By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant -1 position of the acceptor site of intron 1 (c.97-1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E(2) (PGE(2)) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy.

Primary hypertrophic osteoarthropathy (PHO) is a rare monogenetic disease that closely mimics hypertrophic osteoarthropathy secondary to pulmonary or other pathology. The study of PHO provides an opportunity to understand both the pathogenesis of hypertrophic osteoarthropathy and the functions of the underlying genes. PHO is characterized by digital clubbing, periostosis and pachydermia. Two genes are known to be related to PHO: SLCO2A1 and HPGD. Here, we identified a recurrent heterozygous guanine-to-adenine transition at the invariant +1 position of the donor site of intron 7 (c.940+1G>A) and a novel heterozygous missense mutation p.Asn534Lys (c.1602C>A) in exon 11 of SLCO2A1 in a Chinese young man with PHO. Identification of a novel genotype in PHO will provide clues to the phenotype-genotype relations and may assist not only in the clinical diagnosis of PHO but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.

Primary hypertrophic osteoarthropathy (PHO) is a rare monogenetic disease characterized by digital clubbing, periostosis and pachydermia. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been shown to be associated with PHO. Here, we described clinical characteristics in a Chinese patient with PHO, and identified two novel mutations in SLCO2A1: a heterozygous guanine-to-thymidine transition at the invariant -1 position of the acceptor site of intron 2 (c.235-1G>T) and a heterozygous missense mutation p.Pro219Leu (c.656C>T) in exon 5.

Primary hypertrophic osteoarthropathy (PHO) is a rare, autosomal, recessive genetic disease characterized by digital clubbing, periostosis, and pachydermia. The underlying cause for the pathogenesis of this disease is a defect in prostaglandin E2 (PGE2) degradation, caused by mutations in HPGD or SLCO2A1. In this study, we describe the clinical characteristics, SLCO2A1 mutations, and bone metabolic markers of a PHO pedigree from a Chinese consanguineous twin family.

Primary hypertrophic osteoarthropathy (PHO) is a rare disease involving joint, bone and skin. Two underlying genes responsible for this disease-hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1)-are both associated with aberrant accumulation of prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is a key enzyme in PGE2 synthesis. This study was intended to evaluate the safety and efficacy of COX-2 inhibitor in the treatment of PHO.

Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement.

Primary hypertrophic osteoarthropathy (PHO), which is a rare multi‑organic disease characterized by digital clubbing, pachydermia and periosteal reaction, typically begins during childhood or adolescence and progresses gradually over years prior to disease stabilization. To date, only two genes have been reported to be associated with PHO, 15‑hydroxyprostaglandin dehydrogenase and solute carrier organic anion transporter family, member 2A1 (SLCO2A1). However, the pathogenesis and the functions of the underlying genes remain to be fully elucidated. In the present study, a 20‑year‑old Chinese patient with PHO was investigated using sequence analysis of PHO genes and bioinformatics analysis. A novel, compound heterozygous mutation in the SLCO2A1 gene was identified, which contained two novel mutations: c.349delC (p.L117SfsX56) in exon 3 and c.1286A>G (p.Y429C) in exon 9. These two novel genotypes in PHO are the first, to the best of our knowledge, to be reported in PHO. This finding expands the mutation spectrum of PHO, which contributes to improving genetic diagnosis and future genetic counseling, and provides clues to the phenotype‑genotype associations.

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic multi-organic disease characterized by digital clubbing, periostosis and pachydermia. Two genes, HPGD and SLCO2A1, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin transporter (PGT), respectively, have been reported to be related to PHO. Deficiency of aforementioned two genes leads to failure of prostaglandin E2 (PGE2) degradation and thereby elevated levels of PGE2. PGE2 plays an important role in tumorigenesis. Studies revealed a tumor suppressor activity of 15-PGDH in tumors, such 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 of HPGD-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.

Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease that is grouped into PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2) due to different causative genes. Data comparing bone microstructure between the two subtypes are scarce. This is the first study to find that PHOAR1 patients had inferior bone microstructure compared with PHOAR2 patients.

Primary hypertrophic osteoarthropathy, autosomal recessive type 1 (PHOAR1, MIM259100) is caused by mutations in the 15-hydroxyprostaglandin dehydrogenase gene (HPGD, MIM601688) on chromosome 4q34. An induced pluripotent stem cells (iPSCs) line was generated in our lab from peripheral blood mononuclear cells (PBMCs) of a 2-year-7-month-old girl with PHOAR1 carrying a homozygous mutation of c.310_311del in HPGD. The expression of pluripotency markers, absence of episomal vectors, preservation of normal karyotype, the potential of trilineage differentiation in vitro, were confirmed in the obtained iPSCs line.

Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis, and pachydermia. Based on two causative genes, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), PHO is categorized into two subtypes: hypertrophic osteoarthropathy, primary, autosomal recessive 1 (PHOAR1) and hypertrophic osteoarthropathy, primary, autosomal recessive 2 (PHOAR2). In this study, we summarized the clinical manifestations and analyzed SLCO2A1 gene in 23 PHOAR2 patients in our center. As a result, 18 patients displayed complete phenotypes of PHO with digital clubbing, periostosis, and pachydermia. 29 mutations were found in total, and 22 of them were novel mutations including 13 missense, three nonsense, four deletion, one frame-shift and one splicing site mutations. Compared with nine PHOAR1 patients we previously reported, PHO patients with SLCO2A1 mutations were all male and presented with a later onset age. Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients. The urinary level of prostaglandin E2 metabolite (PGEM) is significantly higher in PHOAR2 patients than that in PHOAR1 group. In conclusion, this study was the largest cohort to date to summarize PHOAR2 patients and to assess the phenotypic difference between two subtypes of PHO. The difference of urinary PGEM concentration between two subtypes is helpful for the differential diagnosis of PHO.

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO.

Primary hypertrophic osteoarthropathy (PHO) is a rare familial disorder with reduced penetrance for females. The genetic mutations associated with PHO have been identified in HPGD and SLCO2A1 which involved in prostaglandin E2 metabolism. Here we report 5 PHO patients from 4 non-consanguineous families. Two heterozygous mutations in solute carrier organic anion transporter family member 2A1 (SLCO2A1) were identified in two brothers by whole-exome sequencing. Three heterozygous mutations and 1 homozygous mutation were identified in other 3 PHO families by Sanger sequencing. However, there was no mutation in HPGD. These findings confirmed that homozygous or compound heterozygous mutations of SLCO2A1 were the pathogenic cause of PHO. A female individual shared the same mutations in SLCO2A1 with her PHO brother but did not have any typical PHO symptoms. The influence of sex hormones on the pathogenesis of PHO and its implication were discussed.

The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49-22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89-7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC etiology through the identification of biomarkers of colorectal carcinogenesis might allow a better definition of risk models that are more likely to benefit from targeted preventive strategies to reduce CRC burden.