View source for Medicine:Pachydermoperiostosis

{{short description|Rare genetic disorder that affects bones and skin}}
{{Infobox medical condition (new)
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| synonyms        =  '''Primary hypertrophic osteoarthropathy'''
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'''Pachydermoperiostosis''' ('''PDP''') is a rare [[Medicine:Genetic disorder|genetic disorder]] that affects both bones and [[Biology:Skin|skin]].<ref name="Castori">{{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|s2cid=21973812}}</ref> Other names are '''primary hypertrophic osteoarthropathy''' or '''Touraine-Solente-Golé syndrome'''.<ref name= "Yazici">{{cite journal |vauthors=Yazici Y, Schur PH, Romain PL |title= Malignancy and rheumatic disorders|journal= MA|year= 2011}}</ref> It is mainly characterized by [[Medicine:Pachyderma|pachyderma]] (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  |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|s2cid= 24964091}}</ref>

This disease affects more men than women.<ref name="Castori"/><ref name="Gomez">{{cite journal |vauthors=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  |vauthors=Ghosn S, etal |title= Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.|journal= J. Am. Acad. Dermatol.|volume= 63|issue= 6|pages= 1036–1041|year= 2010|doi=10.1016/j.jaad.2009.08.067|pmid= 20933299}}</ref> Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.<ref name="Ghosn"/><ref name= "Leni">{{cite journal |author= Leni George|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|pmid= 18273728 |s2cid= 27962868 |display-authors=0}}</ref>

In 1868, PDP was first described by Friedreich as 'excessive growth of bone of the entire [[Biology:Skeleton|skeleton]]'. Touraine, Solente and Golé described PDP as the primary form of bone disease [[Medicine:Hypertrophic osteoarthropathy|hypertrophic osteoarthropathy]] in 1935 and distinguished its three known forms.<ref name= "Castori"/>

==Symptoms==

PDP has a number of visible signs. 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, [[Medicine:Arthralgia|arthralgia]] and gastrointestinal abnormalities.<ref name="Castori"/> An overview of all symptoms is provided in table 2.

Table 2. Overview of signs <ref name="Castori"/><ref name="Ghosn"/><ref name="Auger"/><ref name="Rajul">{{cite journal |author= Rajul Rastogi|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|pmid= 19881067 |pmc= 2765176 |display-authors=0 |doi-access= free }}</ref>

{| class="wikitable"
|-
! 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
|-
|
| Keloid formation
|-
! 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
|-
|
| Crohn’s disease
|}

==Cause==
The locally acting mediator [[Chemistry:Prostaglandin E2|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  |vauthors=Uppal S, etal |title= Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy |journal= Nat. Genet. |volume= 40 |pages= 789–793|year= 2008 |doi=10.1038/ng.153 |pmid=18500342 |issue=6|s2cid= 23484059 }}</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"/>

PGE<sub>2</sub> can mimic the activity of osteoblasts and osteoclasts (respectively building and breaking down bone tissue). This is why [[Medicine:Acroosteolysis|acroosteolysis]] and periosteal bone formation can be explained by the action of PGE<sub>2</sub>.<ref name="Yuksel">{{cite journal  |vauthors=Yüksel-Konuk B, etal |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|pmid= 19306095 |s2cid= 34504809 }}</ref> Furthermore, PGE<sub>2</sub> has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.<ref name="Yuksel"/>

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  |vauthors=Bergmann C, etal |title=  Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD⁄HPGD loss-of-function mutations. |journal= Exp Dermatol |volume= 20 |issue= 6 |pages= 531–3 | year= 2011|title-link= palmoplantar hyperhidrosis |doi= 10.1111/j.1600-0625.2011.01248.x |pmid= 21426412 |s2cid= 37699664 |doi-access= free }}</ref><ref name="Sinibaldi">{{cite journal  |vauthors=Sinibaldi L, etal |title= A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol |volume= 28 |issue= 2 |pages= 153–157 |year= 2010 |pmid= 20406614 }}</ref> The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase).<ref name="Ghosn"/><ref name="Uppal"/> This [[Biology:Enzyme|enzyme]] catalyzes the first step in the degradation of PGE<sub>2</sub> and related eicosanoids.<ref name="Uppal"/><ref name="Yuksel"/> So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients.<ref name="Uppal"/><ref name="Yuksel"/><ref name="Sinibaldi"/> Due to these mutations, the binding of the [[Biology:Substrate (biochemistry)|substrate]] PGE<sub>2</sub> to HPGD is disrupted.<ref name="Uppal"/> As a result of this, PGE<sub>2</sub> cannot be transferred into PGE-M down and remain present at high concentrations.{{citation needed|date=October 2020}}

