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Zhen-lin Zhang - One of the best experts on this subject based on the ideXlab platform.
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clinical biochemical and genetic features of 41 han chinese families with primary Hypertrophic Osteoarthropathy and their therapeutic response to etoricoxib results from a six month prospective clinical intervention
Journal of Bone and Mineral Research, 2017Co-Authors: Yujuan Liu, Zhen-lin ZhangAbstract:Primary Hypertrophic Osteoarthropathy (PHO) is a rare inherited disease caused by genetic defects in the prostaglandin metabolism pathway; disturbed prostaglandin E2 (PGE2 ) catabolism resulting in increased PGE2 level is suggested in the pathogenesis. Forty-three Han Chinese patients with PHO were studied and 41 of them were treated. Mutations in the HPGD gene, causing Hypertrophic Osteoarthropathy, primary, autosomal recessive 1 (PHOAR1; OMIM 259100), were identified in seven patients, and mutations in the SLCO2A1 gene, causing Hypertrophic Osteoarthropathy, primary, autosomal recessive 2 (PHOAR2; OMIM 614441), were identified in 36 patients. Clinical phenotypes of PHO varied, ranging from mild isolated finger clubbing to severe pachydermia and disabling joint swelling, even within families. Circulating PGE2 metabolism features of PHOAR2 were different from those of PHOAR1. Different frequency and severity of pachydermia between the subgroups were also indicated. A percentage of PHOAR2 patients suffered from gastrointestinal hemorrhage, but this symptom was not observed in the PHOAR1 subgroup. Clinical evidence highlighted the essential role of sex hormones in prostaglandin transporter regulation with respect to PHOAR2 onset, although no significant associations of urinary PGE2 or PGE-M with sex hormones were identified. Treatment with etoricoxib, a selective cyclooxygenase-2 inhibitor, was proved to be beneficial and safe. We detected its notable efficacy in decreasing urinary PGE2 levels in the majority of the enrolled patients during 6 months of intervention; clinical phenotypes assessed, including pachydermia, finger clubbing, and joint swelling, were improved. We found no visible evidence of a positive effect of etoricoxib on periostosis; however, significant links between urinary PGE2 and serum bone turnover markers indicated a potential role of decreased PGE2 in periostosis management. This is the largest reported cohort of subjects genetically diagnosed with PHO. For the first time, we systematically investigated the biochemical and clinical differences between PHOAR1 and PHOAR2, and prospectively showed the positive efficacy and safety of etoricoxib for PHO patients. © 2017 American Society for Bone and Mineral Research.
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short communicationtwo novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2014Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract: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.
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a novel mutation in the slco2a1 gene in a chinese family with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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two novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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mutations in the slco2a1 gene and primary Hypertrophic Osteoarthropathy a clinical and biochemical characterization
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Context: We previously demonstrated that deficiency of the prostaglandin transporter (SLCO2A1) is a cause of primary Hypertrophic Osteoarthropathy (PHO). However, its clinical and metabolic characteristics have not been well defined. Objective: The objective of the study was to expand this mutational spectrum to better delineate the SLCO2A1 deficiency phenotype and investigate the clinical and metabolic characteristics of a cohort of subjects with PHO. Design, Setting, Patients, and Main Outcome Measure: Eleven affected individuals and their available healthy family members from 9 unrelated Chinese families with PHO (7 of which were previously undescribed) were clinically studied. The SLCO2A1 gene was screened and analyzed. Urinary levels of prostaglandin E2 (PGE2) and prostaglandin E metabolite (PGE-M) were measured using competitive ELISAs. The serum levels of total T, estradiol, sex hormone-binding protein, LH, FSH, and fasting gastrin were detected. Results: Nine different SLCO2A1 mutations were ident...
Zeng Zhang - One of the best experts on this subject based on the ideXlab platform.
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short communicationtwo novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2014Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract: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.
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a novel mutation in the slco2a1 gene in a chinese family with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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two novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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mutations in the slco2a1 gene and primary Hypertrophic Osteoarthropathy a clinical and biochemical characterization
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Context: We previously demonstrated that deficiency of the prostaglandin transporter (SLCO2A1) is a cause of primary Hypertrophic Osteoarthropathy (PHO). However, its clinical and metabolic characteristics have not been well defined. Objective: The objective of the study was to expand this mutational spectrum to better delineate the SLCO2A1 deficiency phenotype and investigate the clinical and metabolic characteristics of a cohort of subjects with PHO. Design, Setting, Patients, and Main Outcome Measure: Eleven affected individuals and their available healthy family members from 9 unrelated Chinese families with PHO (7 of which were previously undescribed) were clinically studied. The SLCO2A1 gene was screened and analyzed. Urinary levels of prostaglandin E2 (PGE2) and prostaglandin E metabolite (PGE-M) were measured using competitive ELISAs. The serum levels of total T, estradiol, sex hormone-binding protein, LH, FSH, and fasting gastrin were detected. Results: Nine different SLCO2A1 mutations were ident...
