Pachydermoperiostosis (PDP) is a rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

that affects both

bones A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...

and

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

. Other names are primary hypertrophic osteoarthropathy or Touraine-Solente-Golé syndrome. It is mainly characterized by 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). This disease affects 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 A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter mem ...

or surgical procedures. In 1868, PDP was first described by Friedreich as 'excessive growth of bone of the entire

skeleton A skeleton is the structural frame that supports the body of most animals. There are several types of skeletons, including the exoskeleton, which is a rigid outer shell that holds up an organism's shape; the endoskeleton, a rigid internal fra ...

'. Touraine, Solente and Golé described PDP as the primary form of bone disease

hypertrophic osteoarthropathy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component Cell (biology), cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Al ...

in 1935 and distinguished its three known forms.

Symptoms and signs

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). Other features include excessive sweating,

arthralgia Arthralgia () literally means ' joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceuti ...

and

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

abnormalities. An overview of all symptoms is provided in table 2. Table 2. Overview of signs

Cause

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 Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functi ...

and

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

(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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

the first step in the degradation of PGE₂ and related

eicosanoids Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub ...

. 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 may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

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 factor Von Willebrand factor (VWF) () is a blood glycoprotein that promotes primary hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thro ...

and

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF). These substances could also have a role in PDP

progression Progression may refer to: In mathematics: * Arithmetic progression, a sequence of numbers such that the difference between any two successive members of the sequence is a constant * Geometric progression, a sequence of numbers such that the quotie ...

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 Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

and

endothelial The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

activation. This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP. VEGF promotes

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

(growth of new

blood vessels Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...

) and differentiation of

, which can explain the clubbing and excessive

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

formation in PDP patients. Other mediators found in increased concentrations in PDP patients, include

osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. Because osteocalcin has ...

endothelin-1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells, as well as by cells in the heart (affecting contractility) and kidney (affecting sodium handling). The prote ...

, b-thromboglobulin,

platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...

(PDGF) and epidermal growth factor (EGF). 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

chromosome 4 Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 190 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the to ...

(4q34.1) and solute carrier organic anion transporter family member 2A1 (

SLCO2A1 Solute carrier organic anion transporter family member 2A1, also known as the prostaglandin transporter (PGT), is a protein that in humans is encoded by the SLCO2A1 gene. This gene encodes a prostaglandin transporter that is a member of the 12-m ...

) in

chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...

(3q22.1-q22.2).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 This syndrome occurs if both copies of either gene are mutated (autosomal recessive inheritance)

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

periosteum The periosteum is a membrane that covers the outer surface of all bones, except at the articular surfaces (i.e. the parts within a joint space) of long bones. (At the joints of long bones the bone's outer surface is lined with "articular cartila ...

can be detected by

radiographs Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical ("diagnostic" radiography and "therapeu ...

of long bones. In order diagnose PDP, often other diseases must be excluded. For example, to exclude secondary hypertrophic osteoarthropathy, any signs of

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

pulmonary The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

intestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

and

mediastinal The mediastinum (from ;: mediastina) is the central compartment of the thoracic cavity. Surrounded by loose connective tissue, it is a region that contains vital organs and structures within the thorax, mainly the heart and its vessels, the eso ...

diseases must be absent. MRI and ultrasound also have characterictic findings.

Skin biopsy Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a 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 day ...

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 () is a term used synonymously with severe hypothyroidism, but also to describe a dermatological change that can occur in hypothyroidism and (rare) paradoxical cases of hyperthyroidism. In this latter sense, myxedema refers to depositi ...

and

hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...

. 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. 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 The phalanges (: phalanx ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. Structu ...

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 The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

PGE₂ can be a useful

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

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

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

. 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 Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

in some patients. However, further investigation is needed to confirm this use of disease monitoring. PGE₂ may also be raised in patients with lung cancer and finger clubbing. This may be related to raised levels of

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

-2, an enzyme involved in the metabolism of prostaglandins. A similar association has been noted in

cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

Classification

PDP is one of the two types of

. It represents approximately 5% of the total hypertrophic osteoarthropathy cases. The other form is secondary hypertrophic osteoarthropathy (SHO). SHO usually has an underlying disease (such as cardiopulmonary diseases,

malignancies Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

paraneoplastic syndrome A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one). It is specifically due to the production of chemical signaling molecules (such as hormones or cytokin ...

). 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

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

. * 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 Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...

symptoms are observed with limited periostosis. The cause of these differentiating pathologies is still unknown.

