Hypertrophic Osteoarthropathy

Back

Background

Hypertrophic osteoarthropathy (HOA) is a syndrome of clubbing of the digits, periostitis of the long (tubular) bones, and arthritis.[1] This clinical triad of digital clubbing, arthralgias, and ossifying periostitis has been recognized since the late 1800s and was previously known as hypertrophic pulmonary osteoarthropathy (HPOA). It is a syndrome characterized by excessive proliferation of skin and bone at the distal parts of extremities and by digital clubbing and periostosis of the tubular bones.[2] Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers.[3] Observations made in modern times by Bamberger (1889), Pierre Marie (1890), and other investigators led to identification of various causes of this digital anomaly, which can be the first manifestation of a severe organic disease such as chronic pulmonary and cardiac diseases,[4] hence also named as Pierre Marie–Bamberger disease.[5] .

The disease is classified either as primary (hereditary or idiopathic) or secondary. Primary hypertrophic osteoarthropathy (also termed primary pachydermoperiostosis or Touraine-Solente-Gole syndrome) was initially described by Friedreich in 1868 and then by Touraine et al in 1935, who recognized its familiar features. The 3 recognized forms of primary osteoarthropathy are (1) complete (pachydermia, digital clubbing, and periostosis), (2) incomplete (no pachydermia), and (3) fruste form (prominent pachydermia with few skeletal manifestations). This classification was proposed by Touraine et al.[6, 7] Primary hypertrophic osteoarthropathy represents 3% of all cases of hypertrophic osteoarthropathy. Its prevalence in the general population is not exactly known.

Interestingly, some patients with primary hypertrophic osteoarthropathy eventually develop diseases (eg, patent ductus arteriosus, Crohn disease, myelofibrosis) that are otherwise known to be underlying causes of secondary hypertrophic osteoarthropathy, as late as 6-20 years after the onset of the osteoarthropathy.[8, 9]

Secondary hypertrophic osteoarthropathy is associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease and often has a more rapid course.

Clubbed digits

Clubbing is elevation of the nail and widening of the distal phalanx caused by swelling of the subungual capillary bed resulting from increased collagen deposition, interstitial inflammation with edema, and proliferation of the capillaries themselves. Increased vascular supply to the nail bed and increased connective tissue growth, together producing the characteristic clubbing.[10] Perivascular infiltrates of lymphocytes and vascular hyperplasia are responsible for thickening of the vessel walls. Electron microscopy reveals Weibel-Palade bodies and prominent Golgi complexes, confirming structural vessel wall damage.[11] Vast numbers of arteriovenous anastomoses may also be seen in the nail bed.[12]

Periosteum

Subperiosteal new bone formation exists along the distal diaphysis of tubular bones, progressing proximally over time. The irregular periosteal proliferation affects predominantly the distal ends of long bones, including the epiphysis in 80-97% of patients. Usually the metacarpus, metatarsus, tibia, fibula, radius, ulna, femur, humerus, and clavicle are involved. The tibia is almost invariably involved.[13, 14, 15] Involvement of the epiphysis distinguishes it from the secondary form that typically spares the epiphysis.

Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum.[13] As this mineralizes, a new layer of bone is formed, and, eventually, the distal long bones may become sheathed with a cuff of new bone.[16]

Bone

The pathological hallmark of hypertrophic osteoarthropathy is neoangiogenesis and edema and osteoblast proliferation in distal tubular bones that leads to subperiosteal new-bone formation.

Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic.[17] Hypertrophy or bony overgrowth predominates in patients with lung cancer and HPOA, whereas acroosteolysis predominates in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy.[18] The type of bone remodeling process depends on the age when clubbing develops.[17] If clubbing appears in childhood, osteolysis is more prominent; however, if it develops after puberty, hypertrophic changes take place. Pineda et al hypothesize that a putative circulating growth factor destroys immature bone.[17]

Synovium

Synovial involvement may occur with subperiosteal changes.[13] Thickening of the subsynovial blood vessels and mild lining-layer hyperplasia may occur.[19, 13] The edematous synovium becomes mildly infiltrated with lymphocytes, plasma cells, and occasional polymorphonuclear leukocytes, but the results from immunohistologic studies are negative. Electron-dense subendothelial deposits are present in vessel walls.[20, 21, 22] In a study of a patient with primary hypertrophic osteoarthropathy and chronic arthritis, Lauter et al found multilayered basement laminae around small subsynovial blood vessels consistent with the late stages of vascular injury.[22] Synovial fluid is usually noninflammatory with low leukocyte counts and few neutrophils.[20, 22]

Skin

Skin changes are more evident in primary hypertrophic osteoarthropathy and are characterized by thick skin or pachyderma which is caused by dysregulation of mesenchymal cells.[23] Characteristic cutaneous manifestations include pachydermia (ie, thickening of facial skin resulting in leonine faces) over the scalp, cutis verticis gyrata, and bilateral ptosis over the eyes resulting in blepharoptosis.[24] These changes yield a characteristic “bull-dog” appearance.[25]

Other influences are acne, eczema, seborrhea, and palmoplantar hyperhidrosis. The skin of the hands and feet are also thickened, but usually not folded.

Pathophysiology

The etiology of hypertrophic osteoarthropathy is unknown. Several mechanisms have been proposed as contributing to the pathophysiology of hypertrophic osteoarthropathy. Paraneoplastic growth factors[26] like prostaglandin E, other cytokines, neurologic, hormonal,[27] and immune mechanisms[20] and vascular thrombi caused by platelets and antiphospholipid antibodies[28] have all been proposed as possible etiologies.[13] All or at least many probably contribute to its development in the different clinical situations. A popular current theory involves the interaction between activated platelets and the endothelium.[26, 28, 29]

The most important of these mechanisms results from the fact that many circulating signaling molecules and growth factors are normally cleared from the blood by the pulmonary endothelium.[19] Normally, platelets are fragmented in the pulmonary microvasculature before they reach the general circulation. In 1987, Dickinson and Martin suggested that hypertrophic osteoarthropathy is related to the presence of megakaryocytes and many circulating factors normally inactivated by the lungs that have bypassed the lung circulatory network and lodged in the fingertip circulation.[30, 4] This has been been proven in patients with cyanotic heart diseases that have been found large circulating platelets with abnormal and, at times, bizarre morphology. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves.[31, 28]

To date, several physiologic and anatomic processes have been defined in which these large particles reach the fingertips and impact release of growth factors, including bypassing of megakaryocytes or megakaryocyte fragments through the lung capillary network (eg, right-to-left intracardiac shunts, carcinoma of the bronchus, anatomic malformation of the vasculature, patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt), formation of large platelet clumps on the left side of the heart or in large arteries (eg, subacute bacterial endocarditis, subclavian aneurysm), or chronic platelet excess (eg, chronic inflammatory bowel disease).[32]

For the reasons above, cyanotic heart diseases is an excellent model for studying hypertrophic osteoarthropathy pathogenesis because more than one third of patients with lifelong clubbing secondary to cyanotic heart disease eventually display the full hypertrophic osteoarthropathy syndrome.[33] Hypertrophic osteoarthropathy caused by intrapulmonary shunting of blood become evident only in the limbs that receive unsaturated blood, for example, in patients with patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt.

