.75–0.96]) for hsa_circRNA_007148.DiscussionThe study suggests that dysregulated circRNAs play a critical role in PTC pathogenesis. PTC-related hsa_circRNA_047771 and hsa_circRNA_007148 may serve as potential diagnostic biomarkers and prognostic predictors for PTC patients.

ContextVon Hippel–Lindau (VHL) disease manifests as a variety of benign and malignant neoplasms. Previous studies of VHL disease have documented several genotype–phenotype correlations; however, many such correlations are still unknown. Increased identification of new mutations and patients with previously described mutations will allow us to better understand how VHL mutations influence disease phenotypes.Patients and designA total of 45 individuals from five unrelated families were evaluated, of which 21 patients were either diagnosed with VHL disease or showed strong evidence related to this disease. We compared the patients’ gene sequencing results with their medical records including CT or MRI scans, eye examinations and laboratory/pathological examinations. Patients were also interviewed to obtain information regarding their family history.ResultsWe identified four missense mutations: c.239G>T (p.Ser80Ile), linked with VHL Type 2B, was associated with renal cell carcinoma, pheochromocytoma and hemangioma in the cerebellum; c.232A>T (p.Asn78Tyr) manifested as RCC alone and likely caused VHL Type 1; c.500G>A (p.Arg167Gln) mutation was more likely to cause VHL Type 2 than Type 1 as it preferentially induced Pheo and HB in the retina, cerebellum and spinal cord; c.293A>G (p.Try98Cys) was associated with Pheo and thus likely induced VHL Type 2.ConclusionsCharacterizing VHL disease genotype–phenotype correlations can enhance the ability to predict the risk of individual patients developing different VHL-related phenotypes. Ultimately, such insight will improve the diagnostics, surveillance and treatment of VHL patients.PrecisFour missense mutations in VHL have been identified in 21 individuals when five unrelated Chinese families with VHL disease were analyzed; VHL mutations are highly associated with unique disease phenotypes.