| 词条 | Primary hypertrophic osteoathropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||
| 释义 |
| name = Pachydermoperiostosis | synonyms = | image = | caption = | pronounce = | field = | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }}Pachydermoperiostosis (PDP) or primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder that affects both bones and skin.[1] Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Golé syndrome.[2] It is mainly characterized by pachydermia (thickening of the skin), periostosis (excessive bone formation) and finger clubbing (swelling of tissue with loss of normal angle between nail and nail bed).[1][3] This disease affects relatively more men than women.[1][4] After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired.[1][5] Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.[5][6] In 1868, PDP was first described by Friedreich as ‘excessive growth of bone of the entire skeleton’. Touraine, Solente and Golé described PDP as the primary form of bone disease hypertrophic osteoarthropathy in 1935 and distinguished its three known forms.[1] SymptomsPDP has a number of visible symptoms. Most important clinical features are: pachydermia (thickening and wrinkling of the skin), furrowing of the face and scalp, periostosis (swelling of periarticular tissue and shaggy periosteal new bone formation of long bones) and digital clubbing (enlargement of fingertips).[1] Other features include excessive sweating, arthralgia and gastrointestinal abnormalities.[1] An overview of all symptoms is provided in table 2. Table 2. Overview of symptoms [1][5][16][7]
CauseAlthough the pathogenesis of PDP is still not fully understood, two theories have been suggested:
Role of PGE2Recently, it has been suggested that the locally acting mediator 2">prostaglandin E2 (PGE2) plays a role in the pathogenesis of PDP.[4][9] In PDP patients, high levels of PGE2 and decreased levels of PGE-M (the metabolite of PGE2) were observed. PGE2 can mimic the activity of osteoblasts and osteoclasts (respectively building and breaking down bone tissue). This is why acroosteolysis and periosteal bone formation can be explained by the action of PGE2.[10] Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.[10] Elevated levels of PGE2 in PDP patients are associated with mutations of HPGD gene. These patients showed typical PDP symptoms such as digital clubbing and periostosis.[9][10][11][12] The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase).[5][9] This enzyme catalyzes the first step in the degradation of PGE2 and related eicosanoids.[9][10] So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients.[9][10][12] Due to these mutations, the binding of the substrate PGE2 to HPGD is disrupted.[9] As a result of this, PGE2 cannot be transferred into PGE-M down and remain present at high concentrations. Role of other mediatorsApart from elevated PGE2 levels, studies in patients with hypertrophic osteoarthropathy also showed increased plasma levels of several other mediators, such as Von Willebrand factor and vascular endothelial growth factor (VEGF).[1][13][14][15] These substances could also have a role in PDP progression and proliferation.[1] In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet. Von Willebrand factor is a marker of platelet and endothelial activation.[14] This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP.[16] VEGF promotes angiogenesis (growth of new blood vessels) and differentiation of osteoblasts, which can explain the clubbing and excessive fibroblast formation in PDP patients.[16][17] Other mediators found in increased concentrations in PDP patients, include osteocalcin, endothelin-1, b-thromboglobulin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF).[1][13][18][19] It has not been described yet what role these mediators have in PDP. DiagnosisDiagnosis{{See also|List of radiographic findings associated with cutaneous conditions}}The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present.[1][20][21] New bone formation under the periosteum can be detected by radiographs of long bones.[21] In order diagnose PDP, often other diseases must be excluded. For example, to exclude secondary hypertrophic osteoarthropathy, any signs of cardiovascular, pulmonary, hepatic, intestinal and mediastinal diseases must be absent.[20] MRI and ultrasound also have characterictic findings.[22] Skin biopsy is another way to diagnose PDP. However, it is not a very specific method, because other diseases share the same skin alterations with PDP, such as myxedema and hypothyroidism. In order to exclude these other diseases, hormonal studies are done. For example, thyrotropin and growth hormone levels should be examined to exclude thyroid acropachy and acrome.