Having escaped fragmentation in the lung microvasculature and reached the systemic circulation, megakaryocytes or megakaryocyte fragment impaction at distal sites may lead to local endothelial cell activation through the release of growth factors ie, bradykinin, slow-reacting substance of anaphylaxis, transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) stored in the platelet alpha-granules. These are all angiogenic, with trophic effects on capillary beds.

In addition, they all enhance the activity of osteoblasts and fibroblasts. This initiates finger clubbing by inducing connective-tissue matrix synthesis periostosis.[28, 29] Increased circulating growth factor levels thus would explain all of the features of hypertrophic osteoarthropathy. PDGF and VEGF are thought to contribute significantly to the development of hypertrophic osteoarthropathy. VEGF is a platelet-derived factor; its action is induced by hypoxia. It is a potent angiogenic and permeability-enhancing factor, as well as a bone-forming agent. VEGF receptors are expressed in subperiosteal bone-forming cells. Both the PDGF and VEGF induce vascular hyperplasia, new bone formation and edema.[34]

In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated von Willebrand factor antigen (vWF:Ag) levels in persons with primary hypertrophic osteoarthropathy and in persons with hypertrophic osteoarthropathy secondary to cyanotic heart disease.[28] vWF:Ag is a surrogate marker of endothelial activation and damage because high plasma levels of vWF:Ag are also found in the vasculitides, myocardial infarction, diabetic microangiopathy, and scleroderma.[28] Thus, a common pathogenetic pathway for hypertrophic osteoarthropathy possibly involves localized activation of endothelial cells by an abnormal platelet population. Macrothrombocyte and endothelial cell activation can also be present in cases of hypertrophic osteoarthropathy associated with other disease entities such as liver cirrhosis, in which a prominent intrapulmonary shunting of blood occurs.[29]

Stimulation of fibroblasts by PDGF, epidermal growth factor (EGF) and TGF-β along with over expression of VEGF have also been linked to extensive myelofibrosis seen in few cases of pachydermoperiostosis.[35]

Kozak et al tested the hypothesis that digital clubbing in patients with lung cancer reflects elevated systemic levels of prostaglandin E2 and found that the median urinary level of the metabolite of prostaglandin E2 was 2.3-fold higher in patients with clubbing compared with patients without clubbing (data not shown).[36]

A second proposed mechanism for the development of HPOA is a vagally-mediated alteration in limb perfusion. Interestingly, the anatomic distribution of vagal nerve fibers correlates to the area of clubbing. Vagotomy and sympatholytic drugs have been reported to reverse or to improve hypertrophic osteoarthropathy, suggesting a role for reflex vagal stimulation.[37] Bazaar and Yun proposed that sympathetic override of the normal protective function of vagal innervation is the basis of hypertrophic osteoarthropathy.[38] Sympathetic activity has been noted to induce cytokine changes consistent with inflammation.

Among these, epinephrine has been shown to induce production of interleukin (IL)-11 in human osteoblasts. Recombinant IL-11 has been shown to cause reversible symmetric periostitis in the extremities. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. Removal of the associated lung neoplasm or correction of a cyanotic heart malformation has similar effects, suggesting that alteration of lung function plays an important role.[26]

A third mechanism is the possibility of ectopic production of hormonelike substances (like VEGF) by tumor or inflammatory tissue, resulting in excessive circulating levels of angiogenic substances that would cause capillary bed hypertrophy and periosteal reaction, as noted earlier.Two case reports have independently noted elevated circulating concentrations of VEGF and evidence of tumor production of VEGF associated with lung cancer. Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement.

Diverse types of cancer growths produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is known to occur in diseases associated with hypertrophic osteoarthropathy, such as mesothelioma, Graves disease and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy. Increase level of VEGF and IL-6 caused by the genetic mutation of K-ras might play a role in the pathogenesis of hypertrophic osteoarthropathy with lung cancer.[39]

Alonso-Bartolome et al suggested involvement of the humoral pathway giving rise to graft infection associated hypertrophic osteoarthropathy syndrome by endotoxin or vasoactive compound activated or released by bacteria adherent to the graft.[4]

Chronic activation of macrophages secondary to pulmonary pathologies may lead to digital clubbing by continual production of profibrotic tissue repair factors (eg, growth factors, fibrogenic cytokines, angiogenic factors, remodelling collagenases). These factors act systemically, but their effect is greatest at those parts of the vasculature which are most sensitive to these actions, such as the nail beds. Hypoxia also triggers the activation of macrophages.[40]

Recently, the role of different cytokines and cell receptors, including IL-6 and osteoprotegerin or RANKL system have been described on the development of the disease. Higher serum levels of IL-6 and RANKL are associated with increased values in markers of bone resorption (degradation products of C-terminal telopeptides of type-I collagen and urinary hydroxyproline/creatinine ratio) and reduced serum levels of bone alkaline phosphatase, a marker of bone formation, suggesting that hypertrophic osteoarthropathy is characterized by increased bone resorption, probably mediated by IL-6 and RANKL.[41]

Pathogenesis underlying the increase involved of males in hypertrophic osteoarthropathy is been described by Bianchi et al, which proposed high levels of nuclear steroid receptors, increased cytosolic estrogen receptors, and no detectable progesterone and androgen cytosolic receptors in hypertrophic osteoarthropathy, suggesting increased tissue sensitivity to different circulating sex steroids, which could enhance tissue epidermal growth factor or transforming growth factor alpha production and use.[41]

Hypertrophic osteoarthropathy can be associated with pregnancy and aging secondary to platelet abnormalities, hormonal disturbances, and cytokine dysfunction.

Enhanced Wnt genetic signaling contributes to the development of pachydermia skin changes in primary hypertrophic osteoarthropathy by enhancing dermal fibroblast functions.[23]

Genetics

Recently, a homozygous mutation in the HPGD gene, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was found to be associated with pachydermoperiostosis. However, mutations in HPGD have not been identified in Japanese pachydermoperiostosis patients.

SLCO2A1 is a novel gene responsible for pachydermoperiostosis. Although the SLCO2A1 gene is only the second gene discovered to be associated with pachydermoperiostosis, it is likely to be a major cause of pachydermoperiostosis in the Japanese population.[42] Associations of primary hypertrophic osteoarthropathy with novel mutations in the SLCO2A1 gene in Chinese patients have also been reported.[43, 44]

Epidemiology

Frequency

United States

Primary hypertrophic osteoarthropathy is a rare condition. The association of hypertrophic osteoarthropathy with chronic lung and heart diseases was established as early as 1890.[4] No systematic prevalence studies have been performed for secondary hypertrophic osteoarthropathy, but hypertrophic osteoarthropathy is associated with many illnesses.

