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Downloaded from Bioscientifica.Com at 09/25/2021 12:14:58PM Via Free Access ID: 19-0149 8 6 Q Pang et al. PHO patients with soft tissue 8:6 736–744 giant tumor caused by HPGD mutation RESEARCH The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation Qianqian Pang1,2, Yuping Xu1,3, Xuan Qi1, Yan Jiang1, Ou Wang1, Mei Li1, Xiaoping Xing1, Ling Qin2 and Weibo Xia1 1Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China 2Musculoskeletal Research Laboratory and Bone Quality and Health Assessment Centre, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong 3Department of Endocrinology, The First Affiliated Hospital of Shanxi Medicalniversity, U Taiyuan, Shanxi, China Correspondence should be addressed to L Qin or W Xia: [email protected] or [email protected] Abstract Background: Primary hypertrophic osteoarthropathy (PHO) is a rare genetic multi-organic Key Words disease characterized by digital clubbing, periostosis and pachydermia. Two genes, f primary hypertrophic HPGD and SLCO2A1, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) osteoarthropathy and prostaglandin transporter (PGT), respectively, have been reported to be related to f PHO PHO. Deficiency of aforementioned two genes leads to failure of prostaglandin E2 (PGE2) f HPGD mutation degradation and thereby elevated levels of PGE2. PGE2 plays an important role in f soft tumor tumorigenesis. Studies revealed a tumor suppressor activity of 15-PGDH in tumors, such f COX2 selective inhibitor treatment as lung, bladder and breast cancers. However, to date, no HPGD-mutated PHO patients presenting concomitant tumor has been documented. In the present study, we reported the first case ofHPGD -mutated PHO patient with soft tissue giant tumors at lower legs and evaluated the efficacy of selective COX-2 inhibitor (etoricoxib) treatment in the patient. Methods: In this study, we summarized the clinical data, collected the serum and urine samples for biochemical test and analyzed the HPGD gene in our patient. Results: A common HPGD mutation c.310_311delCT was identified in the patient. In addition to typical clinical features (digital clubbing, periostosis and pachydermia), the patient demonstrated a new clinical manifestation, a giant soft tissue tumor on the left lower leg which has not been reported in HPGD-mutated PHO patient before. After 6-month treatment with etoricoxib, the patient showed decreased PGE2 levels and improved PHO-related symptoms. Though the soft tissue tumor persisted, it seemed to be controlled under the etoricoxib treatment. Conclusion: This finding expanded the clinical spectrum of PHO and provided unique Endocrine Connections insights into the HPGD-mutated PHO. (2019) 8, 736–744 Introduction Primary hypertrophic osteoarthropathy (PHO; MIM clubbing, periostosis and pachydermia. Accompanying 167100), also known as pachydermoperiostosis or abnormalities include sebaceous hyperplasia, idiopathic hypertrophic osteoarthropathy, is a rare hyperhidrosis, acro-osteolysis, and effusions and pain of genetic multi-organic disease characterized by digital large joints (1, 2). Additional developmental anomalies, https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0149 Published by Bioscientifica Ltd Attribution 4.0 International License. Downloaded from Bioscientifica.com at 09/25/2021 12:14:58PM via free access -19-0149 Q Pang et al. PHO patients with soft tissue 8:6 737 giant tumor caused by HPGD mutation seen in a proportion of PHO patients, include patent bladder and breast cancer (16, 17, 18). Whereas, to date, ductus arteriosus and myelofibrosis (3, 4). no HPGD-mutated PHO patients presenting concomitant To date, two genes have been reported to be associated tumor have been documented. with PHO: hydroxyprostaglandin dehydrogenase (HPGD; Up to now, no standard treatment has been approved MIM 601688), which encodes 15-hydroxyprostaglandin for PHO due to the small number of patients with PHO dehydrogenase (15-PGDH), and solute carrier organic at most clinical centers. There are some case reports anion transporter family, member 2A1 (SLCO2A1; MIM with varying therapeutic option and response, and the 601460), which encodes a prostaglandin transporter treatments are mostly focused on alleviation of symptoms, (1, 5). The pathogenesis and inherited pattern were including nonsteroidal anti-inflammatory drugs (NSAIDS), controversial for a long time until the year 2008, and pamidronate and tamoxifen citrate to relieve painful Uppal et al. identified the mutation ofHPGD as the osteoarthropathy (19, 20). Given that the increased primary causative factor of PHO (1). Subsequently, circulating PGE2 