Pachydermoperiostosis: Difference between revisions
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'''Pachydermoperiostosis''' (PDP) or '''Primary hypertrophic osteoathropathy''' (PHO) is a rare [[genetics|genetic]] disorder that affects both bones and skin.<ref name="Castori">{{cite journal |author=Castori M ''et al.'' |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}}</ref> Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Gole syndrome.<ref name="Yazici">{{cite journal |author= Yazici Y, Schur PH, Romain PL |title= Malignancy and rheumatic disorders|journal= MA|year= 2011}}</ref> 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).<ref name="Castori"/><ref name=" Martínez-Ferrer">{{cite journal |author= Martínez-Ferrer A ''et al'' |title= Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report.|journal= Rheumatol. Clin.|volume= 28|pages= 1229–1233|year=2009}}</ref> |
'''Pachydermoperiostosis''' (PDP) or '''Primary hypertrophic osteoathropathy''' (PHO) is a rare [[genetics|genetic]] disorder that affects both bones and skin.<ref name="Castori">{{cite journal |author=Castori M ''et al.'' |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}}</ref> Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Gole syndrome.<ref name="Yazici">{{cite journal |author= Yazici Y, Schur PH, Romain PL |title= Malignancy and rheumatic disorders|journal= MA|year= 2011}}</ref> 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).<ref name="Castori"/><ref name=" Martínez-Ferrer">{{cite journal |author= Martínez-Ferrer A ''et al'' |title= Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report.|journal= Rheumatol. Clin.|volume= 28|pages= 1229–1233|year=2009|doi=10.1007/s10067-009-1197-9}}</ref> |
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This disease affects relatively more men than women.<ref name="Castori"/><ref name="Gomez">{{cite journal |author= Gómez Rodríguez N, Ibáñez Ruán J, González Pérez M.|title= Primary hypertrophic osteoarthropathy (pachydermoperiostosis). Report of 2 familial cases and literature review.|journal= Rheumatol Clin. |volume= 5|issue= 6|pages= 259–263|year= 2009}}</ref> After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired.<ref name="Castori"/><ref name="Ghosn">{{cite journal |author= Ghosn S ''et al.'' |title= Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.|journal= J Am. Acad. Dermatol.|volume= 63|pages= 1036–1041|year= 2010}}</ref> Currently, symptomatic treatments are [[NSAIDs]] and [[steroids]] or surgical procedures.<ref name="Ghosn"/><ref name="Leni">{{cite journal |author= Leni George ''et al.'' |title= Frontal rhytidectomy as surgical treatment for pachydermoperiostosis. |journal= J Dermatol Treat. |volume= 19 |issue= 1 |pages= 61–63 |year= 2008}}</ref> |
This disease affects relatively more men than women.<ref name="Castori"/><ref name="Gomez">{{cite journal |author= Gómez Rodríguez N, Ibáñez Ruán J, González Pérez M.|title= Primary hypertrophic osteoarthropathy (pachydermoperiostosis). Report of 2 familial cases and literature review.|journal= Rheumatol Clin. |volume= 5|issue= 6|pages= 259–263|year= 2009|doi=10.1016/s2173-5743(09)70134-0}}</ref> After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired.<ref name="Castori"/><ref name="Ghosn">{{cite journal |author= Ghosn S ''et al.'' |title= Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.|journal= J Am. Acad. Dermatol.|volume= 63|pages= 1036–1041|year= 2010|doi=10.1016/j.jaad.2009.08.067}}</ref> Currently, symptomatic treatments are [[NSAIDs]] and [[steroids]] or surgical procedures.<ref name="Ghosn"/><ref name="Leni">{{cite journal |author= Leni George ''et al.'' |title= Frontal rhytidectomy as surgical treatment for pachydermoperiostosis. |journal= J Dermatol Treat. |volume= 19 |issue= 1 |pages= 61–63 |year= 2008 |doi=10.1080/09546630701389955}}</ref> |
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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.<ref name="Castori"/> |
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.<ref name="Castori"/> |
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==Cause== |
==Cause== |
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Although the [[pathogenesis]] of PDP is still not fully understood, two theories have been suggested: |
Although the [[pathogenesis]] of PDP is still not fully understood, two theories have been suggested: |
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* The [[neurogenic]] theory proposes that stimulation of the [[vagus nerve]] leads to [[vasodilation]], increased [[blood flow]] and PDP.<ref name="Athappan">{{cite journal |author= Athappan G ''et al.'' |title= Touraine Solente Gole syndrome: the disease and associated tongue fissuring. |journal= Rheumatol Int. |volume= 29 |pages= 1091–1093 |year= 2009}}</ref> |