[16] However, skin biopsy helps to diagnose PDP in patients without skin manifestations.When clubbing is observed, it is helpful to check whether acroosteolysis of distal phalanges of fingers is present. This is useful to diagnose PDP, because the combination of clubbing and acroosteolysis is only found in PDP and Cheney’s syndrome.[8] Biomarkers and mutation analysisSince elevated PGE2 levels are correlated with PDP, urinary PGE2 can be a useful biomarker for this disease.[9] Additionally, HPGD mutation analyses are relatively cheap and simple and may prove to be useful in early investigation in patients with unexplained clubbing or children presenting PDP-like features. Early positive results can prevent expensive and longtime tests at identifying the pathology.[9][23] For the follow-up of PDP disease activity, bone formation markers such as TAP, BAP, BGP, carbodyterminal propeptide of type I procallagen or NTX can play an important role. Other biomarkers that can be considered are IL-6 and receptor activator of NF-κB ligand (RANKL), which are associated with increased bone resorption in some patients. However, further investigation is needed to confirm this use of disease monitoring. Prostaglandin E2 may also be raised in patients with lung cancer and finger clubbing.[24] This may be related to raised levels of cyclooxygenase-2, an enzyme involved in the metabolism of prostaglandins.[25] A similar association has been noted in cystic fibrosis.[26] ClassificationPDP is one of the two types of hypertrophic osteoarthropathy. It represents approximately 5% of the total hypertrophic osteoarthropathy cases.[4] The other form is secondary hypertrophic osteoarthropathy (SHO). SHO usually has an underlying disease (e.g. cardiopulmonary diseases, malignancies or paraneoplastic syndrome). Unlike SHO, PDP does not have an underlying disease or malignancy.[1] PDP can be divided into three categories:
The cause of these differentiating pathologies is still unknown.[1][27] TreatmentThe effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports.[28] Although the HPGD enzyme is likely to be involved into the pathogenesis of PDP, no strategies against this mutation have been reported yet, since it is hard to tackle a defective enzyme. Gene therapy could be a solution for this, although this has not been reported yet in literature. Conventional PDP drug treatment to decrease inflammation and pain includes NSAIDs and corticosteroids.[4] Other drugs used by PDP patients target bone formation or skin manifestations.[4] Surgical care is used to improve cosmetic appearance.[6] Inflammation and pain drug treatmentNon-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most used in PDP treatment.[4] These drugs inhibit cyclo-oxygenase activity and thereby prostaglandin synthesis.[29] Since PGE2 is likely to be involved in periosteal bone formation and acroosteolysis, this is why these drugs can alleviate the polyarthritis associated with PDP.[4] In addition, NSAIDs and corticosteroids decrease formation of inflammatory mediators, reducing inflammation and pain.[29] In case of possible gastropathy, the COX-2 selective NSAID etorixocib is preferred.[4]Infliximab can reduce pain and arthritis in PDP. It is a monoclonal antibody that blocks the biological action of TNF-α (tumor necrosis factor-alpha). TNF-α is an inflammatory cytokine found in high levels in PDP and it is involved in the production of other inflammatory mediators which increase the expression of RANKL. RANKL is thought to increase bone resorption.[17]Bone formation and pain drug treatmentRheumatologic symptoms can be improved by treatment with bisphosphonates, such as pamidronate or risedronate. Bisphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.[4]In isolated cases, tamoxifen was effective in PDP treatment, especially for bone and joint pain. In PDP patients, high levels of nuclear receptors were found for steroids, which was the rationale to use tamoxifen, an estrogen receptor antagonist.[4][20] Tamoxifen and several of its metabolites competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases DNA synthesis. Cells are accumulated in G0 and G1 phases.[30] In vitro studies showed that tamoxifen acts as an estrogen agonist on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).[31] Skin manifestations drug treatmentRetinoids are used to improve skin manifestations.[4] Retinoids can act on retinoid nuclear receptors and thus regulate transcription.[32] For example, isotretinoin, the most effective drug to treat acne, improves cosmetic features by inducing apoptosis within human sebaceous glands.[33] As a result of this, the increase of connective tissue and hyperplasia of the sebaceous glands is inhibited.[33][34] Retinoids also decrease procollagen mRNA in fibroblasts, improving pachyderma.[8]Like retinoids, colchicines can also improve skin manifestations.