=== Role of other mediators ===

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 [[Biology:Von Willebrand factor|Von Willebrand factor]] and [[Biology:Vascular endothelial growth factor|vascular endothelial growth factor]] (VEGF).<ref name="Castori"/><ref name="Silveri">{{cite journal  |vauthors=Silver F, etal |title= Hypertrophic osteoarthropathy: endothelium and platelet function. |journal= Clin Rheumatol |volume= 15 |issue= 5 | pages= 435–439 |year= 1996 |doi=10.1007/bf02229639|pmid= 8894355 |s2cid= 11830195 }}</ref><ref name="Mattuci">{{cite journal |author= Mattuci-Cerinic|title= Von Willebrand factor antigen in hypertrophic osteoarthropathy. |journal= J Rheumatol |volume= 19 |pages= 765–767 |year= 1992|issue= 5 |pmid= 1613707 |display-authors=0}}</ref><ref name="Silveria">{{cite journal  |vauthors=Silveria LH, etal |title= Vascular endothelial growth factor and hypertrophic osteoarthropathy. |journal= Clin Exp Rheumatol. |volume= 18 |issue= 1 |pages= 57–62 |year=2000|pmid= 10728444 }}</ref> These substances could also have a role in PDP progression and proliferation.<ref name="Castori"/> In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet.{{citation needed|date=October 2020}}

Von Willebrand factor is a marker of [[Biology:Platelet|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|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|pmid= 15201523 |pmc= 2816858 |display-authors=0}}</ref> VEGF promotes [[Biology:Angiogenesis|angiogenesis]] (growth of new blood vessels) and [[Biology: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  |vauthors=Vicente da Costa F, etal |title= Infliximab treatment in Pachydermoperiostosis. |journal= J Clin Rheumatol |volume= 16 |issue= 4 |pages= 183–184 |year= 2010 |doi=10.1097/rhu.0b013e3181df91c6|pmid= 20414127 }}</ref>
Other mediators found in increased concentrations in PDP patients, include [[Biology:Osteocalcin|osteocalcin]], endothelin-1, b-thromboglobulin, [[Biology:Platelet-derived growth factor|platelet-derived growth factor]] (PDGF) and [[Biology:Epidermal growth factor|epidermal growth factor]] (EGF).<ref name="Castori"/><ref name="Silveri"/><ref name="Fonseca">{{cite journal  |vauthors=Fonseca C, etal |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  |vauthors=Bianchi L, etal |title= Pachydermoperiostosis, study of epidermal growth factor and steroid receptors.  |journal= Br J Dermatol |volume= 133 |issue= 1 |pages=128–133 |year= 1995 |doi=10.1111/j.1365-2133.1995.tb08638.x|pmid= 7756124 |s2cid= 23015271 }}</ref> It has not been described yet what role these mediators have in PDP.

==Genetics==

Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD)  (HPGD) in [[Biology:Chromosome 4|chromosome 4]] (4q34.1) and solute carrier organic anion transporter family member 2A1 ([[Biology:SLCO2A1|SLCO2A1]]) in [[Biology:Chromosome 3|chromosome 3]] (3q22.1-q22.2).<ref name=Torgutalp2019>Torgutalp M, Durmaz CD, Karabulut HG, Seifert W, Horn D, Akkaya Z, Turgay M (2019) Primary hypertrophic osteoarthropathy mimicking juvenile idiopathic arthritis: A novel SLCO2A1 mutation and imaging findings. Cytogenet Genome Res</ref> This syndrome occurs if both copies of either gene are mutated (autosomal recessive inheritance){{citation needed|date=October 2020}}