* The [[neurogenic]] theory proposes that stimulation of the [[vagus nerve]] leads to [[vasodilation]], increased [[blood flow]] and PDP.<ref name="Athappan">{{cite journal |author= Athappan G ''et al.'' |title= Touraine Solente Gole syndrome: the disease and associated tongue fissuring. |journal= Rheumatol Int. |volume= 29 |pages= 1091–1093 |year= 2009 |doi=10.1007/s00296-008-0798-y}}</ref> |
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* The [[humoral]] theory proposes that mediators such as [[growth factors]] or [[inflammatory mediators]] are increased, leading to [[fibroblast]] [[Cell growth|proliferation]] and PDP.<ref name="Castori"/><ref name="Athappan"/> This theory is explained in the next sections. |
* The [[humoral]] theory proposes that mediators such as [[growth factors]] or [[inflammatory mediators]] are increased, leading to [[fibroblast]] [[Cell growth|proliferation]] and PDP.<ref name="Castori"/><ref name="Athappan"/> This theory is explained in the next sections. |
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=== Role of PGE<sub>2</sub> === |
=== Role of PGE<sub>2</sub> === |
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Recently, it has been suggested that the locally acting mediator [[prostaglandin E<sub>2</sub>]] (PGE<sub>2</sub>) plays a role in the pathogenesis of PDP.<ref name="Gomez"/><ref name="Uppal">{{cite journal |author= Uppal S ''et al.'' |title= Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy |journal= NatGenet |volume= 40 |pages= 789–793|year= 2008}}</ref> In PDP patients, high levels of PGE<sub>2</sub> and decreased levels of PGE-M (the metabolite of PGE<sub>2</sub>) were observed.<ref name="Martínez-Ferrer"/> |
Recently, it has been suggested that the locally acting mediator [[prostaglandin E<sub>2</sub>]] (PGE<sub>2</sub>) plays a role in the pathogenesis of PDP.<ref name="Gomez"/><ref name="Uppal">{{cite journal |author= Uppal S ''et al.'' |title= Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy |journal= NatGenet |volume= 40 |pages= 789–793|year= 2008 |doi=10.1038/ng.153}}</ref> In PDP patients, high levels of PGE<sub>2</sub> and decreased levels of PGE-M (the metabolite of PGE<sub>2</sub>) were observed.<ref name="Martínez-Ferrer"/> |
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PGE<sub>2</sub> 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 PGE<sub>2</sub>.<ref name="Yuksel">{{cite journal |author= Yüksel-Konuk B ''et al.'' |title= Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy. |journal= Rheumatol Int. |volume= 30 |issue= 1 |pages= 39–43 |year= 2009}}</ref> Furthermore, PGE<sub>2</sub> has vasodilatory effects, which is consistent with prolonged local vasodilation in [[digital clubbing]].<ref name="Yuksel"/> |
PGE<sub>2</sub> 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 PGE<sub>2</sub>.<ref name="Yuksel">{{cite journal |author= Yüksel-Konuk B ''et al.'' |title= Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy. |journal= Rheumatol Int. |volume= 30 |issue= 1 |pages= 39–43 |year= 2009 |doi=10.1007/s00296-009-0895-6}}</ref> Furthermore, PGE<sub>2</sub> has vasodilatory effects, which is consistent with prolonged local vasodilation in [[digital clubbing]].<ref name="Yuksel"/> |
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Elevated levels of PGE<sub>2</sub> in PDP patients are associated with mutations of [[HPGD gene]]. These patients showed typical PDP symptoms such as digital clubbing and periostosis.<ref name="Uppal"/><ref name="Yuksel"/><ref name="Bergmann">{{cite journal |author= Bergmann C ''et al.'' |title= |
Elevated levels of PGE<sub>2</sub> in PDP patients are associated with mutations of [[HPGD gene]]. These patients showed typical PDP symptoms such as digital clubbing and periostosis.<ref name="Uppal"/><ref name="Yuksel"/><ref name="Bergmann">{{cite journal |author= Bergmann C ''et al.'' |title= |
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Apart from elevated PGE<sub>2</sub> 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).<ref name="Castori"/><ref name="Silveri">{{cite journal |author= Silver F ''et al.'' |title= Hypertrophic osteoarthropathy: endothelium and platelet function. |journal= Clin Rheumatol. |volume= 15 | pages= 435–439 |year= 1996}}</ref><ref name="Mattuci">{{cite journal |author= Mattuci-Cerinic ''et al.'' |title= Von Willebrand factor antigen in hypertrophic osteoarthropathy. |journal= J Rheumatol |volume= 19 |pages= 765–767 |year= 1992}}</ref><ref name="Silveria">{{cite journal |author= Silveria LH ''et al.'' |title= Vascular endothelial growth factor and hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol. |volume= 18 |pages= 57–62 |year=2000}}</ref> These substances could also have a role in PDP [[Cisternal progression|progression]] and proliferation.<ref name="Castori"/> In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet. |
