Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations.

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disease mainly affecting the skeletal and skin. Two genes involved in prostaglandin degradation are known to be responsible for PHO: HPGD and SLCO2A1. HPGD gene mutation can cause PHO autosomal recessive 1 (PHOAR1). The purpose of the present study is to analyze the clinical and biochemical characteristics and HPGD gene mutations of 12 Chinese PHOAR1 patients. Twelve PHOAR1 patients from eleven families, including eleven males and one female, were enrolled in this study. Digital clubbing and periostosis came out to be the most common features, which always occur in the early childhood. We performed HPGD gene analysis and identified six novel (c.1A>G, c.34G>T, c.317T>A, c.475G>T, c.548C>T and c.421+1G>T) and one known (c.310_311delCT) HPGD mutations. The recurrent mutation c.310_311delCT were found in all eleven patients, suggesting it is a hotspot mutation. PHOAR1 patients are considered to have an autosomal recessive inheritance pattern. Here, in addition to nine compound heterozygous patients and two homozygous patients, we found one heterozygous patient and reviewed two heterozygous patients reported in other studies. In terms of biochemical characteristics, our PHOAR1 patients have elevated urinary prostaglandin E2 (PGE2) levels (P<0.001) and decreased urinary prostaglandin E metabolite (PGE-M) levels (P=0.04) compared with healthy controls. The patients' PGE2/PGE-M (E/M) ratio came out to be lower than normal subjects (P<0.001). This study provides a comprehensive description of the clinical phenotypes of Chinese PHOAR1 patients and expands the genotypic spectrum of the disease.

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.

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.

Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy.

BACKGROUND: Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. OBJECTIVE: We aimed to identify the genetic cause of 2 unrelated patients with PHO. METHOD: Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. RESULTS: The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. CONCLUSIONS: Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients.

Mutations in the SLCO2A1 gene and primary hypertrophic osteoarthropathy: a clinical and biochemical characterization.

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 identified in affected individuals in the 7 previously undescribed families, 7 of which (Glu165X, Ala286GlnfsX35, Gln356AlafsX77, Gly369Asp, Gly379Glu, Glu465Lys, and c.861+2T>C) were novel. The urinary levels of PGE2 and PGE-M were much higher in the SLCO2A1-deficient individuals and decreased with age. There was no relationship between sex hormones and PGE2 or PGE-M. There was no significant difference in the levels of fasting serum gastrin between PHO patients with watery diarrhea and their relatives. CONCLUSIONS: The present findings broaden the allelic spectrum of SLCO2A1 mutations. The urinary levels of PGE2 and PGE-M in the SLCO2A1-deficient individuals decreased with age. The measurement of the excreted PGE2 and PGE-M may have implications in the differential diagnosis, treatment, and follow-up of PHO.

Pachydermoperiostosis: study of epidermal growth factor and steroid receptors.

Pachydermoperiostosis is a rare osteo-cutaneous disease characterized by hypertrophy of bones and surrounding soft tissues. The cutaneous manifestations include coarsening of facial features, cutis verticis gyrata, digital clubbing, hyperhidrosis and seborrhoea. The pathogenetic mechanism of the disease is still debated, and proposed aetiological factors include genetic influences, anomalies in fibroblast activity, or alteration in peripheral blood flow. We studied a patient with the incomplete form of pachydermoperiostosis, assessing epidermal growth factor receptor (EGF-R) and sex hormone steroid receptors (SR) in the affected skin, and also evaluating the urinary excretion of EGF. The results showed high levels of nuclear steroid receptors, increased cytosolic oestrogen receptors, and no detectable progesterone and androgen cytosolic receptors. EGF-R was also undetectable, and the urinary excretion of EGF was elevated. These findings suggest that the increased tissue sensitivity to circulating sex-steroids could induce enhanced tissue EGF/transforming growth factor alpha (TGF-alpha) production and utilization. The SR-EGF-R system could therefore be involved in determining hypertrophy of the affected tissues.