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 therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

could be a solution for this, although this has not been reported yet in literature. Conventional PDP drug treatment to decrease

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

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 A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor m ...

(NSAIDs) and

corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...

are most used in PDP treatment. These drugs inhibit

cyclo-oxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as pr ...

activity and thereby prostaglandin

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of organi ...

. Since PGE₂ is likely to be involved in periosteal bone formation and acroosteolysis, this is why these drugs can alleviate the

polyarthritis Polyarthritis is any type of arthritis that involves 5 or more joints simultaneously. It can be associated with autoimmune conditions; it may be experienced at any age and is not sex specific. Causes Polyarthritis is often caused by an auto-immun ...

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, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing ...

can reduce pain and

arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

in PDP. It is a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

that blocks the biological action of

TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

(tumor necrosis factor-alpha). TNF-α is an inflammatory

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

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 Rheumatology () is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatology covers more than 100 different complex diseases, c ...

symptoms can be improved by treatment with

bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...

s, such as

pamidronate Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis. It was patented in 1971 and approved for medical use in 1987. Medical uses It is used to pr ...

risedronate Risedronic acid, often used as its sodium salt risedronate sodium, is a bisphosphonate. It slows down the cells which break down bone. It's used to treat or prevent osteoporosis, and treat Paget's disease of bone. It is taken by mouth. It was p ...

. Bisphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis. In isolated cases,

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

was effective in PDP treatment, especially for bone and joint pain. In PDP patients, high levels of

nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These intracellular receptor (biochemistry) ...

were found for steroids, which was the rationale to use tamoxifen, an

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Tamoxifen and several of its

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occu ...

. Cells are accumulated in G₀ and G₁ phases.

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

studies showed that tamoxifen acts as an estrogen

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).

Skin manifestations drug treatment

Retinoids The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are utilized in cosmetic formulations, clinical dermatology, and the treatment of some forms of cancer ...

are used to improve skin manifestations. Retinoids can act on retinoid nuclear receptors and thus regulate transcription. For example,

isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderat ...

, the most effective drug to treat

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

, improves cosmetic features by inducing

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

within human

sebaceous glands A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in t ...

. As a result of this, the increase of

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

and

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of Tissue (biology), organic tissue that results from ...

of the sebaceous glands is inhibited. Retinoids also decrease

procollagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

in fibroblasts, improving pachyderma. Like retinoids, colchicines can also improve skin manifestations. It is able to bind to the ends of

microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

to prevent its elongation. Because microtubules are involved in

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

and

regulation Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

, colchicine can inhibit cell division and inflammatory processes (e.g. action of

neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

and

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

). It is suggested that colchicine inhibit

chemotactic Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

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 (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

acting at the

neuromuscular A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

junction. Furthermore, it blocks

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

transmission to the sweat glands and therefore inhibits sweat

secretion Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...

. 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

rhytidectomy A facelift, technically known as a rhytidectomy (from the Ancient Greek () 'wrinkle', and () 'excision', the surgical removal of wrinkles), is a type of cosmetic surgery procedure intended to give a more youthful facial appearance. There are ...

. 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.

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 another form of osteoarthropathy – familial idiopathic osteoarthropathy (FIO) - was also taken into account in this analysis. PDP usually progresses for 5 to 20 years, until it becomes stable.

Life expectancy Human life expectancy is a statistical measure of the estimate of the average remaining years of life at a given age. The most commonly used measure is ''life expectancy at birth'' (LEB, or in demographic notation ''e''0, where '' ...

may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and

leonine facies Leonine facies is a Facies (medical), facies 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. It is a dermatological symptom, with charact ...

Epidemiology

Prevalence

PDP is a rare genetic disease. At least 204 cases of PDP have been reported. The precise incidence and

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

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).

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 inherited in different ways: either autosomal dominant inheritance (involving a dominant allele) or

autosomal recessive inheritance In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

(involving a recessive allele). The autosomal dominant model of inheritance with

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...

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 A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

and

features. Male-female ratio in PDP is

skewed In probability theory and statistics, skewness is a measure of the asymmetry of the probability distribution of a real-valued random variable about its mean. The skewness value can be positive, zero, negative, or undefined. For a unimodal ...

towards males. Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) ( HPGD) and solute carrier organic anion transporter family, member 2A1/

prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

transporter (

).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 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, France, Greece, and Poland). The other two are located in Australia and Morocco (the Association Marocaine des Génodermatoses).

References

External links

{{Eicosanoid metabolism disorders Osteopathies Genodermatoses Eicosanoid metabolism disorders