Apart from elevated PGE<sub>2</sub> 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).<ref name="Castori"/><ref name="Silveri">{{cite journal |author= Silver F ''et al.'' |title= Hypertrophic osteoarthropathy: endothelium and platelet function. |journal= Clin Rheumatol. |volume= 15 | pages= 435–439 |year= 1996}}</ref><ref name="Mattuci">{{cite journal |author= Mattuci-Cerinic ''et al.'' |title= Von Willebrand factor antigen in hypertrophic osteoarthropathy. |journal= J Rheumatol |volume= 19 |pages= 765–767 |year= 1992}}</ref><ref name="Silveria">{{cite journal |author= Silveria LH ''et al.'' |title= Vascular endothelial growth factor and hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol. |volume= 18 |pages= 57–62 |year=2000}}</ref> These substances could also have a role in PDP [[Cisternal progression|progression]] and proliferation.<ref name="Castori"/> In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet. |
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Von Willebrand factor is a marker of [[platelet]] and [[endothelial]] activation.<ref name="Mattuci"/> This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP.<ref name="Jin">{{cite journal |author= Jin Hyun Kim ''et al.'' |title= A Case of Hypertrophic Osteoarthropathy Associated with Epithelioid Hemangioendothelioma. |journal= J Korean Med Sci.|volume= 19 |issue= 3 |pages= 484–486 |year= 2004}}</ref> VEGF promotes [[angiogenesis]] (growth of new [[blood vessels]]) and [[Cellular differentiation|differentiation]] of [[osteoblasts]], which can explain the clubbing and excessive [[fibroblast]] formation in PDP patients.<ref name="Jin"/><ref name="Vicente">{{cite journal |author= Vicente da Costa F ''et al.'' |title= Infliximab treatment in Pachydermoperiostosis. |journal= J Clin Rheumatol |volume= 16 |issue= 4 |pages= 183–184 |year= 2010}}</ref> |
Von Willebrand factor is a marker of [[platelet]] and [[endothelial]] activation.<ref name="Mattuci"/> This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP.<ref name="Jin">{{cite journal |author= Jin Hyun Kim ''et al.'' |title= A Case of Hypertrophic Osteoarthropathy Associated with Epithelioid Hemangioendothelioma. |journal= J Korean Med Sci.|volume= 19 |issue= 3 |pages= 484–486 |year= 2004 |doi=10.3346/jkms.2004.19.3.484}}</ref> VEGF promotes [[angiogenesis]] (growth of new [[blood vessels]]) and [[Cellular differentiation|differentiation]] of [[osteoblasts]], which can explain the clubbing and excessive [[fibroblast]] formation in PDP patients.<ref name="Jin"/><ref name="Vicente">{{cite journal |author= Vicente da Costa F ''et al.'' |title= Infliximab treatment in Pachydermoperiostosis. |journal= J Clin Rheumatol |volume= 16 |issue= 4 |pages= 183–184 |year= 2010}}</ref> |
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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).<ref name="Castori"/><ref name="Silveri"/><ref name="Fonseca">{{cite journal |author= Fonseca C ''et al.'' |title= Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol |volume= 10 |issue= 7 |page= 72 |year= 1992}}</ref><ref name="Bianchi">{{cite journal |author= Bianchi L ''et al.'' |title= Pachydermoperiostosis, study of epidermal growth factor and steroid receptors. |journal= Br J Dermatol. |volume= 133 |issue= 1 |pages=128–133 |year= 1995}}</ref> It has not been described yet what role these mediators have in PDP. |
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).<ref name="Castori"/><ref name="Silveri"/><ref name="Fonseca">{{cite journal |author= Fonseca C ''et al.'' |title= Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol |volume= 10 |issue= 7 |page= 72 |year= 1992}}</ref><ref name="Bianchi">{{cite journal |author= Bianchi L ''et al.'' |title= Pachydermoperiostosis, study of epidermal growth factor and steroid receptors. |journal= Br J Dermatol. |volume= 133 |issue= 1 |pages=128–133 |year= 1995}}</ref> It has not been described yet what role these mediators have in PDP. |
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PDP has a lot 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).<ref name="Castori"/> Other features include excessive sweating, [[arthralgia]] and [[gastrointestinal]] abnormalities.<ref name="Castori"/> An overview of all symptoms is provided in table 2. |
PDP has a lot 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).<ref name="Castori"/> Other features include excessive sweating, [[arthralgia]] and [[gastrointestinal]] abnormalities.<ref name="Castori"/> An overview of all symptoms is provided in table 2. |
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Table 2. Overview of symptoms <ref name="Castori"/><ref name="Ghosn"/><ref name="Auger"/><ref name="Rajul">{{cite journal |author= Rajul Rastogi ''et al.'' |title= Pachydermoperiostosis or primary hypertrophic osteoarthropathy: A rare clinicoradiologic case. |journal= Indian J Radiol Imaging |volume= 19 |issue= 2 |pages= 123–126 |year= 2009}}</ref> |
