Pachydermoperiostosis
Encyclopedia
Pachydermoperiostosis or Primary hypertrophic osteoathropathy (PHO) is a rare genetic
disorder that affects both bones and skin. Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Gole syndrome. 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).
This disease affects relatively more men than women. After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired. Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.
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.
). Unlike SHO, PDP does not have an underlying disease or malignancy.
PDP can be divided into three categories:
The cause of these differentiating pathologies is still unknown.
of PDP are still unknown. A prevalence of 0.16% was suggested by Jajic et Jajic.
Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).
in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).
The autosomal dominant model of inheritance with penetrance
and variable expression
is confirmed in about half of the families, associated with the incomplete form. 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.
of PDP is still not fully understood, two theories have been suggested:
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. Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.
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. The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase). This enzyme
catalyzes the first step in the degradation of PGE2 and related eicosanoids. So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients. Due to these mutations, the binding of the substrate
PGE2 to HPGD is disrupted. As a result of this, PGE2 cannot be transferred into PGE-M down and remain present at high concentrations.
and vascular endothelial growth factor
(VEGF). These substances could also have a role in PDP progression and proliferation. 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. This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP. VEGF promotes angiogenesis
(growth of new blood vessels) and differentiation
of osteoblasts, which can explain the clubbing and excessive fibroblast
formation in PDP patients.
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). It has not been described yet what role these mediators have in PDP.
and gastrointestinal abnormalities. An overview of all symptoms is provided in table 2.
Table 2. Overview of symptoms
can be detected by radiographs of long bones. 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.
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. 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.
.
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.
PDP usually progresses for 5 to 20 years, until it becomes stable. Life expectancy
may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and leonine facies
.
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. Other drugs used by PDP patients target bone formation or skin manifestations. Surgical care is used to improve cosmetic appearance.
. 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. In addition, NSAIDs and corticosteroids decrease formation of inflammatory mediators, reducing inflammation and pain. In case of possible gastropathy, the COX-2 selective NSAID etorixocib is preferred.
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.
. Biphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.
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
. 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. In vitro
studies showed that tamoxifen acts as an estrogen agonist
on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).
. For example, isotretinoin
, the most effective drug to treat acne
, improves cosmetic features by inducing apoptosis
within human sebaceous glands. As a result of this, the increase of connective tissue
and hyperplasia
of the sebaceous glands is inhibited. Retinoids also decrease procollagen mRNA in fibroblasts, improving pachyderma.
Like retinoids, colchicines can also improve skin manifestations. 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). It is suggested that colchicine inhibit chemotactic activity of leukocytes, which leads to reduction of pachydermia.
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.
. 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. A second option is plastic surgery. This is also used for eye drooping.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
disorder that affects both bones and skin. Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Gole syndrome. 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).
This disease affects relatively more men than women. After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired. Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.
In 1868, PDP was first described by Friedreich as ‘excessive growth of bone of the entire skeleton
Skeleton
The skeleton is the body part that forms the supporting structure of an organism. There are two different skeletal types: the exoskeleton, which is the stable outer shell of an organism, and the endoskeleton, which forms the support structure inside the body.In a figurative sense, skeleton can...
’. Touraine, Solente and Golé described PDP as the primary form of bone disease hypertrophic osteoarthropathy in 1935 and distinguished its three known forms.
Classification
PDP is one of the two types of hypertrophic osteoarthropathy. It represents approximately 5% of the total hypertrophic osteoarthropathy cases. The other form is secondary hypertrophic osteoarthropathy (SHO). SHO usually has an underlying disease (e.g. cardiopulmonary diseases, malignancies or paraneoplastic syndromeParaneoplastic syndrome
A paraneoplastic syndrome is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors excreted by tumor cells or by an immune response against the tumor...
). Unlike SHO, PDP does not have an underlying disease or malignancy.
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 phenotypePhenotypeA phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. - 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.
- 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.
The cause of these differentiating pathologies is still unknown.
Prevalence
PDP is a rare genetic disease. At least 204 cases of PDP have been reported. The precise incidence and prevalencePrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of PDP are still unknown. A prevalence of 0.16% was suggested by Jajic et Jajic.
Distribution
PDP occurs more frequently in men than in women (ratio around 7:1). Moreover, men suffer from more severe symptoms (see table 1). African American people are affected to a higher extent.Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).
| 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. It is suggested that the incomplete form and complete form are inheritedHeredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).
The autosomal dominant model of inheritance with penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
and variable expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is confirmed in about half of the families, associated with the incomplete form. Of several families, an autosomal recessive model of inheritance is known, associated with the complete form with much more severe symptoms involving joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
, bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
and skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
features. While the male-female ratio in PDP is skewed, this cannot be fully explained by X-linked inheritance.
Cause
Although the pathogenesisPathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of PDP is still not fully understood, two theories have been suggested:
- The neurogenic theory proposes that stimulation of the vagus nerveVagus nerveThe vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
leads to vasodilationVasodilationVasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, increased blood flowBlood flowBlood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
and PDP. - The humoral theory proposes that mediators such as growth factors or inflammatory mediators are increased, leading to fibroblastFibroblastA fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
proliferationCell growthThe term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
and PDP. 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. 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
Acroosteolysis
Acroosteolysis is a cutaneous condition characterized by destructive changes in the distal phalangeal bone, and may be associated with minimal skin changes or with ischemic skin lesions that may result in digital necrosis....
and periosteal bone formation can be explained by the action of PGE2. Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.