==Diagnosis==

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  |vauthors=Okten A, etal |title= Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia. |journal= Rheumatol Clin. |volume= 26 |issue= 1 |pages= 8–11 |year= 2007 |doi=10.1007/s10067-005-1161-2|pmid= 16738844 |s2cid= 6656163 }}</ref><ref name="Latos">{{cite journal  |vauthors= Latos-Bielensk A, etal |title= Pachydermoperiostosis–critical analysis with report of five unusual cases. |journal= Eur J Pediatr |volume= 166 |issue= 12 |pages= 1237–1243|year= 2007 |doi=10.1007/s00431-006-0407-6|pmid= 17285282 |s2cid= 24196660 }}</ref> New bone formation under the [[Biology:Periosteum|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"/> MRI and ultrasound also have characterictic findings.<ref name= Adams2017>{{cite journal| vauthors= Adams B, Amin T, Leone V, Wood M, Kraft JK | year= 2017| title= Primary hypertrophic osteoarthropathy: ultrasound and MRI findings| journal= Pediatr Radiol| volume= 46 |number= 5| pages= 727–730| doi= 10.1007/s00247-016-3544-8| pmid= 26939972| s2cid= 44002008}}</ref>

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 [[Medicine:Hypothyroidism|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 acromegaly.<ref name="Auger"/> However, skin biopsy helps to diagnose PDP in patients without skin manifestations.<ref name= "Martínez-Ferrer"/>

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.<ref name="Athappan">{{cite journal  |vauthors= Athappan G, etal |title= Touraine Solente Gole syndrome: the disease and associated tongue fissuring. |journal= Rheumatol Int. |volume= 29 |issue= 9 |pages= 1091–1093 |year= 2009 |doi=10.1007/s00296-008-0798-y|pmid= 19050893 |s2cid= 5673717 }}</ref>

=== Biomarkers and mutation analysis ===

Since elevated PGE<sub>2</sub> levels are correlated with PDP, urinary PGE<sub>2</sub> can be a useful [[Biology:Biomarker|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 [[Biology:Pathology|pathology]].<ref name="Uppal"/><ref name= "Diggle">{{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 |doi-access= free }}</ref>

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 IL-6 and receptor activator of NF-κB ligand (RANKL), which are associated with increased [[Medicine:Bone resorption|bone resorption]] in some patients. However, further investigation is needed to confirm this use of disease monitoring.<ref name="Martínez-Ferrer"/>

PGE<sub>2</sub> may also be raised in patients with lung cancer and finger clubbing.<ref name= Kozak2012>{{cite journal |vauthors=Kozak KR, Milne GL, Bentzen SM, Yock T | year = 2012 | title = Elevation of prostaglandin E2 in lung cancer patients with digital clubbing | journal = J Thorac Oncol | volume = 7 | issue = 12| pages = 1877–1878 | doi=10.1097/jto.0b013e3181fc76a9| pmid = 22024643 | pmc = 3371124 }}</ref> This may be related to raised levels of [[Biology:Cyclooxygenase|cyclooxygenase]]-2, an enzyme involved in the metabolism of prostaglandins.<ref name= Rotas2016>{{cite journal |vauthors=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 | journal = Ann Thorac Surg | volume = 101 | issue = 2| pages = e51–3 | doi = 10.1016/j.athoracsur.2015.09.023 | pmid = 26777972 | doi-access = free }}</ref> A similar association has been noted in [[Medicine:Cystic fibrosis|cystic fibrosis]].<ref name= Lemen1978>{{cite journal |vauthors=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 | journal = Am Rev Respir Dis | volume = 17 | issue = 4| pages = 639–646 }}</ref>

===Classification===

PDP is one of the two types of [[Medicine:Hypertrophic osteoarthropathy|hypertrophic osteoarthropathy]]. It represents approximately 5% of the total hypertrophic osteoarthropathy cases.<ref name="Gomez" /> The other form is secondary hypertrophic osteoarthropathy (SHO). SHO usually has an underlying disease (such as cardiopulmonary diseases, malignancies or paraneoplastic syndrome). Unlike SHO, PDP does not have an underlying disease or malignancy.<ref name="Castori" />

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 [[Biology:Phenotype|phenotype]].<ref name="Castori" /><ref name= "Auger">{{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 }}</ref>
* 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.<ref name="Castori" /><ref name="Auger" />
* 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.<ref name="Castori" /><ref name="Auger" />

The cause of these differentiating pathologies is still unknown.<ref name="Castori" /><ref name= "Auger" />