Table 2. Overview of symptoms <ref name="Castori"/><ref name="Ghosn"/><ref name="Auger"/><ref name="Rajul">{{cite journal |author= Rajul Rastogi ''et al.'' |title= Pachydermoperiostosis or primary hypertrophic osteoarthropathy: A rare clinicoradiologic case. |journal= Indian J Radiol Imaging |volume= 19 |issue= 2 |pages= 123–126 |year= 2009 |doi=10.4103/0971-3026.50829}}</ref> |
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=== Diagnosis === |
=== Diagnosis === |
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{{See also|List of radiographic findings associated with cutaneous conditions}} |
{{See also|List of radiographic findings associated with cutaneous conditions}} |
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The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present.<ref name="Castori"/><ref name="Okten">{{cite journal |author= Okten A ''et al.'' |title= Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia. |journal= Rheumatol Clin. |volume= 26 |pages= 8–11 |year= 2007}}</ref><ref name="Latos">{{cite journal |author= Latos-Bielensk A ''et al.'' |title= Pachydermoperiostosis–critical analysis with report of five unusual cases. |journal= Eur J Pediatr |volume= 166 |pages= 1237–1243|year= 2007}}</ref> New bone formation under the [[periosteum]] can be detected by [[radiographs]] of long bones.<ref name="Latos"/> 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.<ref name="Okten"/> |
The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present.<ref name="Castori"/><ref name="Okten">{{cite journal |author= Okten A ''et al.'' |title= Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia. |journal= Rheumatol Clin. |volume= 26 |pages= 8–11 |year= 2007 |doi=10.1007/s10067-005-1161-2}}</ref><ref name="Latos">{{cite journal |author= Latos-Bielensk A ''et al.'' |title= Pachydermoperiostosis–critical analysis with report of five unusual cases. |journal= Eur J Pediatr |volume= 166 |pages= 1237–1243|year= 2007 |doi=10.1007/s00431-006-0407-6}}</ref> New bone formation under the [[periosteum]] can be detected by [[radiographs]] of long bones.<ref name="Latos"/> 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.<ref name="Okten"/> |
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[[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]].<ref name="Martínez-Ferrer"/> 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.<ref name="Auger"/> However, skin biopsy helps to diagnose PDP in patients without skin manifestations.<ref name="Martínez-Ferrer"/> |
[[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]].<ref name="Martínez-Ferrer"/> 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.<ref name="Auger"/> However, skin biopsy helps to diagnose PDP in patients without skin manifestations.<ref name="Martínez-Ferrer"/> |
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=== Biomarkers and mutation analysis === |
=== Biomarkers and mutation analysis === |
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Since elevated PGE2 levels are correlated with PDP, [[urinary]] PGE2 can be a useful [[biomarker]] for this disease.<ref name="Uppal"/> 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]].<ref name="Uppal"/><ref name="Diggle">{{cite journal |author= Diggle CP ''et al.'' |title= Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. |journal= Rheumatol. |volume= 49 |pages= 1056–1062|year= 2010}}</ref> |
Since elevated PGE2 levels are correlated with PDP, [[urinary]] PGE2 can be a useful [[biomarker]] for this disease.<ref name="Uppal"/> 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]].<ref name="Uppal"/><ref name="Diggle">{{cite journal |author= Diggle CP ''et al.'' |title= Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. |journal= Rheumatol. |volume= 49 |pages= 1056–1062|year= 2010 |doi=10.1093/rheumatology/keq048}}</ref> |
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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.<ref name="Martínez-Ferrer"/> Other biomarkers that can be considered are [[Interleukin 6|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.<ref name="Martínez-Ferrer"/> |
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.<ref name="Martínez-Ferrer"/> Other biomarkers that can be considered are [[Interleukin 6|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.<ref name="Martínez-Ferrer"/> |
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== Treatment == |
== Treatment == |
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The effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports.<ref name="Jaejoon">{{cite journal |author= Jaejoon Lee ''et al.'' |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}}</ref> 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. |
The effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports.<ref name="Jaejoon">{{cite journal |author= Jaejoon Lee ''et al.'' |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}}</ref> 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. |
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Conventional PDP drug treatment to decrease [[inflammation]] and pain includes NSAIDs and corticosteroids.<ref name="Gomez"/> Other drugs used by PDP patients target bone formation or skin manifestations.<ref name="Gomez"/> Surgical care is used to improve cosmetic appearance.<ref name="Leni"/> |
Conventional PDP drug treatment to decrease [[inflammation]] and pain includes NSAIDs and corticosteroids.<ref name="Gomez"/> Other drugs used by PDP patients target bone formation or skin manifestations.<ref name="Gomez"/> Surgical care is used to improve cosmetic appearance.<ref name="Leni"/> |
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[[Rheumatologic]] symptoms can be improved by treatment with [[biphosphonates]], such as [[pamidronate]] or [[risedronate]]. Biphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.<ref name="Gomez"/> |
[[Rheumatologic]] symptoms can be improved by treatment with [[biphosphonates]], such as [[pamidronate]] or [[risedronate]]. Biphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.<ref name="Gomez"/> |
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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]].<ref name="Gomez"/><ref name="Okten"/> Tamoxifen and several of its [[metabolites]] competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases [[DNA replication|DNA synthesis]]. Cells are [[wikt:accumulation|accumulated]] in G<sub>0</sub> and G<sub>1</sub> phases.<ref name="Gold">{{cite journal |author= Gold JM ''et al.'' |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}}</ref> [[In vitro]] studies showed that tamoxifen acts as an estrogen [[agonist]] on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).<ref name="Molad">{{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}}</ref> |
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]].<ref name="Gomez"/><ref name="Okten"/> Tamoxifen and several of its [[metabolites]] competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases [[DNA replication|DNA synthesis]]. Cells are [[wikt:accumulation|accumulated]] in G<sub>0</sub> and G<sub>1</sub> phases.<ref name="Gold">{{cite journal |author= Gold JM ''et al.'' |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}}</ref> [[In vitro]] studies showed that tamoxifen acts as an estrogen [[agonist]] on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).<ref name="Molad">{{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}}</ref> |
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=== Skin manifestations drug treatment === |
=== Skin manifestations drug treatment === |
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[[Retinoids]] are used to improve skin manifestations.<ref name="Gomez"/> Retinoids can act on [[retinoid nuclear receptors]] and thus regulate [[Transcription (genetics)|transcription]].<ref name="Nelson">{{cite journal |author= Nelson AM ''et al.'' |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}}</ref> For example, [[isotretinoin]], the most effective drug to treat [[acne]], improves cosmetic features by inducing [[apoptosis]] within human [[sebaceous glands]].<ref name="Balmer">{{cite journal |author= Balmer JE ''et al.'' |title= Gene expression regulation by retinoic acid. |journal= J Lipid Res.|volume= 43 |pages= 1773–1780 |year= 2002 }}</ref> As a result of this, the increase of [[connective tissue]] and [[hyperplasia]] of the sebaceous glands is inhibited.<ref name="Balmer"/><ref name="Park">{{cite journal |author= Park YK ''et al.'' |title= Pachydermoperiostosis: trial with isotretinoin. |journal= Yonsei Medical Journal |volume=29 |issue= 2 |pages= 204–207 |year= 1988}}</ref> Retinoids also decrease [[procollagen]] [[mRNA]] in fibroblasts, improving pachyderma.<ref name="Athappan"/> |
[[Retinoids]] are used to improve skin manifestations.<ref name="Gomez"/> Retinoids can act on [[retinoid nuclear receptors]] and thus regulate [[Transcription (genetics)|transcription]].<ref name="Nelson">{{cite journal |author= Nelson AM ''et al.'' |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}}</ref> For example, [[isotretinoin]], the most effective drug to treat [[acne]], improves cosmetic features by inducing [[apoptosis]] within human [[sebaceous glands]].<ref name="Balmer">{{cite journal |author= Balmer JE ''et al.'' |title= Gene expression regulation by retinoic acid. |journal= J Lipid Res.|volume= 43 |pages= 1773–1780 |year= 2002 |doi=10.1194/jlr.r100015-jlr200}}</ref> As a result of this, the increase of [[connective tissue]] and [[hyperplasia]] of the sebaceous glands is inhibited.<ref name="Balmer"/><ref name="Park">{{cite journal |author= Park YK ''et al.'' |title= Pachydermoperiostosis: trial with isotretinoin. |journal= Yonsei Medical Journal |volume=29 |issue= 2 |pages= 204–207 |year= 1988}}</ref> Retinoids also decrease [[procollagen]] [[mRNA]] in fibroblasts, improving pachyderma.<ref name="Athappan"/> |