According to Rassam et al, the occurrence of hypertrophic osteoarthropathy in lung cancer was about 3% (9 of 280) in a consecutive series seen between 1970-1975. Other literature has described a higher prevalence in primary lung cancer of about 4–32%.[4]

In congenital cardiac disease, hypertrophic osteoarthropathy has been found in 10 of 32 patients (31%). Hypertrophic osteoarthropathy associated with respiratory failure is reported to be present in 2–7% of patients.

International

Hypertrophic osteoarthropathy likely has the same incidence and prevalence around the world.

Mortality/Morbidity

The mortality and morbidity of hypertrophic osteoarthropathy vary with the associated illness.

PHO has a self-limiting course, and progression stops at the end of adolescence. There is no curative treatment for the skeletal abnormalities.[9]

Race

Hypertrophic osteoarthropathy affects persons of all races.

Sex

Hypertrophic osteoarthropathy has a marked predominance in males, with a male-to-female ratio of 9:1.[45] It has an autosomal dominant pattern of inheritance, with mainly variable expression and incomplete penetrance and familial aggregation in 25-38% of cases.[7, 25] Recessive autosomal inheritance and X-linked mutations may also be present, but they may differ in severity and prevalence of clinical features.[46] Secondary osteoarthropathy has the same sex ratio as the associated illnesses.

Age

Primary hypertrophic osteoarthropathy has a bimodal peak of onset that occurs in patients younger than 1 year and in patients who are around puberty, ie, approximately age 15 years.[45] Secondary hypertrophic osteoarthropathy is rarely encountered in children and adolescents. It most commonly affects individuals aged 55-75 years.[4]

History

The clinical presentation of hypertrophic osteoarthropathy (HOA) varies according to the rapidity of onset and the evolution of the underlying disease.

Physical

The diagnostic criteria for hypertrophic osteoarthropathy include clubbing and periostosis of the tubular bones.[2] Three incomplete forms of hypertrophic osteoarthropathy are described. These include (1) clubbing alone, (2) periostosis without clubbing in the setting of an illness known to be associated with hypertrophic osteoarthropathy, and (3) pachydermia associated with minor manifestations (eg, synovial effusion, seborrhea, hyperhidrosis, hypertrophic gastropathy, acroosteolysis).

The presence of periostitis and limb pain/swelling even if without clubbing can make the diagnosis of an incomplete form of hypertrophic osteoarthropathy. A diagnosis of the complete form of hypertrophic osteoarthropathy is usually made based on the triad of digital clubbing, periostitis of the tubular bones, and painful swelling of the limbs.[5]

Clubbing

Clubbing usually progresses through the following 4 phases[13] :

  1. Fluctuation and softening of the nail bed, with a rocking sensation upon palpation due to increased edema and soft tissue
  2. Loss of the normal 15° angle (Lovibond angle[47] ) between the nail and cuticle. The angle formed by the dorsal surface of the distal phalanx and the nail plate (Lovibond’s angle) is approximately 160°; however, with clubbing this angle is obliterated and becomes 180° or greater.
  3. Accentuation of the convexity of the nails and clubbed appearance of the fingertips, with warmth and sweating
  4. Shiny or glossy change in the nail and adjacent skin, with disappearance of the normal creases and appearance of longitudinal striation of the nail

Clubbing can be classified into 3 topographical groups.[48, 49]

Clubbing can also be classified into 3 color groups (personal observations).

Five clinical signs can be used to describe clubbing.

Confirming clubbing requires using instruments to determine the nail bed angles or the phalangeal depth ratio (PDR) and is not performed routinely. In 1976, Schamroth reported a clinical sign associated with clubbing: obliteration in clubbed fingers of the diamond-shaped window normally produced when the dorsal surfaces of the corresponding finger of each hand are opposed. Validity and reliability of the Schamroth sign for the diagnosis of clubbing have been proven.[51, 52]

Bone and joint symptoms

Periostosis may be asymptomatic or may cause a severe burning and deep-seated pain in the distal extremities. This pain is aggravated with dependency and relieved with elevation.[13] In some cases, dysesthesia of the fingers is present, with accompanying heat, sweating, clumsiness, and stiffness of the hands.[13] Adults with primary hypertrophic osteoarthropathy are asymptomatic.[45]

Joint symptoms range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles (see image below).[13] The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints, eg, knees, ankles, and wrists, as depicted in the image below.[52] Arthrocentesis reveals a very thick noninflammatory fluid, with a cell count of less than 500 cells/µL.[20] The effusions are more likely a sympathetic reaction to nearby periostosis.


View Image

Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and a....

There might be inflammation and reduction of the joint space, and contractures may develop in later stages. Rarely, periarticular erosions can occur.[25, 53] In the axial skeleton, changes are spondylolisthesis, with narrowing of intervertebral disk spaces and foramina, ligamentous ossification,l and laxity.[25, 53]

Cutaneous symptoms

They are more prominent in, but not exclusive to, primary hypertrophic osteoarthropathy.

Cutaneous gland dysfunction occurs, resulting in acne, hyperhydrosis, or seborrhea.[45]

Hypertrophy of soft tissues occurs, resulting in coarse facial features, cylindrical calves (elephant feet), ptosis of the lids, and cutis verticis gyrata or prominent frontal cerebroid wrinkles.

Causes

Clubbing and hypertrophic osteoarthropathy likely represent different stages of the same disease process. Hypertrophic osteoarthropathy can be classified as either primary or secondary.

Primary or idiopathic hypertrophic osteoarthropathy (pachydermoperiostosis) comprises about 3-5% of all cases of hypertrophic osteoarthropathy.[54] PDP is considered to be hereditary, although a family history of the disease can, in fact, only be traced in around 25-38% of cases. Familial recurrence of PDP has been reported in 33–100% of pedigrees. It has autosomal dominant inheritance and suggested autosomal recessive and X-linked inheritance.[9] It has a male predominance who usually show a more severe phenotype (male-to-female ratio of 9:1).[40] PDP is more common in African Americans.[55]

The precise incidence of this osteo-arthro-dermopathic syndrome is unknown. According to one study, it has an estimated prevalence of 0.16%. It is associated with significant morbidity with advancing age.[56] . In as many as one-third of the patients, PDP occurs as a hereditary disease with autosomal dominance of variable penetrance. Based on variable expression and penetration three forms of PDP have been recognized: (1) a complete form with pachydermia and periostitis; (2) an incomplete form with evidence of bone abnormalities but lacking pachydermia; and (3) a forme fruste with prominent pachydermia and minimal-to-absent skeletal changes.[55]

Two milder variant of the complete form of pachydermoperiostosis have been defined in literature.[57]

PDP has been recently mapped to band 4q33-q34 on chromosome 4. Homozygous and compound heterozygous germline mutations in HPGD encoding 15-hydroxyprostaglandin dehydrogenase, whose enzyme activity is NAD+ dependent. The key enzyme of prostaglandin degradation has been identified.[55] Homozygous HPGD mutations have so far been reported in 10 families; all but one displayed parental consanguinity. Only 2 of these families were of European origin. The c.175_176delCT frameshift mutation appears to be recurrent and to be the most common HPGD mutation in Caucasian families.[58]

So far, 7 HPGD alterations are known. Allelic spectrum of HPGD gene include a novel c.217+1G>A mutation. Seven coding HPGD exons encode the 266 amino acid 15-hydroxyprostaglandin dehydrogenase, which is ubiquitously expressed. All HPGD mutations constitute loss-of-function alleles due to protein truncation or missense changes that affect hydrogen bonds lining the 15-PGDH enzyme reaction cavity. Individuals with homozygous mutations have chronically elevated prostaglandin E2 (PGE2) levels. The various clinical manifestations of PDP fit well with the pleiotropic range of physiologic actions of PGE2 in different tissues. Excess PGE2 may account for the periostosis, acro-osteolysis, clubbing, and patent ductus arteriosus. The exact effects of PGE2 on the skin are not completely understood. Various mechanism suggested are effect of PGE2 on vasculature and Wnt signaling.