== Treatment ==

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|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=0|doi-access= free }}</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. [[Biology:Gene therapy|Gene therapy]] could be a solution for this, although this has not been reported yet in literature.{{citation needed|date=October 2020}}

Conventional PDP drug treatment to decrease [[Medicine:Inflammation|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"/>

=== Inflammation and pain drug treatment ===

Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most used in PDP treatment.<ref name="Gomez"/> These drugs inhibit cyclo-oxygenase activity and thereby prostaglandin [[Biology:Biosynthesis|synthesis]].<ref name="Rang">{{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 }}</ref> Since PGE<sub>2</sub> is likely to be involved in periosteal bone formation and acroosteolysis, this is why these drugs can alleviate the [[Medicine:Polyarthritis|polyarthritis]] associated with PDP.<ref name="Gomez"/> In addition, NSAIDs and corticosteroids decrease formation of inflammatory mediators, reducing inflammation and pain.<ref name="Rang"/> In case of possible gastropathy, the COX-2 selective NSAID etorixocib is preferred.<ref name="Gomez"/>

[[Chemistry:Infliximab|Infliximab]] can reduce pain and [[Medicine:Arthritis|arthritis]] in PDP. It is a [[Biology:Monoclonal antibody|monoclonal antibody]] that blocks the biological action of TNF-α (tumor necrosis factor-alpha). TNF-α is an inflammatory [[Biology:Cytokine|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.<ref name="Vicente"/>

=== Bone formation and pain drug treatment ===

Rheumatologic symptoms can be improved by treatment with [[Chemistry:Bisphosphonate|bisphosphonate]]s, such as pamidronate or risedronate. Bisphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.<ref name="Gomez"/>

In isolated cases, [[Chemistry:Tamoxifen|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 [[Biology:Estrogen receptor|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 [[Biology:DNA replication|DNA synthesis]]. Cells are accumulated in G<sub>0</sub> and G<sub>1</sub> phases.<ref name="Gold">{{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|pmid= 19322949}}</ref> [[In vitro]] studies showed that tamoxifen acts as an estrogen [[Biology:Agonist|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 |pmid=12010611|s2cid= 4507579}}</ref>

=== Skin manifestations drug treatment ===

Retinoids are used to improve skin manifestations.<ref name="Gomez"/> Retinoids can act on retinoid nuclear receptors and thus regulate transcription.<ref name="Nelson">{{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}}</ref> For example, [[Chemistry:Isotretinoin|isotretinoin]], the most effective drug to treat [[Engineering:Acne|acne]], improves cosmetic features by inducing [[Biology:Apoptosis|apoptosis]] within human sebaceous glands.<ref name="Balmer">{{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|pmid= 12401878 |s2cid= 22957863 |url= http://www.jlr.org/content/43/11/1773.full.pdf |doi-access= free }}</ref> As a result of this, the increase of connective tissue and [[Medicine:Hyperplasia|hyperplasia]] of the sebaceous glands is inhibited.<ref name="Balmer"/><ref name="Park">{{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 |doi-access= free }}</ref> Retinoids also decrease [[Biology:Procollagen|procollagen]] [[Biology:MRNA|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 [[Biology:Cell division|cell division]], [[Biology:Signal transduction|signal transduction]] and [[Finance:Regulation|regulation]] of [[Biology:Gene expression|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 |doi=10.1016/j.semarthrit.2008.08.006 |pmid= 18973929 |journal=Seminars in Arthritis and Rheumatism}}</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|title= Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis. |journal= Rheumatol Int. |volume= 8 |issue= 4 |pages= 185–188 |year= 1998 |display-authors=0|doi= 10.1007/BF00270458 |pmid= 3187331 |s2cid= 1399956 }}</ref>

Use of botulinum toxin type A (BTX-A) improved leonine facies of patients. BTX-A inhibits release of [[Chemistry:Acetylcholine|acetylcholine]] acting at the neuromuscular junction. Furthermore, it blocks [[Biology:Cholinergic|cholinergic]] transmission to the sweat glands and therefore inhibits sweat [[Biology:Secretion|secretion]]. However, the exact mechanism for improving leonine faces is unknown and needs to be further investigated.<ref name="Ghosn"/>

