Abstract
Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease characterized by digital clubbing, periostosis, and pachydermia. The HPGD gene encoding 15-prostaglandin dehydrogenase and SLCO2A1 encoding one type of prostaglandin transporter were found to be responsible for PHO. Mutations of either gene would lead to increased level of prostaglandin E2 (PGE2), which might contribute to the constellation of the symptoms. The aim of the study was to analyze the HPGD gene and the clinical characteristics in nine patients with the diagnosis of PHO. Nine patients, (eight males and one female) including two siblings and seven sporadic cases, were enrolled in the study. Clinical features were summarized, and blood and urine samples were collected. Sanger method was used to sequence the HPGD gene to detect mutations. Urinary PGE2 and prostaglandin metabolite (PGE-M) levels for each patient were measured and compared to the healthy controls. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). The levels of PGE2 in urine were much higher than normal in all patients, along with lower PGE-M levels. In conclusion, nine PHO patients were characterized by typical clinical manifestations including digital clubbing, periostosis, and pachydermia. A common mutation and a novel mutation in HPGD gene were identified to be responsible for the disease, and c.310_311delCT mutation is likely to be a hot-spot mutation site for Asian PHO patients.
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References
Rimoin DL (1965) Pachydermoperiostosis (idiopathic clubbing and periostosis): genetic and physiologic considerations. N Engl J Med 272:923–931
Castori M, Sinibaldi L, Mingarelli R, Lachman RS, Rimoin DL, Dallapiccola B (2005) Pachydermoperiostosis: an update. Clin Genet 68:477–486
Marrie TJ, Brown N (2007) Clubbing of the digits. Am J Med 120:940–941
Uppal S, Diggle CP, Carr IM, Fishwick CWG, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bieleńska A, Phillips SEV, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 40:789–793
Zhang Z, Xia W, He J, Zhang Z, Ke Y, Yue H, Wang C, Zhang H, Gu J, Hu W, Fu W, Hu Y, Li M, Liu Y (2012) Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet 90:125–132
Zhang Z, He J, Fu W, Zhang C, Zhang Z (2013) Mutations in the SLCO2A1 gene and primary hypertrophic osteoarthropathy: a clinical and biochemical characterization. J Clin Endocrinol Metab 98:923–933
Seifert W, Kuhnisch J, Tuysuz B, Specker C, Brouwers A, Horn D (2012) Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing. Hum Mutat 33:660–664
Bergmann C, Wobser M, Morbach H, Falkenbach A, Wittenhagen D, Lassay L, Ott H, Zerres K, Girschick HJ, Hamm H (2011) Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD/HPGD loss-of-function mutations. Exp Dermatol 20:531–533
Tariq M, Azeem Z, Ali G, Chishti MS, Ahmad W (2008) Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet 46:14–20
Seifert W, Beninde J, Hoffmann K, Lindner TH, Bassir C, Aksu F, Hübner C, Verbeek NE, Mundlos S, Horn D (2009) HPGD mutations cause cranioosteoarthropathy but not autosomal dominant digital clubbing. Eur J Hum Genet 17:1570–1576
Yüksel-Konuk B, Sırmacı A, Ayten GE, Özdemir M, Aslan İ, Yılmaz-Turay Ü, Erdoğan Y, Tekin M (2009) Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy. Rheumatol Int 30:39–43
Diggle CP, Carr IM, Zitt E, Wusik K, Hopkin RJ, Prada CE, Calabrese O, Rittinger O, Punaro MG, Markham AF, Bonthron DT (2010) Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. Rheumatology 49:1056–1062
Sinibaldi L, Harifi G, Bottillo I, Iannicelli M, El HS, Brancati F, Dallapiccola B (2010) A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy. Clin Exp Rheumatol 28:153–157
Erken E, Köroğlu Ç, Yıldız F, Özer HTE, Gülek B, Tolun A (2015) A novel recessive 15-hydroxyprostaglandin dehydrogenase mutation in a family with primary hypertrophic osteoarthropathy. Mod Rheumatol 25:315–321
Sakai T, Hatano Y, Matsuda-Hirose H, Nishiyori R, Fujiwara S (2015) Atopic dermatitis-like dermatitis emerges unevenly on different sites in flaky tail mice. J Dermatol Sci 78:151–153
Wang L, Yu J, Li Y, Liu X, Zhang Z (2015) Genetic diagnosis for a Chinese Han family with primary hypertrophic osteoarthropathy. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 32:213–217
Diggle CP, Parry DA, Logan CV, Laissue P, Rivera C, Restrepo CM, Fonseca DJ, Morgan JE, Allanore Y, Fontenay M, Wipff J, Varret M, Gibault L, Dalantaeva N, Korbonits M, Zhou B, Yuan G, Harifi G, Cefle K, Palanduz S, Akoglu H, Zwijnenburg PJ, Lichtenbelt KD, Aubry-Rozier B, Superti-Furga A, Dallapiccola B, Accadia M, Brancati F, Sheridan EG, Taylor GR, Carr IM, Johnson CA, Markham AF, Bonthron DT (2012) Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis. Hum Mutat 33:1175–1181
Tüysüz B, Yılmaz S, Kasapçopur Ö, Erener-Ercan T, Ceyhun E, Bilguvar K, Günel M (2014) Primary hypertrophic osteoarthropathy caused by homozygous deletion in HPGD gene in a family: changing clinical and radiological findings with long-term follow-up. Rheumatol Int 11:1539–1544
Basit S, Malibari O, Al AM, Abdusamad F, Ismail FA (2014) A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families. Ann Saudi Med 34:390–395
Aoyama Y, Yamamoto T, Sakaguchi N, Ishige M, Tanaka T, Ichihara T, Ohara K, Kouzan H, Kinosada Y, Fukao T (2015) Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Int J Mol Med 35(6):1554–1560
Hoebeeck J, Speleman F, Vandesompele J (2007) Real-time quantitative PCR as an alternative to Southern blot or fluorescence in situ hybridization for detection of gene copy number changes. Methods Mol Biol 353:205–226
Wittenberg RH, Willburger RE, Kleemeyer KS, Peskar BA (1993) In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint diseases. Arthritis Rheum 36:1444–1450
Acknowledgments
The authors thank the patients for their involvement in this study. This study was funded in full by National Natural Science Foundation of China (Nos. 81471088, 81070687, and 81170805), National Science and Technology Pillar Program (2006BAI02B03), National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (Grant 2008ZX09312-016), Beijing Natural Science Foundation (No. 7121012), and National Key Program of Clinical Science (WBYZ2011-873).
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All authors state that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Ethics Committee of Peking Union Medical College Hospital, China) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
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Lu Yuan, Ling Chen, and Ruo-xi Liao have contributed equally to this work.
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Yuan, L., Chen, L., Liao, Rx. et al. A Common Mutation and a Novel Mutation in the HPGD Gene in Nine Patients with Primary Hypertrophic Osteoarthropathy. Calcif Tissue Int 97, 336–342 (2015). https://doi.org/10.1007/s00223-015-0024-3
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DOI: https://doi.org/10.1007/s00223-015-0024-3