[4] It is able to bind to the ends of microtubules to prevent its elongation. Because microtubules are involved in cell division, signal transduction and regulation of gene expression, colchicine can inhibit cell division and inflammatory processes (e.g. action of neutrophils and leukocytes).[35] It is suggested that colchicine inhibit chemotactic activity of leukocytes, which leads to reduction of pachydermia.[36] Use of botulinum toxin type A (BTX-A) improved leonine facies of patients. BTX-A inhibits release of acetylcholine acting at the neuromuscular junction. Furthermore, it blocks cholinergic transmission to the sweat glands and therefore inhibits sweat secretion. However, the exact mechanism for improving leonine faces is unknown and needs to be further investigated.[5] Surgical CareAside from drug treatments, there are many surgical methods to improve the facial appearance. One of them is facelift, technically known as facial rhytidectomy. This method is a type of cosmetic surgery procedure used to give a more youthful appearance. It involves the removal of excess facial skin and tightening of the skin on the face and neck.[6] A second option is plastic surgery.[6] This is also used for eye drooping.[4] PrognosisThe age of onset is often in puberty.[1][4] Of the described cases, as high as 80% of the affected individuals was suffering from the disease prior to the age of 18.[1] However, Latos-Bielenska et al. stated that this percentage should be lower, because also another form of osteoarthropathy – familial idiopathic osteoarthropathy (FIO) - was taken into account in this analysis.[21] PDP usually progresses for 5 to 20 years, until it becomes stable.[1] Life expectancy may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and leonine facies.[1][5] EpidemiologyPrevalencePDP is a rare genetic disease.[1] At least 204 cases of PDP have been reported.[1][27] The precise incidence and prevalence of PDP are still unknown.[1] A prevalence of 0.16% was suggested by Jajic et Jajic.[37] DistributionPDP occurs more frequently in men than in women (ratio around 7:1).[1][4] Moreover, men suffer from more severe symptoms (see table 1).[1] African American people are affected to a higher extent.[5] Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).[1]
HeredityIn 25-38% of the cases, patients have a familial history of PDP.[4] It is suggested that the incomplete form and complete form are inherited in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).[1] The autosomal dominant model of inheritance with penetrance and variable expression is confirmed in about half of the families, associated with the incomplete form.[1] Of several families, an autosomal recessive model of inheritance is known, associated with the complete form with much more severe symptoms involving joint, bone and skin features. While the male-female ratio in PDP is skewed, this cannot be fully explained by X-linked inheritance.[1] Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and solute carrier organic anion transporter family, member 2A1/prostaglandin transporter (SLCO2A1).[38][39][40] The underlying pathophysiology appears to be an abnormality of prostglandin E2 but the details have yet to be elucidated. Society6 patient organizations facilitate support for PDP patients. 4 of them are situated in Europe (Finland , France [https://web.archive.org/web/20110811230540/http://asso.orpha.net/FFP/], Greece and Poland ). The other two are located at Australia and Morocco [Association Marocaine des Génodermatoses]. References1. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 {{cite journal |vauthors=Castori M, etal |title=Pachydermoperiostosis: an update|journal=Clin. Genet. |volume=68 |pages=477–486 |year=2005 |doi=10.1111/j.1399-0004.2005.00533.x |pmid=16283874 |issue=6}} 2. ^{{cite journal |vauthors=Yazici Y, Schur PH, Romain PL |title= Malignancy and rheumatic disorders|journal= MA|year= 2011}} 3. ^{{cite journal |vauthors=Martínez-Ferrer A, etal |title= Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report.|journal= Rheumatol. Clin.|volume= 28|issue= 10|pages= 1229–1233|year=2009|doi=10.1007/s10067-009-1197-9|pmid= 19455364}} 4. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 {{cite journal |vauthors=Gómez Rodríguez N, Ibáñez Ruán J, González Pérez M |title= Primary hypertrophic osteoarthropathy (pachydermoperiostosis). 