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. The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase). This enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
catalyzes the first step in the degradation of PGE2 and related eicosanoids. So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients. Due to these mutations, the binding of the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
PGE2 to HPGD is disrupted. 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 factorVon Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
and vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF). These substances could also have a role in PDP progression and proliferation. In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet.
Von Willebrand factor is a marker of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
and endothelial activation. This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP. VEGF promotes angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
(growth of new blood vessels) and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
of osteoblasts, which can explain the clubbing and excessive fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
formation in PDP patients.
Other mediators found in increased concentrations in PDP patients, include osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...
, endothelin-1, b-thromboglobulin, platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF) and epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
(EGF). 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). Other features include excessive sweating, arthralgiaArthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
and gastrointestinal abnormalities. An overview of all symptoms is provided in table 2.
Table 2. Overview of symptoms
| 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 | Muslce discomfort |
| Hair | Decreased facial and pubic hair |
| Vascular | Peripheral vascular stasis |
| Gastrointestinal involvement | Peptic ulcer |
| Chronic gastritis | |
| Chron’s disease |
Diagnosis
The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present. New bone formation under the periosteumPeriosteum
Periosteum is a membrane that lines the outer surface of all bones, except at the joints of long bones. Endosteum lines the inner surface of all bones....
can be detected by radiographs of long bones. 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.
Skin biopsy
Skin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed and sent to the pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. It is commonly performed by dermatologists. Skin...
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
Myxedema
Myxedema describes a specific form of cutaneous and dermal edema secondary to increased deposition of connective tissue components in subcutaneous tissue as seen in various forms of hypothyroidism and Graves' disease. It is more common in women than in men...
and hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
. 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. 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
Distal phalanges
The distal or terminal phalanges are the terminal limb bones located at the tip of the digits...
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.
Biomarkers and mutation analysis
Since elevated PGE2 levels are correlated with PDP, urinary PGE2 can be a useful biomarker for this disease. 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 pathologyPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
.
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
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
and receptor activator of NF-κB ligand (RANKL), which are associated with increased bone resorption
Bone resorption
Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood....
in some patients. However, further investigation is needed to confirm this use of disease monitoring.
Prognosis
The age of onset is often in puberty. Of the described cases, as high as 80% of the affected individuals was suffering from the disease prior to the age of 18. 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.PDP usually progresses for 5 to 20 years, until it becomes stable. Life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and leonine facies
Leonine facies
Leonine facies: a face that resembles that of a lion. It is seen in multiple conditions and has been classically described for Lepromatous leprosy as well as Paget's disease of bone...
.
Treatment
The effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports. 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 therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
could be a solution for this, although this has not been reported yet in literature.
Conventional PDP drug treatment to decrease inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and pain includes NSAIDs and corticosteroids. Other drugs used by PDP patients target bone formation or skin manifestations. Surgical care is used to improve cosmetic appearance.
Inflammation and pain drug treatment
Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most used in PDP treatment. These drugs inhibit cyclo-oxygenase activity and thereby prostaglandin synthesisBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
. Since PGE2 is likely to be involved in periosteal bone formation and acroosteolysis, this is why these drugs can alleviate the polyarthritis
Polyarthritis
Polyarthritis is any type of arthritis which involves 5 or more joints simultaneously. It is usually associated with autoimmune conditions.Polyarthritis may be experienced at any age and is not gender specific.-Causes:...
associated with PDP. In addition, NSAIDs and corticosteroids decrease formation of inflammatory mediators, reducing inflammation and pain. In case of possible gastropathy, the COX-2 selective NSAID etorixocib is preferred.
Infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
can reduce pain and arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
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
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
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.
Bone formation and pain drug treatment
Rheumatologic symptoms can be improved by treatment with biphosphonates, such as pamidronate or risedronateRisedronate
Risedronic acid or risedronate sodium is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Warner Chilcott, Sanofi-Aventis, and in Japan by Takeda under the trade names Actonel, Atelvia, and Benet...
. Biphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.
In isolated cases, tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
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
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
. Tamoxifen and several of its metabolites competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases DNA synthesis
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
. Cells are accumulated in G0 and G1 phases. In vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
studies showed that tamoxifen acts as an estrogen agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).
Skin manifestations drug treatment
Retinoids are used to improve skin manifestations. Retinoids can act on retinoid nuclear receptors and thus regulate transcriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. For example, isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
, the most effective drug to treat acne
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
, improves cosmetic features by inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
within human sebaceous glands. As a result of this, the increase of connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
and hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
of the sebaceous glands is inhibited. Retinoids also decrease procollagen mRNA in fibroblasts, improving pachyderma.
Like retinoids, colchicines can also improve skin manifestations. It is able to bind to the ends of microtubules to prevent its elongation. Because microtubules are involved in cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
and regulation
Regulation
Regulation is administrative legislation that constitutes or constrains rights and allocates responsibilities. It can be distinguished from primary legislation on the one hand and judge-made law on the other...
of gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, colchicine can inhibit cell division and inflammatory processes (e.g. action of neutrophils and leukocytes). It is suggested that colchicine inhibit chemotactic activity of leukocytes, which leads to reduction of pachydermia.
Use of botulinum toxin type A (BTX-A) improved leonine facies of patients. BTX-A inhibits release of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
acting at the neuromuscular junction. Furthermore, it blocks cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
transmission to the sweat glands and therefore inhibits sweat secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
. However, the exact mechanism for improving leonine faces is unknown and needs to be further investigated.
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 rhytidectomyRhytidectomy
A facelift, technically known as a rhytidectomy , is a type of cosmetic surgery procedure used to give a more youthful appearance...
. 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. A second option is plastic surgery. This is also used for eye drooping.