The Wnt signaling consists of canonical and noncanonical pathways. These signaling pathways are mediated by Wnt protein, which binds to a frizzled Wnt receptor. Wnt signaling is modulated by several different families of secreted down-regulators. Among them, Dickkopf (DKK) is a family of cysteine-rich proteins comprising at least four different forms (DKK1, DKK2, DKK3, and DKK4), which are coordinately expressed in mesodermal lineages.

The best studied of these is DKK1, which blocks the canonical Wnt signaling by inducing endocytosis of lipoprotein receptor-related protein 5/6 (LRP5/6) complex12 without affecting the frizzled Wnt receptor. High mRNA levels of DKK1 in human dermal fibroblasts of the palms and soles inhibit the function and proliferation of melanocytes via the suppression of catenin and microphthalmia- associated transcription factor. These findings suggest that DKK1 is deeply involved in the formation and differentiation of the skin. Decreased expression of DKK1 in fibroblasts and enhanced expression of catenin in the skin of patients with PDP, suggest that Wnt signaling is enhanced in PDP. These results suggest that enhanced Wnt signaling contributes to the development of pachydermia.[23]

Primary hypertrophic osteoarthropathy has a bimodal age distribution, with one peak in the first year of life and another at age 15 years. It develops gradually from adulthood. It usually begins as clubbing usually during adolescence, followed by progressive changes in the skeleton and skin over the next 5–20 years, resulting in significant morbidity and then remains unchanged for life. The activity of the illness is limited to the growth period, with adults becoming asymptomatic. Although the progression of PDP typically ceases after 10 years, patients may be left with significant morbidity from severe kyphosis, restricted motion, and neurologic problems.[55]

It has been described in many different races.[54] The longest time interval between the onset of PDP symptoms to the onset of lung lesion symptoms is 18 months.[59] This syndrome has familial and idiopathic forms differentiating it from secondary pulmonary hypertrophic osteoarthropathy. The familial or idiopathic hypertrophic osteoarthropathy appears at puberty and is not associated with other underlying diseases.[56] The familial or idiopathic forms of hypertrophic osteoarthropathy occur either in the first year of life or at puberty.[60]

The etiology of primary hypertrophic osteoarthropathy is still unclear with 2 widely floated theories: (1) neurogenic, neural reflexes initiated by vagal stimulation lead to vasodilation, increased blood flow, and hypertrophic osteoarthropathy and (2) humoral mediators that include various growth factors like platelet derived growth factors, epidermal growth factor, transforming growth factor and VEGF have been found to be increased in patients with hypertrophic osteoarthropathy leading to fibroblast proliferation and subsequent fibrosis.

The most common clinical features of primary hypertrophic osteoarthropathy include clubbing (89%); radiographic periostitis of the distal long bones periostosis, swelling of periarticular tissue and subperiosteal new bone formation revealed by radiography (97%); pachyderma, coarsening of skin, seborrhea (90%); acne, folliculitis, palmo-plantar hyperhidrosis (44-67%); partial ptosis and cutis verticis gyrata (24%). The major diagnostic criteria include a triad of digital clubbing, hypertrophic skin changes (pachydermia), and periostosis of long bones.[61] Earliest manifestations include delayed closure of the cranial sutures and PDA[62]

Other common clinical presentations include progressive widening of distal part of long bones, bulbous deformities of fingers and toes, synovial effusions (41%), arthritis (20-40%), and paresthesias. The skeletal involvement occurs commonly in the form of symmetrical distal long bone enlargement. In advanced disease, proximal long bones and flat bones of the pelvic and shoulder girdles, musculotendinous insertions, and interosseous membranes get involved.[63]

Long-standing clubbing and a positive family history suggest primary hypertrophic osteoarthropathy, but excluding any associated illness is still of utmost importance. Ruling out secondary causes of hypertrophic osteoarthropathy (eg, suppurative lung disease, lung cancer,congenital cyanotic heart disease, infective endocarditis) is important. Bone lesions in the secondary form are more painful and progress more rapidly while the skin changes are slight to moderate.

In secondary hypertrophic osteoarthropathy, the underlying disease usually appears first but hypertrophic osteoarthropathy can precede symptoms of the underlying disorder by more than a year, hence follow-up of patients is essential. In PHO, the progress is slow and patients rarely report symptoms voluntarily as the skin manifestations and clubbing have over time become part of the patient's body image, and the patient considers them to be more or less normal. The patients initially seek medical help for minor pains in the shoulder, hands, or recurrent swelling of a mechanical nature in the knees or ankles (effusions).[9] Patients with PDP often have autonomic dysfunction, such as dyshidrosis or blood pressure control disturbances. Hyperactivity of the sympathetic nerve system may cause hypertension and hyperhidrosis of the palms and soles.[64]

Other differentials include acromegaly, thyroid acropachy, and scleromyxedema, syphilitic periostitis, osteopetrosis, and Paget disease. In the case of acromegaly, however, bones in general are larger in the face, jaw (prognathism), skull, and limbs; this is very evident in a radiographic study in the absence of signs of periostosis. The disfigurements in facial and skeletal appearances have been confused with leprosy and syphilis. These 2 conditions have widespread psychological and social problems especially in developing countries making the differentiation from hypertrophic osteoarthropathy imperative.

Primary hypertrophic osteoarthropathy usually presents with painless involvement of bones and only occasional epiphyseal involvement.[63] Anemia in such patients is usually multifactorial, caused by GI bleeding, myelofibrosis, and serum inhibitors of erythropoiesis.[63]

Symmetrical cylindrical thickening of long bones occurs because of periosteal proliferation and subperiosteal new bone formation. It may appear as elephant foot in one fourth of the cases. Articular and periarticular pain, particularly in ankles and knees is prevalent and mild articular limitation of motion may be due to periarticular bony over growth. Symmetrical involvement of small and large joints may appear as rheumatoid arthritis. Synovial fluid is noninflammatory and synovial histology shows hypercellularity and vascular thickening without inflammatory cell infiltration. Radiological findings are periostitis and symmetrical thickening of distal tubular bones, particularly tibia, fibula, radius, and ulna. Radiographic signs of bilateral and symmetrical periostosis are frequently observed as a marked irregular periosteal ossification of the tibias and fibulas.[23]

In pachyderma, the skin of the face and forehead is thickened and furrowed, which results in leonine facies, a major cause of cosmetic and functional morbidity in these patients.[55] The scalp skin is also thickened and folded and appears as "cutis verticis gyrata." Ocular findings consist mainly of ptosis and chronic tarsitis; however, corneal leucoma, cataract, and presenile macular dystrophy have been reported. Thickened and ptotic upper eyelids are a common feature of PDP. This floppy eyelid syndrome was first described by Culbertson and Ostler in 1981.