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Primary Hypertrophic Osteoarthropathy: an update
Frontiers of medicine, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and Hypertrophic Osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary Hypertrophic Osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of Hypertrophic Osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis.
Alexander F. Markham - One of the best experts on this subject based on the ideXlab platform.
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primary Hypertrophic Osteoarthropathy an update on patient features and treatment
The Journal of Rheumatology, 2015Co-Authors: Gabriella Giancane, Christine P. Diggle, Ian M. Carr, Alexander F. Markham, Elizabeth G Legger, Janneke Tekstra, Berent J Prakken, Arjan B Brenkman, David T Bonthron, Nico M WulffraatAbstract:To the Editor: Hypertrophic Osteoarthropathy (HO) is a disorder characterized by changes to the skin and bones, and occurs either in a rare familial primary form [primary Hypertrophic Osteoarthropathy, (PHO)], also called pachydermoperiostosis (PDP), with a 9:1 male:female prevalence ratio, or more commonly secondary to an underlying pathology1. Key features include digital clubbing, periostosis with bone and joint enlargement, and skin changes, such as pachydermia, abnormal furrowing, seborrhea, and hyperhidrosis. Specific developmental abnormalities have been found in some patients with PHO, such as wide cranial sutures, Wormian bones, and patent ductus arteriosus 2. In adults, when all major clinical features are present, PHO is relatively easy to diagnose. However, for the pediatrician, who often has to contend with an incomplete clinical presentation3, diagnosis may be a challenge. The discovery of mutations in 2 prostaglandin pathway genes HPGD and SLCO2A1 has clarified the autosomal recessive inheritance [Mendelian Inheritance in Man (MIM) #259100, MIM #614441] of this genetically heterogeneous condition4,5,6,7. Here we present 4 previously undescribed patients who exemplify the gene-dependent presentations of PHO and provide diagnostic and treatment advice. The subjects’ written consent was obtained in conformance to the Declaration of Helsinki. Key clinical features are listed in Table 1. Secondary causes of HO were excluded8, and DNA sequence analysis (Supplementary Data available online at jrheum.org) confirmed the clinical diagnoses of PHO/PDP. View this table: Table 1. Patients’ clinical features. A 20-year-old male patient had begun limping at the age of 14 months. At 3 years old, chronic arthritis of both knees was investigated by arthroscopy, with nonspecific chronic synovial inflammation at biopsy. Oligoarticular juvenile idiopathic arthritis (JIA) was diagnosed, and the patient was treated with nonsteroidal antiinflammatory drugs (NSAID), with clinical improvement. At age 5, coarse facies was noted. … Address correspondence to Dr. Gabriella Giancane, Department of Pediatric Immunology, University Medical Centre Utrecht, 3508 AB, Utrecht, the Netherlands. E-mail: gabriella.giancane{at}gmail.com, ggiancan{at}umcutrecht.nl
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common and recurrent hpgd mutations in caucasian individuals with primary Hypertrophic Osteoarthropathy
Rheumatology, 2010Co-Authors: Christine P. Diggle, Ian M. Carr, Emanuel Zitt, Katie Wusik, Robert J Hopkin, Carlos E Prada, Olga Calabrese, Olaf Rittinger, Marilynn Punaro, Alexander F. MarkhamAbstract:Objective. Homozygous recessive germline mutations of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene, encoding 15-hydroxyprostaglandin dehydrogenase, result in persistent elevation of circulating PGE2 levels, causing the syndrome of primary Hypertrophic Osteoarthropathy (PHO). Homozygous HPGD mutations have so far been reported in 10 families, all but one displaying parental consanguinity. Only two of these families were of European origin. We wished to determine the role of HPGD in causing PHO in non-consanguineous European families. Methods. Five previously unreported families of Caucasian European origin, with one or more individuals affected with typical PHO, were characterized clinically and by complete sequencing of the HPGD coding exons. Results. Biallelic HPGD mutations were identified in affected individuals in all the five families, confirming a very specific association of this phenotype with HPGD mutations. The previously described c.175_176delCT frameshift mutation was observed in association with two different alleles of an adjacent single nucleotide polymorphism. Conclusions. Biallelic HPGD mutations are found in the majority of patients with typical PHO, and sequencing of the HPGD gene is a highly specific first-line investigation for patients presenting in this way, particularly during childhood. The c.175_176delCT frameshift mutation appears to be recurrent and to be the commonest HPGD mutation in Caucasian families.