||
Like retinoids, [[colchicines]] can also improve skin manifestations.<ref name="Gomez"/> 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]]).<ref name="Terkeltaub">{{cite journal |author= Terkeltaub RA |title= Colchicine update. Seminars in arthritis and rheumatism. |volume= 38 |issue= 6 |pages= 411–419 |year= 2009 }}</ref> It is suggested that colchicine inhibit [[chemotactic]] activity of leukocytes, which leads to reduction of pachydermia.<ref name="Mattuci_2">{{cite journal |author= Mattuci-Cerinic ''et al.'' |title= Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis. |journal= Rheumatol Int. |volume= 8 |pages= 185–188 |year= 1998 }}</ref> |
Like retinoids, [[colchicines]] can also improve skin manifestations.<ref name="Gomez"/> 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]]).<ref name="Terkeltaub">{{cite journal |author= Terkeltaub RA |title= Colchicine update. Seminars in arthritis and rheumatism. |volume= 38 |issue= 6 |pages= 411–419 |year= 2009 }}</ref> It is suggested that colchicine inhibit [[chemotactic]] activity of leukocytes, which leads to reduction of pachydermia.<ref name="Mattuci_2">{{cite journal |author= Mattuci-Cerinic ''et al.'' |title= Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis. |journal= Rheumatol Int. |volume= 8 |pages= 185–188 |year= 1998 }}</ref> |
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Revision as of 11:47, 23 May 2014
| Pachydermoperiostosis | |
|---|---|
| Specialty | Rheumatology  |
Pachydermoperiostosis (PDP) or Primary hypertrophic osteoathropathy (PHO) is a rare genetic disorder that affects both bones and skin.[1] Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Gole 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]
Classification
PDP 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 complete form occurs in 40% of the cases and can involve all the symptoms but mainly pachydermia, periostosis and finger clubbing. This is also referred to as the full-blown phenotype.[1][7]
- The incomplete form occurs in 54% of the cases and is characterized by having mainly effect on the bones and thereby the skeletal changes. Its effect on the skin (causing for instance pachydermia) is very limited.[1][7]
- The fruste form occurs in only 6% of the cases and is the opposite of the incomplete form. Minor skeletal changes are found and mostly cutaneous symptoms are observed with limited periostosis.[1][7]
The cause of these differentiating pathologies is still unknown.[1][7]
Epidemiology
Prevalence
PDP is a rare genetic disease.[1] At least 204 cases of PDP have been reported.[1][7] The precise incidence and prevalence of PDP are still unknown.[1] A prevalence of 0.16% was suggested by Jajic et Jajic.[8]
Distribution
PDP 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]
| Form of PDP | Sex | |
|---|---|---|
| Men | Women | |
| Complete | 45% | 18% |
| Incomplete | 50% | 71% |
| Fruste | 5% | 12% |
Heredity
In 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]
Cause
Although the pathogenesis of PDP is still not fully understood, two theories have been suggested:
- The neurogenic theory proposes that stimulation of the vagus nerve leads to vasodilation, increased blood flow and PDP.[9]
- The humoral theory proposes that mediators such as growth factors or inflammatory mediators are increased, leading to fibroblast proliferation and PDP.[1][9] This theory is explained in the next sections.
Role of PGE2
Recently, it has been suggested that the locally acting mediator [[prostaglandin E2]] (PGE2) plays a role in the pathogenesis of PDP.[4][10] In PDP patients, high levels of PGE2 and decreased levels of PGE-M (the metabolite of PGE2) were observed.[3]
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.[11] Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.[11]
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.[10][11][12][13] The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase).[5][10] This enzyme catalyzes the first step in the degradation of PGE2 and related eicosanoids.[10][11] So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients.[10][11][13] Due to these mutations, the binding of the substrate PGE2 to HPGD is disrupted.[10] As a result of this, PGE2 cannot be transferred into PGE-M down and remain present at high concentrations.