=== 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 [[Medicine:Rhytidectomy|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.<ref name="Leni"/> A second option is plastic surgery.<ref name="Leni"/> This is also used for eye drooping.<ref name="Gomez"/>

== Prognosis ==

The age of onset is often in puberty.<ref name="Castori"/><ref name="Gomez"/> Of the described cases, as high as 80% of the affected individuals was suffering from the disease prior to the age of 18.<ref name="Castori"/> 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.<ref name="Latos"/>

PDP usually progresses for 5 to 20 years, until it becomes stable.<ref name="Castori"/> [[Biology:Life expectancy|Life expectancy]] may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and leonine facies.<ref name="Castori"/><ref name="Ghosn"/>

==Epidemiology==

===Prevalence===
PDP is a rare genetic disease.<ref name="Castori"/> At least 204 cases of PDP have been reported.<ref name="Castori"/><ref name="Auger"/> The precise incidence and [[Prevalence|prevalence]] of PDP are still unknown.<ref name="Castori"/> A prevalence of 0.16% was suggested by Jajic et Jajic.<ref name="Jajic">{{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}}</ref>

===Distribution===

PDP occurs more frequently in men than in women (ratio around 7:1).<ref name="Castori"/><ref name="Gomez"/> Moreover, men suffer from more severe symptoms (see table 1).<ref name="Castori"/> African American people are affected to a higher extent.<ref name="Ghosn"/>

Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).<ref name="Castori"/>
{| class="wikitable"
|-
! 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.<ref name="Gomez"/> It is suggested that the incomplete form and complete form are [[Biology:Heredity|inherited]] in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).<ref name="Castori"/>

The autosomal dominant model of inheritance with [[Biology:Penetrance|penetrance]] and variable [[Biology:Gene expression|expression]] is confirmed in about half of the families, associated with the incomplete form.<ref name="Castori"/> Of several families, an autosomal recessive model of inheritance is known, associated with the complete form with much more severe symptoms involving [[Biology:Joint|joint]], [[Biology:Bone|bone]] and [[Biology:Skin|skin]] features. Male-female ratio in PDP is skewed towards males.<ref name="Castori"/>

Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and solute carrier organic anion transporter family, member 2A1/prostaglandin transporter ([[Biology:SLCO2A1|SLCO2A1]]).<ref name=Khan2017>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</ref><ref name="pmid22197487">{{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 }}</ref><ref name=Hou2018>{{cite journal |vauthors=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 | journal = Bone | volume = 106 | pages = 96–102 | doi = 10.1016/j.bone.2017.09.015 | pmid = 28963081 }}</ref> The underlying pathophysiology appears to be an abnormality of prostglandin E2 but the details have yet to be elucidated.

== Society ==

6 patient organizations facilitate support for PDP patients. 4 of them are situated in Europe (Finland,<ref>{{cite web |url=http://www.iholiitto.fi/ |title=Home |website=iholiitto.fi}}</ref> France,<ref>{{cite web |url=http://asso.orpha.net/FFP/ |title=Accueil |website=asso.orpha.net |access-date=12 January 2022 |archive-url=https://web.archive.org/web/20110811230540/http://asso.orpha.net/FFP/ |archive-date=11 August 2011 |url-status=dead}}</ref> Greece,<ref>{{cite web |url=http://www.tomellon.com.gr/ |title = Το Μέλλον {{!}}}}</ref> and Poland).<ref>{{cite web |url=http://www.gen.org.pl/ |url-status=dead |archive-url=https://web.archive.org/web/20031021045555/http://www.gen.org.pl/ |archive-date=2003-10-21 |title=Wortal Stowarzyszenia na Rzecz Dzieci z Zaburzeniami Genetycznymi GEN}}</ref> The other two are located in Australia<ref>{{cite web |url=http://www.agsa-geneticsupport.org.au/ |title = Genetic Support – Genetic Resources}}</ref> and Morocco (the Association Marocaine des Génodermatoses).

==References==
{{Reflist}}

== 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       = {{OMIM|259100||none}}
|  MedlinePlus     = 
|  eMedicineSubj   = derm 
|  eMedicineTopic  = 815 
|  MeshID          = D010004
}}
{{Diseases of the musculoskeletal system and connective tissue}}

[[Category:Osteopathies]]
[[Category:Genodermatoses]]

{{Sourceattribution|Pachydermoperiostosis}}