levels is responsible for pathogenic Zhang et al. (5) confirmed the second geneSLCO2A1 mechanism of PHO, cyclo-oxygenase (COX) inhibition to be responsible for PHO. According to the molecular may represent a targeted therapeutic option. Recently, findings, PHO has been categorized into two subtypes: COX-2 selective inhibitors, which inhibit the COX-2 (1) hypertrophic osteoarthropathy, primary, autosomal enzyme and thereby suppress PGE2 biosynthesis, represent recessive, type 1 (PHOAR1; MIM 259100), caused by promising treatment options for PHO. A few studies have HPGD deficiency and (2) hypertrophic osteoarthropathy, shown that etoricoxib, a novel COX-2 selective inhibitor, primary, autosomal recessive, type 2 (PHOAR2; MIM has a positive therapeutic effect on PHO patients in terms 614441), caused by SLCO2A1 deficiency. Both HPGD of decreased urinary PGE2 levels and improvement of and SLCO2A1 deficiency can independently lead to clinical phenotypes including pachydermia, clubbing failure of PGE2 degradation, resulting in elevated levels finger and joint swelling (21, 22, 23). of prostaglandin E2 (PGE2) in the circulation, which is Here we reported the first case of a Chinese thought to contribute to the pathogenesis for PHO (1, 6). HPGD-mutated PHO patient with soft tissue giant tumors PHO is a clinically heterogeneous disease. The onset age of at bilateral lower legs, as well as evaluated the efficacy PHO is bimodal distribution. Peaking onset age of clinical of selective COX-2 inhibition (etoricoxib) treatment in manifestations is usually the first year of life in PHOAR1 this patient. with HPGD mutations, and at puberty in PHOAR2 with SLCO2A1 mutations (6). Sefiertet al. (7) revealed that manifestations of bones and joints found in patients with homozygous mutations in the HPGD, usually appear Methods and materials earlier than those in the SLCO2A1, suggesting the clinical Human subjects heterogeneity between the two subtypes of PHO. It is widely acknowledged that PGE2 plays an important This study was approved by the Local Ethics Committee role in the development of tumors. PGE2 can stimulate cell of the Department of Scientific Research at Peking Union proliferation, angiogenesis and motility while inhibiting Medical College Hospital (PUMCH). The Chinese PHO apoptosis and immune surveillance (8, 9, 10). Reduced patient signed informed consent documents before 15-PGDH and SLCO2A1 are believed to contribute to entering the study. elevated levels of PGE2 in the circulation thereby leading to the pathogenesis of these tumors (11, 12, 13, 14). However, Biochemical parameters in humans, reports of HPGD and SLCO2A1 mutation cases have only been focused on the typical features such as The patient was admitted into our hospital and went digital clubbing, periostosis and pachydermia. Till 2014, through detailed clinical, biochemical and radiographic Guda et al. (15) reported a French-Canadian family investigation. For biochemical analysis, fasting blood with SLCO2A1 mutation presenting digital clubbing samples and 24-h urine were collected. Serum calcium and early-onset colon neoplasm, suggesting a link (Ca), serum phosphate (Pi), serum alkaline phosphatase between PHO and tumors. 15-PGDH is the major enzyme (ALP), serum creatinine (SCr), erythrocyte sedimentation responsible for prostaglandin degradation. Numerous rate (ESR), hypersensitive C reactive protein (hsCRP), studies have demonstrated a tumor suppressor activity of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) 15-PGDH in a number of different tumors, such as lung, were measured spectrophostometrically using routine https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0149 Published by Bioscientifica Ltd Attribution 4.0 International License. Downloaded from Bioscientifica.com at 09/25/2021 12:14:58PM via free access PB–9 Q Pang et al. PHO patients with soft tissue 8:6 738 giant tumor caused by HPGD mutation assays available at the central laboratory of PUMCH. Serum Bioinformatics analysis intact parathyroid hormone (iPTH) and beta- C-terminal The identified mutation in HPGD gene was analyzed at the telopeptide of type I collagen (β-CTX) were measured by protein level. Protein modeling was conducted based on an automated Roche electrochemiluminescence system the data of 15-PGDH structure in Protein Date Bank (PDB (Roche Diagnostics). Serum and urinary PGE and PGEM 2 ID: 2GDZ, http://www.rcsb.org), and the mutational- (a metabolite of PGE ) levels were measured by competitive 2 related residues were positioned in the constructed enzyme-linked immunosorbent assay (ELISA) according 3D structural model
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