Role of other mediators
Apart 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][14][15][16] 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.[15] This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP.[17] VEGF promotes angiogenesis (growth of new blood vessels) and differentiation of osteoblasts, which can explain the clubbing and excessive fibroblast formation in PDP patients.[17][18] 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][14][19][20] It has not been described yet what role these mediators have in PDP.
Symptoms
PDP has a lot 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][7][21]
| Skin features | Pachydermia |
|---|---|
| Coarse skin | |
| Oily skin | |
| Eczema | |
| Thick hand and foot skin | |
| Leonine facies | |
| Furrowing | |
| Cutis verticis gyrate | |
| Increased secretion of sebum | |
| Sebborheic hyperplasia | |
| Bone features | Periostosis |
| Acroosteolysis | |
| Mylefibrosis | |
| Thick toe and finger bones | |
| Widening of bone formation | |
| Clubbing | Digital clubbing |
| Sweating | Hyperhidrosis |
| Eye features | Drooping eyelids |
| Thick stratum corneum | |
| Joints | Arthralgia |
| Joint effusion | |
| Muscles | Muscle discomfort |
| Hair | Decreased facial and pubic hair |
| Vascular | Peripheral vascular stasis |
| Gastrointestinal involvement | Peptic ulcer |
| Chronic gastritis | |
| Chron’s disease |
Diagnosis
Diagnosis
The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present.[1][22][23] New bone formation under the periosteum can be detected by radiographs of long bones.[23] 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.[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.[3] 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.[7] However, skin biopsy helps to diagnose PDP in patients without skin manifestations.[3] 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.[9]
Biomarkers and mutation analysis
Since elevated PGE2 levels are correlated with PDP, urinary PGE2 can be a useful biomarker for this disease.[10] 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.[10][24]
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.[3] 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.[3]
Prognosis
The 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.[23]
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]
Treatment
The effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports.[25] 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 treatment
Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most used in PDP treatment.[4] These drugs inhibit cyclo-oxygenase activity and thereby prostaglandin synthesis.[26] 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.[26] 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.[18]
Bone formation and pain drug treatment
Rheumatologic symptoms can be improved by treatment with biphosphonates, such as pamidronate or risedronate. Biphosphonates 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][22] 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.[27] In vitro studies showed that tamoxifen acts as an estrogen agonist on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).[28]
Skin manifestations drug treatment
Retinoids are used to improve skin manifestations.[4] Retinoids can act on retinoid nuclear receptors and thus regulate transcription.[29] For example, isotretinoin, the most effective drug to treat acne, improves cosmetic features by inducing apoptosis within human sebaceous glands.[30] As a result of this, the increase of connective tissue and hyperplasia of the sebaceous glands is inhibited.[30][31] Retinoids also decrease procollagen mRNA in fibroblasts, improving pachyderma.[9]
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).[32] It is suggested that colchicine inhibit chemotactic activity of leukocytes, which leads to reduction of pachydermia.[33]
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 Care
Aside 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]
Patient Organisation
6 patient organizations facilitate support for PDP patients. 4 of them are situated in Europe (Finland [1], France [2], Greece [3] and Poland [4]). The other two are located at Australia [5] and Morocco [Association Marocaine des Génodermatoses].
References
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae Castori M; et al. (2005). "Pachydermoperiostosis: an update". Clin. Genet. 68: 477–486. doi:10.1111/j.1399-0004.2005.00533.x. PMID 16283874.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Yazici Y, Schur PH, Romain PL (2011). "Malignancy and rheumatic disorders". MA.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d e f Martínez-Ferrer A; et al. (2009). "Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report". Rheumatol. Clin. 28: 1229–1233. doi:10.1007/s10067-009-1197-9.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c d e f g h i j k l m n o p Gómez Rodríguez N, Ibáñez Ruán J, González Pérez M. (2009). "Primary hypertrophic osteoarthropathy (pachydermoperiostosis). Report of 2 familial cases and literature review". Rheumatol Clin. 5 (6): 259–263. doi:10.1016/s2173-5743(09)70134-0.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d e f g Ghosn S; et al. (2010). "Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.". J Am. Acad. Dermatol. 63: 1036–1041. doi:10.1016/j.jaad.2009.08.067.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c d Leni George; et al. (2008). "Frontal rhytidectomy as surgical treatment for pachydermoperiostosis". J Dermatol Treat. 19 (1): 61–63. doi:10.1080/09546630701389955.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c d e f g Auger M, Stavrianeas N. (2004). "Pachydermoperiostosis" (PDF). Orphanet Encyclopedia.