All these features cause the patient to look prematurely aged. Thickened ears and lips may appear. Hyperhidrosis and over activity of sebaceous glands of the skin, particularly of scalp and face, is common. In a review of the PDP literature, hyperhidrosis was found to be present in 27% of 126 patients.[64] The skin of palms and soles is also thickened and rough, and the thenar and hypothenar areas become prominent.

Other skin manifestations may appear as seborrheic dermatitis, as eczematoid dermatitis of hands and feet, and also as acne vulgaris. Histopathologic findings of the eyelid in PDP include sebaceous gland hyperplasia, enlargement of sweat glands, thickening of the dermis with an increase in collagen content, deposition of mucin, and perivascular lymphocytic infiltration.[65] Although promotional influences of prostaglandins and prostaglandin analogues on the hair follicle are obvious by virtue of clinical observations and experimental data, hair growth and hair structure are usually not affected in PHO.[66]

Skeletal manifestations include over growth, thickening and pain of distal long bones, clubbing of the fingers and toes, and arthritis. Therefore, PDP must be recognized early because of the social stigmata linked to its cutaneous manifestations, and its uniformly good prognosis if treated.

Acroosteolysis is not a rare complication and may affect the terminal phalanges of fingers and toes.[54] Very often, a history of arthralgia of the ankles, knees, wrists, elbows, and occasionally the small joints is noted. Most likely this pain does not originate from the joints per se but rather is caused by active inflammation of the periosteum. Typically, these rheumatologic symptoms disappear when the periostitis is arrested.[54] Thickened fissured tongue is a rare manifestations of PDP.

Clubbing in conjunction with osteolysis helps to differentiate primary hypertrophic osteoarthropathy from all other causes of acroosteolysis except Cheney syndrome. These are the only 2 causes of clubbing with acroosteolysis and must be recognized.

Various rare associations like hypertrophic gastropathy, peptic ulcers, gynecomastia, acro-osteolysis of fingers and toes, Crohn disease, an atherothrombotic brain infarction,[64] renal amyloid A (AA) amyloidosis, and bone marrow failure due to myelofibrosis have been described. Only 6 cases of myelofibrosis in primary hypertrophic osteoarthropathy have been described so far. The development of myelofibrosis makes PHO a disease with unfavorable outcome.[63]

Several factors including increased collagen fibers, infiltration and overgrowth of fibroblasts in bone marrow, and overactivity of platelet-derived growth factor may play a role in this complication.[67] An increase in human leukocyte antigen (HLA) B12 has been shown in one study of this syndrome.[35] Tanaka et al reported pulsed steroid therapy with parenteral iron having been able to improve the anemia and pancytopenia but insufficient to relieve the bone marrow fibrosis, splenomegaly, or cause any resolution in his skin or bone findings. Other associated abnormalities include cranial suture defects, gynecomastia, female hair distribution, striae, compressive neuropathy, corneal leukemia, and patent ductus arteriosus.[66]

Incomplete expression of pachydermoperiostosis. Most patients with congenital and familial clubbing are asymptomatic and have relatives with the same disorder. This syndrome may reflect incomplete expression of pachydermoperiostosis. A case report in Germany described a family with a variant form of primary hypertrophic osteoarthropathy restricted to the lower extremities without digital clubbing or cutaneous changes. Three family members had pain, swelling, and hyperhidrosis in both feet. Radiographs showed destruction and osteoproliferative changes of the metatarsal bones with periosteal hyperostosis close to the talus. All known infectious, neurologic, metabolic, and malignant diseases that affect the bone and joints were excluded.

Variants of PDP include Rosenfeld-Kloepfer syndrome, which is characterized by enlargement of the jaws, especially mandible, and of the hands and feet, nose, lips, tongue, and forehead, along with cutis vertices gyrata and corneal leukoma; Currarino idiopathic osteoarthropathy, which is an incomplete form of PDP seen in children and adolescents and characterized by the presence of eczema and sutural diastases; and a localized form with only the radiographic features of PDP in the lower extremities. Among these 3 variants, the secondary form is commonest, whereas COA is the rarest and only about 30 cases have been reported.[68]

Goldbloom syndrome is a rare, idiopathic, diffuse, painful, hypertrophic periostosis occurring transiently in children. Clubbing and skin involvement are usually absent. The clinical picture consists of a high fever with weight loss and severe bone pain in the mandibles and long bones. It is accompanied by a major acute-phase reaction and polyclonal hypergammaglobulinemia. The syndrome spontaneously resolves in 4-8 weeks, and radiographic and bone scan abnormalities return to normal within the next few years. Long-term follow-up shows normal growth thereafter, without permanent sequelae.

Secondary hypertrophic osteoarthropathy is also called Pierre Marie-Bamberger syndrome. In adulthood, 90% of generalized hypertrophic osteoarthropathy is associated with an intrathoracic infectious or neoplastic condition, as depicted in the image below.


View Image

In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition.

Features include clubbing, skin hypertrophy, thickening of tubular bones, periostosis, and effusions of large joints. The disease progresses more rapidly than primary hypertrophic osteoarthropathy. The underlying disease usually appears first. However, hypertrophic osteoarthropathy occasionally precedes symptoms of the underlying disorder by more than a year.[13, 69] In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition. The association with malignancy is relatively common in adults.[70, 71]

Digital clubbing and hypertrophic osteoarthropathy are linked, and many authors postulate a single pathological entity, regardless of the etiology, which evolves in a centripetal fashion, with finger or toe clubbing appearing first and thickening of the tubular bones of the extremities occurring at later stages of the process. Hypertrophic osteoarthropathy with no clubbed nails appears to be rare and few cases have been reported earlier. Periosteal new bone formation is a hallmark of hypertrophic osteoarthropathy and it mostly affects the appendicular skeleton, usually bilaterally and symmetrically along the metadiaphyseal regions of the bones.[72]

Even without digital clubbing, hypertrophic osteoarthropathy should be considered in patients with isolated calcaneal cortical reaction bilaterally, which is a new addition to the literature on the spectrum of potential presentations of this syndrome,[72] as secondary hypertrophic osteoarthropathy may manifest with isolated calcaneal periostitis bilaterally. Hypertrophic osteoarthropathy may present as a partial syndrome without clubbing and about 20% of cases have hypertrophic osteoarthropathy without detectable malignancy.[73]

Conditions underlying secondary hypertrophic osteoarthropathy can be easily separated into malignant and nonmalignant diseases. Paraneoplastic hypertrophic osteoarthropathy is more common in subjects aged 50–70 years.[60] Among malignancy-related hypertrophic osteoarthropathy, pulmonary malignancies compose 80% of reported hypertrophic osteoarthropathy cases, most of which are non-small cell lung cancer such as squamous cell or adenocarcinoma. As many as 5% of adults with lung cancer demonstrate signs of hypertrophic osteoarthropathy.[34]

On the other hand, lung cancer accounts for almost 20% of isolated digital clubbing and over 60% of hypertrophic osteoarthropathy in adults.[4] These data suggest that hypertrophic osteoarthropathy or simple digital clubbing in adults must be considered as a warning and should prompt lung cancer screening, even in the absence of detectable respiratory symptoms, so that patients could benefit from early treatment ensuring better outcome.