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Pediatr Radiol 46(5):727-730. doi: 10.1007/s00247-016-3544-8 23. ^{{cite journal |vauthors=Diggle CP, etal |title= Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. |journal= Rheumatol. |volume= 49 |issue= 6 |pages= 1056–1062|year= 2010 |doi=10.1093/rheumatology/keq048|pmid= 20299379 }} 24. ^{{cite journal | author = Kozak KR, Milne GL, Bentzen SM, Yock T | year = 2012 | title = Elevation of prostaglandin E2 in lung cancer patients with digital clubbing | url = | journal = J Thorac Oncol | volume = 7 | issue = 12| pages = 1877–1878 | doi=10.1097/jto.0b013e3181fc76a9| pmid = 22024643 | pmc = 3371124 }} 25. ^{{cite journal | author = Rotas I, Cito G, Letovanec I, Christodoulou M, Perentes JY | year = 2016 | title = Cyclooxygenase-2 expression in non-small Cell lung cancer correlates With hypertrophic osteoarthropathy | url = | journal = Ann Thorac Surg | volume = 101 | issue = 2| pages = e51–3 | doi = 10.1016/j.athoracsur.2015.09.023 | pmid = 26777972 }} 26. ^{{cite journal | author = Lemen RJ, Gates AJ, Mathé AA, Waring WW, Hyman AL, Kadowitz PD | year = 1978 | title = Relationships among digital clubbing, disease severity, and serum prostaglandins F2alpha and E concentrations in cystic fibrosis patients | url = | journal = Am Rev Respir Dis | volume = 17 | issue = 4| pages = 639–646 }} 27. ^1 2 3 4 5 6 {{cite journal |vauthors=Auger M, Stavrianeas N |title= Pachydermoperiostosis |journal= Orphanet Encyclopedia | year= 2004| url= http://www.orpha.net/data/patho/GB/uk-pachydermoperiostosis.pdf }} 28. ^{{cite journal |author= Jaejoon Lee|title= Arthroscopic Synovectomy in a Patient with Primary Hypertrophic Osteoarthropathy Korean Rheum Assoc. |journal= Korean Rheum Assoc |volume= 15 |issue= 3 |pages= 261–267 |year= 2008 |doi=10.4078/jkra.2008.15.3.261|display-authors=etal}} 29. ^1 {{cite book |vauthors=Rang HP, Dale MM, Ritter JM, Flower JM |title= Rang and Dale's Pharmacology |publisher= Elsevier|issue= 6th edition |pages=230–232, 363 |year= 2007 }} 30. ^{{cite journal |vauthors=Gold JM, etal |title= Improving tolerance of AIs: predicting risk and uncovering mechanisms musculoskeletal toxicity|journal= Oncology (Williston Park)|volume= 22 |issue= 12 |pages= 1416–1424|year= 2008}} 31. ^{{cite journal |author= Molad Y |title= Update on colchichine and its mechanism of action|journal= Current Rheumatology Reports|volume= 4 |issue= 3 |pages= 252–256 |year= 2002 |doi=10.1007/s11926-002-0073-2 |pmid=12010611}} 32. ^{{cite journal |vauthors=Nelson AM, etal |title= Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells|pmid=18317594|doi=10.1172/JCI33869|journal= J Clin Invest|volume= 118 |issue= 4 |pages= 1468–1478 |year= 2008 |pmc=2262030}} 33. ^1 {{cite journal |vauthors=Balmer JE, etal |title= Gene expression regulation by retinoic acid. |journal= J Lipid Res|volume= 43 |issue= 11 |pages= 1773–1780 |year= 2002 |doi=10.1194/jlr.r100015-jlr200}} 34. ^{{cite journal |vauthors=Park YK, etal |title= Pachydermoperiostosis: trial with isotretinoin. |journal= Yonsei Medical Journal |volume=29 |issue= 2 |pages= 204–207 |year= 1988 |doi=10.3349/ymj.1988.29.2.204|pmid= 3064439 }} 35. ^{{cite journal |author= Terkeltaub RA |title= Colchicine update. Seminars in arthritis and rheumatism. |volume= 38 |issue= 6 |pages= 411–419 |year= 2009 |doi=10.1016/j.semarthrit.2008.08.006 |pmid= 18973929 |journal=Seminars in Arthritis and Rheumatism}} 36. ^{{cite journal |author= Mattuci-Cerinic|title= Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis. |journal= Rheumatol Int. |volume= 8 |pages= 185–188 |year= 1998 |display-authors=etal}} 37. ^{{cite journal |vauthors=Jajic I, Jajic Z |title= Prevalence of primary hypertrophic osteoarthropathy in selected population. |journal= Clin Exp Rheumatol. |volume= 10 |issue= 7|page= 73|year= 1992}} 38. ^Khan AK, Muhammad N, Khan SA, Ullah W, Nasir A, Afzal S, Ramzan K, Basit S, Khan S (2017) A novel mutation in the HPGD gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family. Ann Hum Genet doi: 10.1111/ahg.12239 39. ^{{cite journal | vauthors = 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 | title = Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy | journal = American Journal of Human Genetics | volume = 90 | issue = 1 | pages = 125–32 | date = January 2012 | pmid = 22197487 | pmc = 3257902 | doi = 10.1016/j.ajhg.2011.11.019 }} 40. ^{{cite journal | author = Hou Y, Lin Y, Qi X, Yuan L, Liao R, Pang Q, Cui L, Jiang Y, Wang O, Li M, Dong J, Xia W | year = 2018 | title = Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study | url = | journal = Bone | volume = 106 | issue = | pages = 96–102 | doi = 10.1016/j.bone.2017.09.015 | pmid = 28963081 }} External links{{Medical resources| DiseasesDB = 29069 | ICD10 = {{ICD10|L|62|0|l|60}}, {{ICD10|M|89|4|m|86}} | ICD9 = {{ICD9|731.2}}, {{ICD9|757.39}} | ICDO = | OMIM = 167100 | OMIM_mult = {{OMIM2|259100}} | MedlinePlus = | eMedicineSubj = derm | eMedicineTopic = 815 | MeshID = D010004 }}{{Disorders of skin appendages}}{{Diseases of the musculoskeletal system and connective tissue}}{{Eicosanoid metabolism disorders}} 3 : Osteopathies|Genodermatoses|Eicosanoid metabolism disorders |
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