- ^ Jajic I, Jajic Z. (1992). "Prevalence of primary hypertrophic osteoarthropathy in selected population". Clin Exp Rheumatol. 10 (7): 73.
- ^ a b c d Athappan G; et al. (2009). "Touraine Solente Gole syndrome: the disease and associated tongue fissuring". Rheumatol Int. 29: 1091–1093. doi:10.1007/s00296-008-0798-y.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c d e f g h Uppal S; et al. (2008). "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy". NatGenet. 40: 789–793. doi:10.1038/ng.153.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c d e Yüksel-Konuk B; et al. (2009). "Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy". Rheumatol Int. 30 (1): 39–43. doi:10.1007/s00296-009-0895-6.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Bergmann C; et al. (2011). "Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD⁄HPGD loss-of-function mutations". Exp Dermatol.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Sinibaldi L; et al. (2010). "A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy". Clin Exp Rheumatol. 28 (2): 153–157.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Silver F; et al. (1996). "Hypertrophic osteoarthropathy: endothelium and platelet function". Clin Rheumatol. 15: 435–439.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Mattuci-Cerinic; et al. (1992). "Von Willebrand factor antigen in hypertrophic osteoarthropathy". J Rheumatol. 19: 765–767.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Silveria LH; et al. (2000). "Vascular endothelial growth factor and hypertrophic osteoarthropathy". Clin Exp Rheumatol. 18: 57–62.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Jin Hyun Kim; et al. (2004). "A Case of Hypertrophic Osteoarthropathy Associated with Epithelioid Hemangioendothelioma". J Korean Med Sci. 19 (3): 484–486. doi:10.3346/jkms.2004.19.3.484.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Vicente da Costa F; et al. (2010). "Infliximab treatment in Pachydermoperiostosis". J Clin Rheumatol. 16 (4): 183–184.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Fonseca C; et al. (1992). "Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy". Clin Exp Rheumatol. 10 (7): 72.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Bianchi L; et al. (1995). "Pachydermoperiostosis, study of epidermal growth factor and steroid receptors". Br J Dermatol. 133 (1): 128–133.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Rajul Rastogi; et al. (2009). "Pachydermoperiostosis or primary hypertrophic osteoarthropathy: A rare clinicoradiologic case". Indian J Radiol Imaging. 19 (2): 123–126. doi:10.4103/0971-3026.50829.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: unflagged free DOI (link) - ^ a b c Okten A; et al. (2007). "Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia". Rheumatol Clin. 26: 8–11. doi:10.1007/s10067-005-1161-2.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b c Latos-Bielensk A; et al. (2007). "Pachydermoperiostosis–critical analysis with report of five unusual cases". Eur J Pediatr. 166: 1237–1243. doi:10.1007/s00431-006-0407-6.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Diggle CP; et al. (2010). "Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy". Rheumatol. 49: 1056–1062. doi:10.1093/rheumatology/keq048.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Jaejoon Lee; et al. (2008). "Arthroscopic Synovectomy in a Patient with Primary Hypertrophic Osteoarthropathy Korean Rheum Assoc". Korean Rheum Assoc. 15 (3): 261–267. doi:10.4078/jkra.2008.15.3.261.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Rang HP, Dale MM, Ritter JM, Flower JM (2007). "Rang and Dale's Pharmacology". Elsevier (6th edition): 230–232, 363.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Gold JM; et al. (2008). "Improving tolerance of AIs: predicting risk and uncovering mechanisms musculoskeletal toxicity". Oncology (Williston Park). 22 (12): 1416–1424.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Molad Y (2002). "Update on colchichine and its mechanism of action". Current Rheumatology Reports. 4 (3): 252–256. doi:10.1007/s11926-002-0073-2.
- ^ Nelson AM; et al. (2008). "Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells". J Clin Invest. 118 (4): 1468–1478. doi:10.1172/JCI33869. PMC 2262030. PMID 18317594.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Balmer JE; et al. (2002). "Gene expression regulation by retinoic acid". J Lipid Res. 43: 1773–1780. doi:10.1194/jlr.r100015-jlr200.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: unflagged free DOI (link) - ^ Park YK; et al. (1988). "Pachydermoperiostosis: trial with isotretinoin". Yonsei Medical Journal. 29 (2): 204–207.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Terkeltaub RA (2009). "Colchicine update. Seminars in arthritis and rheumatism". 38 (6): 411–419.
{{cite journal}}: Cite journal requires|journal=(help) - ^ Mattuci-Cerinic; et al. (1998). "Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis". Rheumatol Int. 8: 185–188.
{{cite journal}}: Explicit use of et al. in:|author=(help)