Over 90% of secondary HOA cases develop as a paraneoplastic syndrome or the anomaly associated with chronic suppurative infections and can precede the diagnosis of an underlying disease.[60]

However, patients with hypertrophic osteoarthropathy rarely show the complete triad of signs. Less than 1% of the lung cancer patients developed hypertrophic osteoarthropathy as a paraneoplastic manifestation. Males, heavy smokers, and advanced disease predominated in lung cancer patients with hypertrophic osteoarthropathy.[74] Other malignancies reported in the literature to be associated with HOA include nasopharyngeal cancer, mesothelioma, renal cell carcinoma, esophageal cancer, gastric tumor, pancreatic cancer, breast phyllodes tumor, melanoma, thymic cancer and Hodgkin’s lymphoma.[4] The symptoms and bone scintigram findings of hypertrophic osteoarthropathy improved in half of the patients on treating the lung cancer.[16] Nonmalignant causes of hypertrophic osteoarthropathy include a number of GI and other diseases, including neoplastic, pulmonary, cardiac, infectious, endocrine, psychiatric, and multisystem diseases.

Chronic respiratory diseases include cystic fibrosis, pulmonary fibrosis, sarcoidosis, lung transplant,[16] chronic obstructive lung disease, and chronic infections like pulmonary tuberculosis, pulmonary primary intestinal lymphangiectasia (Waldmann disease), pulmonary epithelioid hemangioendothelioma, bronchiectasis, diffuse inflammatory lung disease, pulmonary arteriovenous malformations, and chronic hypoxemia. Yao and coworkers described the first case of hypertrophic osteoarthropathy associated with chronic lung transplant rejection.[75] An association of sarcoidosis with hypertrophic osteoarthropathy has been reported and nodular periostitis by roentgenography has been reported in 1 case.[76]

Inflammatory bowel disease (Crohn disease and ulcerative colitis), celiac sprue,[45] gastric hypertrophy, laxative abuse, polyposis, intestinal acute cellular rejection ACR, primary intestinal lymphoma, juvenile polyps of the stomach, and gastric adenocarcinoma are associated with hypertrophic osteoarthropathy. Hypertrophic osteoarthropathy has been associated with organ transplant in one isolated liver transplant recipient with chronic liver rejection.[77]

Liver disease and cirrhosis resulting from cholestasis, chronic active hepatitis, biliary atresia, primary sclerosing cholangitis, Wilson disease, primary biliary cirrhosis, and alcoholic cirrhosis are also causes.[4] These also include hepatocellular carcinoma and primary liver rhabdomyosarcoma.

To our knowledge, hypertrophic osteoarthropathy has not been reported to occur with liver steatosis in the English literature. No association with transplant medications has been noted.[30]

Congenital cyanotic congenital heart diseases, rheumatic diseases, and left ventricular tumors have been noted.[78]

Neurologic causes include primitive neuroectodermal tumors (PNETs).[79]

Other causes include chronic infections associated with cystic fibrosis, HIV,[30] tuberculosis, aspergillus, infective endocarditis, subacute bacterial endocarditis, vascular prosthesis infections, syphilis, and immune deficiency syndrome and amyloidosis.

Mediastinal causes include esophageal carcinoma, thymoma, and achalasia.

Miscellaneous causes include the following:

Primary hypertrophic osteoarthropathy and POEMS syndrome overlap; both conditions are associated with digital clubbing, pachyderma, hyperhidrosis, gynecomastia, and bone proliferation.

Voriconazole has been reported to probably induce periostitis, but no apparent inflammatory arthritis was present in the case series report.[34] The presentation more closely resembles nodular periostitis or periostitis deformans than hypertrophic osteoarthropathy. Unlike patients with hypertrophic osteoarthropathy, patients with voriconazole-associated periostitis lack the cardinal features of digital clubbing and noninflammatory joint effusions.[80] The periosteal reaction was dense and irregular, as opposed to the smooth and single layer periostitis described in lung-cancer-associated hypertrophic osteoarthropathy.

In addition to the involvement of tubular bones characteristic of classic hypertrophic osteoarthropathy, the patients also had variable involvement of the clavicles, ribs, scapulae, and pelvis. Chen and Mulligan suggested that fluoride toxicity may be the cause of voriconazole-associated periostitis.[81]

Hypertrophic osteoarthropathy was also noted in one case after a long-term use of bevacizumab metastatic colorectal cancer.[82]

Various medications including prostaglandin, vitamin A, and fluoride can produce periostitis and bony changes resembling hypertrophic osteoarthropathy.[80] The association between finger clubbing and senna misuse and the reversibility of finger clubbing, were reported in 1975.

Hypertrophic osteoarthropathy is an uncommon disease in the pediatric age group characterized by noninflammatory joint effusions, terminal digit clubbing, and radiographic evidence of periosteal new bone formation affecting the hands, feet, and distal limbs. The hepatopulmonary syndrome is also uncommon in childhood and presents as hepatic dysfunction, impaired arterial oxygenation, and intrapulmonary shunting. Consider hypertrophic osteoarthropathy as an imitator of juvenile rheumatoid arthritis, recognize its known association with chronic liver disease, and know that hepatopulmonary syndrome can occur in the setting of hypertrophic osteoarthropathy.[83]

In children, most cases of generalized hypertrophic osteoarthropathy are due to non-neoplastic causes such as pulmonary infections, cystic fibrosis, and congenital cyanotic heart disease.[34] Case reports have described an association with biliary atresia. Cyanotic heart disease is the prototype of hypertrophic osteoarthropathy because almost all patients have clubbing and more than a third of patients have the full-blown syndrome. Malignancy-associated hypertrophic osteoarthropathy in children and young adults is not well documented but numerous case reports describe the association with carcinoma of the nasopharynx, osteosarcoma with lung metastasis, rhabdomyosarcoma, Hodgkin lymphoma, thymic carcinoma and pleural mesothelioma.[34] A case report has described hypertrophic osteoarthropathy presenting as the first symptom of recurrent infantile fibrosarcoma.[84]