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Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary Hypertrophic Osteoarthropathy
Nature genetics, 2008Co-Authors: S. Uppal, Christine P. Diggle, Ian M. Carr, Colin W. G. Fishwick, Mushtaq Ahmed, Gamal H Ibrahim, Philip S Helliwell, Anna Latos-bielenska, Simon E. V. Phillips, Alexander F. MarkhamAbstract:Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary Hypertrophic Osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm1. The pathogenesis of clubbing and Hypertrophic Osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of Hypertrophic Osteoarthropathy (PHO) is recognized2,3. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33–q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E2 levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.
Changqing Zhang - One of the best experts on this subject based on the ideXlab platform.
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short communicationtwo novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2014Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract: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.
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a novel mutation in the slco2a1 gene in a chinese family with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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two novel mutations in the slco2a1 gene in a chinese patient with primary Hypertrophic Osteoarthropathy
Gene, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Abstract 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.
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mutations in the slco2a1 gene and primary Hypertrophic Osteoarthropathy a clinical and biochemical characterization
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Context: We previously demonstrated that deficiency of the prostaglandin transporter (SLCO2A1) is a cause of primary Hypertrophic Osteoarthropathy (PHO). However, its clinical and metabolic characteristics have not been well defined. Objective: The objective of the study was to expand this mutational spectrum to better delineate the SLCO2A1 deficiency phenotype and investigate the clinical and metabolic characteristics of a cohort of subjects with PHO. Design, Setting, Patients, and Main Outcome Measure: Eleven affected individuals and their available healthy family members from 9 unrelated Chinese families with PHO (7 of which were previously undescribed) were clinically studied. The SLCO2A1 gene was screened and analyzed. Urinary levels of prostaglandin E2 (PGE2) and prostaglandin E metabolite (PGE-M) were measured using competitive ELISAs. The serum levels of total T, estradiol, sex hormone-binding protein, LH, FSH, and fasting gastrin were detected. Results: Nine different SLCO2A1 mutations were ident...
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Primary Hypertrophic Osteoarthropathy: an update
Frontiers of medicine, 2013Co-Authors: Zeng Zhang, Changqing Zhang, Zhen-lin ZhangAbstract:Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and Hypertrophic Osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary Hypertrophic Osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of Hypertrophic Osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis.
Denise Horn - One of the best experts on this subject based on the ideXlab platform.
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Primary Hypertrophic Osteoarthropathy Mimicking Juvenile Idiopathic Arthritis: A Novel SLCO2A1 Mutation and Imaging Findings.
Cytogenetic and genome research, 2019Co-Authors: Murat Torgutalp, Wenke Seifert, Denise Horn, Ceren D. Durmaz, Halil Gürhan Karabulut, Zehra Akkaya, Murat TurgayAbstract:Primary Hypertrophic Osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, Osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.
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Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary Hypertrophic Osteoarthropathy and isolated digital clubbing.
Human mutation, 2012Co-Authors: Wenke Seifert, Jirko Kühnisch, Beyhan Tüysüz, Christof Specker, Ad Brouwers, Denise HornAbstract:Digital clubbing is usually secondary to different acquired diseases. Primary Hypertrophic Osteoarthropathy (PHO) is a rare hereditary disorder with variable digital clubbing as the most prominent feature, subperiosteal new bone formation, and arthropathy. Recently, mutations in the 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) encoding gene HPGD were found to cause PHO. Here, we identified three unrelated families with different mutations in the prostaglandin transporter (PGT) encoding gene SLCO2A1 which presumably result in reduced metabolic clearance by 15-PGDH due to diminished cellular uptake of prostaglandin E2 (PGE2) by mutant PGT. In two consanguineous families, homozygous mutations, an intragenic deletion that results in frameshift and a missense mutation, are associated with a severe PHO phenotype. In a third family, a heterozygous carrier of a stop mutation presents with isolated digital clubbing. Thus, our study further supports the importance of PGE2 metabolism in the pathogenesis of digital clubbing and PHO. Hum Mutat 33:660–664, 2012. © 2012 Wiley Periodicals, Inc.