The authors did not identify any reported cases of hypertrophic osteoarthropathy associated with lung carcinoma in children or young adults in the literature.[34] Intrathoracic disease should be considered when hypertrophic osteoarthropathy is detected in a child with a known or suspected malignant disease, and the occurrence of hypertrophic osteoarthropathy during follow-up should alert the physicians for possible recurrence of the neoplastic disease or intrathoracic involvement. To the authors' knowledge, only 34 pediatric patients with hypertrophic osteoarthropathy have been reported to have neoplastic diseases to date. Among these, 12 had carcinoma of the nasopharynx, 8 had osteosarcoma, 8 had Hodgkin lymphoma, 3 had thymic carcinoma, 1 had periosteal sarcoma, 1 had pleural mesothelioma, and 1 had recurrent infantile fibrosarcoma.[85, 84]

An atypical form of hypertrophic osteoarthropathy has presentation limited to lower extremities.[86]

Various causes of unidigital clubbing include aortic/subclavian aneurysm, brachial plexus injury, shoulder subluxation, superior sulcus (Pancoast) tumor, median nerve injury, trauma, Maffucci syndrome, gout, sarcoidosis, severe herpetic whitlow, and hemodialysis. Localized clubbing, similar to unilateral digital clubbing, has been described in association with local vascular lesions such as aneurysms; arteriovenous fistulas; and venous abnormalities of the arm, axilla, and thoracic outlet.[48, 49]

Other causes of localized hypertrophic osteoarthropathy include hemiplegia, patent ductus arteriosus with pulmonary hypertension, infected arterial grafts, endothelial infections, and extensive endothelial injury of a limb.[49] In patients with patent ductus arteriosus, pulmonary hypertension causes right-to-left shunting of blood, which may cause hypertrophic osteoarthropathy of the toes and fingers on the left side.[49, 29] Development of hypertrophic osteoarthropathy localized to areas distal to a vascular prosthesis may allow early diagnosis of graft infection. Around 30 cases of bilateral or monomelic hypertrophic osteoarthropathy of the lower limbs (or isolated clubbing of the toes) revealing an aortic prosthesis infection have been reported in the last 40 years.[87] Therefore, unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet.[49]

Thomas first described thyroid acropachy in 1933.[88] It is a rare condition associated with prior or active Graves disease. Thyroid acropachy is characterized by the triad of (1) clubbing; (2) noninflammatory swelling of the soft tissues of the hands and feet; and (3) asymptomatic, asymmetrical, exuberant, periosteal proliferation preferentially affecting the diaphysis of the metacarpal and metatarsal bones.[89] It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid.[52]

Laboratory Studies

The erythrocyte sedimentation rate may be elevated in persons with pachydermoperiostosis and is often elevated in those with secondary hypertrophic osteoarthropathy.[13] .

Serum alkaline phosphatase levels may be elevated secondary to periosteal new bone formation.[13] These bone markers can be used to follow-up the disease activity. Isolated reports have shown an increase in some bone formation markers and resorption such as TAP, BAP, BGP, carboxyterminal propeptide of type I procollagen, or NTX (see N-Terminal Telopeptide) in patients with either primary or secondary hypertrophic osteoarthropathy, suggesting that its measurement could be useful for monitoring disease activity. Moreover, an increase in the serum levels of IL-6 and receptor activator of nuclear factor (NF)-κB ligand have been recently related to the increased bone resorption observed in some of these patients, suggesting a possible role of these cytokines in the regulation of bone turnover in this process.[61]

Studies in patients with PDP or PHO evidenced increased plasma levels of several substances, such as endothelin-1, β-thromboglobulin, platelet-derived factor, von Willebrand factor, and vascular endothelial factor, among others, which could have a role in disease progression and periosteal proliferation.[61]

Biallelic HPGD mutations are found in most patients with typical PHO, and sequencing of the HPGD gene is a highly specific first-line investigation for patients presenting in this way, particularly during childhood.[90]

Finally, as commented above, data indicate that mutations in 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation, can be the cause of PHO. Homozygous individuals with this mutation also show elevated levels of prostaglandin E2 and its metabolite, PGE-M, thus suggesting that its measurement can be useful in early investigations of patients with hypertrophic osteoarthropathy.

If an effusion is present, the synovial fluid is noninflammatory (cell count < 500/µL), with a predominantly lymphocytic and monocytic infiltrate.

The combination of symptoms of proliferation of skin, bone, and capillaries with periostosis of the long bones should initiate an intensive search for an underlying malignant disease usually of thoracic organs.[5]

Imaging Studies

Distinguishing between clubbed and nonclubbed fingers, in vivo, using plain radiograph is possible.[91]

Plain radiographs show 2 types of changes, bone formation with hypertrophy and bone dissolution with acroosteolysis.[17]

Periosteal thickening occurs along the shafts of long and short bones, initially appearing in the distal diaphyseal regions of the long bones. Periosteal changes are seen as a continuous thin line of sclerotic new bone separated from the cortex by a radiolucent space. Over time, the periosteal new bone thickens and fuses with the cortex, and the process extends proximally to the diaphysis and metaphysis. These changes are most commonly observed in the tibia, radius, ulna, fibula, and femur. PHO is distinguished by more exuberant periosteal new bone formation that extends to the epiphyseal regions.[13] But there are documented HOA cases without radiographically detectable periostitis.[72]

Acroosteolysis may be seen in the distal tufts in patients with long-standing hypertrophic osteoarthropathy.

Radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. Because of its ability to delineate the subtleties in progression and regression of the disease these findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies, as depicted in the images below.[13, 52]


View Image

Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This i....


View Image

Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and a....


View Image

For hypertrophic osteoarthropathy diagnosis, radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the ....

More recently,99m Tc-diphosphonate complexes has emerged as the most sensitive tool for the detection and evaluation of the extent of hypertrophic osteoarthropathy.[72]

Angiography findings may demonstrate hypervascularization of the finger pads.[92, 19]

Other Tests

An evaluation for the primary condition is warranted in patients with possible secondary hypertrophic osteoarthropathy; for example, search for an intrathoracic malignancy or infection.

Histologic Findings

Biopsy of the skin and bone marrow may show an exacerbated proliferation of fibroblasts, which are associated with diffuse epidermal hyperplasia and lymphohistiocytic infiltration with collagen redistribution.

Medical Care

Pachydermoperiostosis

So far, no medical treatment has been suggested to alleviate this morbidity. Botulinum toxin A (BTX-A) administration is a simple procedure that may be of value in providing temporary cosmetic improvement.

Medical care of PDP is palliative and includes nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, tamoxifen citrate, retinoids, and risedronate sodium to alleviate the painful polyarthritis/osteoarthropathy.[4] Colchicine may be helpful for the pain due to subperiosteal new bone formation. Colchicine inhibits neutrophil chemotaxis and tissue edema; thereby improving joint symptoms, pachyderma, and folliculitis. Steroids and bisphosphonate work by inhibition of osteoclasts and antiresorptive effects have been tried with promising results for rheumatological symptoms of hypertrophic osteoarthropathy. Retinoids, by decreasing procollagen mRNA in fibroblasts, have shown improvements in pachyderma, seborrhea, acne, folliculitis, and cutis vertices gyrate.

Isolated reports suggest that pamidronate (30–60 mg intravenous) and Octreotide help in relieving bone pain in some cases.

For correction of gross disfigurement, plastic and reconstructive surgery may be indicated. Otherwise, reassurance is all that is required. Prognosis for life is excellent but the effect on function depends on the degree of bone and joint involvement.[9]

Secondary hypertrophic osteoarthropathy

Hypertrophic osteoarthropathy represents a dilemma in medicine in which diagnosis is relatively simple whereas management is exceedingly difficult due to obscure pathogenesis mechanism, various treatment modalities, and individualized treatment responses. The management and prognosis of hypertrophic osteoarthropathy depend on the underlying disease and, past studies have shown that hypertrophic osteoarthropathy most commonly improves with treatment of the primary tumor. To date several treatment modalities have been suggested, with various degrees of success.[4]

Treatments for hypertrophic osteoarthropathy is classified into 2 categories: (1) treatment of primary cause (eg, resection of tumor, surgery for cardiac anomalies, chemotherapy, radiotherapy, treatment of infection) and (2) symptomatic treatments (eg, bisphosphonates, octreotide, NSAIDs, vagotomy).

Primary treatment is the most widely reported modality to be efficacious. Although removal of the primary tumor usually resolves this syndrome, effective treatment in patients with advanced lung cancer has not been established. Treatment of Pneumocystis pneumonia, pulmonary pseudotumor, and pulmonary tuberculosis have been reported to result in resolution of associated hypertrophic osteoarthropathy, as has corticosteroid treatment of inflammatory interstitial lung disease with associated hypertrophic osteoarthropathy.[93] In cases in which primary therapy is not possible, several symptomatic treatment modalities are suggested, with various degree of success.[4]

NSAIDs may be helpful for the painful osteoarthropathy in controlling the symptoms. In 2006, a case study published by Kozak et al raised the possibility that cyclo-oxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) could have a role in hypertrophic osteoarthropathy pathogenesis. COX-2 is an enzyme that is involved in the formation of prostaglandins, which are critical mediators of many physiologic and pathologic processes. He described a case of hypertrophic osteoarthropathy in a 65-year-old woman with recurrent non-small cell lung cancer and adrenal metastasis who had clinical improvement with rofecoxib (a COX-2 inhibitor). Finally, the measured levels of urinary prostaglandin E (PGE) in these patients correlated with their pain level.[4]

Aside from rofecoxib, other NSAIDs including ketorolac and indomethacin have also been reported in various case series to be effective at relieving hypertrophic osteoarthropathy pain symptoms. In humans, PGE has been found to induce periostitis and overt hypertrophic osteoarthropathy symptoms. Letts et al reported 5 cases of infants developing limp pain and swelling in association with periostitis after chronic infusion of PGE for congenital duct-dependent heart disease. In these cases, periostitis gradually improved once PGE was discontinued. Although involvement of PGE in the pathogenesis of hypertrophic osteoarthropathy is still unclear, successful use of NSAIDs to relieve hypertrophic osteoarthropathy pain symptoms warrants further investigation.[4]

Given the evidence supporting a role of VEGF in hypertrophic osteoarthropathy and the pathogenesis theory of pulmonary shunting of vascular growth factors, a logical proposed treatment involves the use of VEGF inhibitor agents. According to Atkinson et al, VEGF may partly mediate clubbing by providing a persistent positive autocrine and paracrine loop to drive cellular and stromal changes including angiogenesis resulting in increased microvessel density, new bone formation, and edema.

Furthermore, both VEGF plasma levels and tissue expression have been reported in almost all of the medical diseases associated with HOA and has been found to be correlated with disease activity. This discovery supports the use of agents with VEGF inhibition in the treatment of HOA. Recent clinical trials have showed that a specific anti-VEGF antibody, bevacizumab, combined with standard first-line chemotherapy provide a statistically and clinically significant survival advantage and anti-tumor efficacy in non-small cell lung cancer.

Thus, bevacizumab may be investigated for use in alleviating pain symptoms in patients with non-small cell lung cancer with secondary hypertrophic osteoarthropathy. As anti-VEGF monoclonal antibodies (eg, bevacizumab) and VEGF pathway inhibitors (several drugs in different phases of clinical trials) become more frequently used in the clinical practice of various cancers, more knowledge about the pathogenesis of hypertrophic osteoarthropathy may be revealed in the near future.[94]

Another promising treatment outcome for hypertrophic osteoarthropathy has been reported with octreotide. The first case report was in 1997 when Johnson et al treated a patient with hypertrophic osteoarthropathy secondary to squamous cell carcinoma with 200 μg of subcutaneous octreotide daily resulting in complete relief of pain. Perhaps, the success of this treatment is due to the similarities of hypertrophic osteoarthropathy to acromegaly. Octreotide as a somatostatin analog has a well-established role in controlling the growth and secretions from pituitary adenomas, particularly in acromegaly and neuroendocrine tumors. Of note, octreotide also has a nonopioid analgesic effect by intrathecal infusion, which has been reported in an uncontrolled series of 6 patients and further supported by growing evidence on inhibitory effects of octreotide on nociceptive neurons.

Angel-Moreno Maroto et al also reported complete pain relief with octreotide in a young patient with hypertrophic osteoarthropathy symptoms after having a bypass procedure to treat Fallot tetralogy with pulmonary artery atresia. The pain-relieving efficacy of octreotide for hypertrophic osteoarthropathy may also be due to its inhibitory effect on the production of VEGF and endothelial proliferation.[95, 4]

Bisphosphonates such as zoledronic acid and pamidronate are also effective for pain relief in hypertrophic osteoarthropathy.[96, 97] Generally, these nitrogen-containing bisphosphonates promote osteoclast apoptosis by inhibiting the activity of farnesyl pyrophosphate synthase. Their mechanisms also involve inhibiting osteocyte apoptosis and targeting monocytes/macrophages. In addition, bisphosphonates may also have antitumor, anti-inflammatory, anti-angiogenic effects and reduce VEGF in patients with metastatic solid tumors.[76]

In 1997, Speden et al reported 3 cases of hypertrophic osteoarthropathy in bronchogenic carcinoma that responded to the use of pamidronate with pain reduction in all 3 cases along with reduced radiolabel uptake in 2 of those cases. The beneficial effect of pamidronate in alleviating hypertrophic osteoarthropathy symptoms was replicated in 2 additional case reports of hypertrophic osteoarthropathy in metastatic breast carcinoma and in hypertrophic osteoarthropathy complicating cystic fibrosis.[4] In 2004, Amital et al also described a case of hypertrophic osteoarthropathy in a 50 year-old woman with cyanotic congenital heart disease, who responded to a single intravenous infusion of pamidronate 60 mg, leading to resolution of her limb pain.

Bisphosphonates, notably pamidronate, have been used to treat hypertrophic osteoarthropathy associated pain. However, the data on zoledronic acid (ZA), a more potent bisphosphonate with demonstrated 40-fold to 850-fold greater potency than pamidronate, in managing hypertrophic osteoarthropathy–associated pain is scarce.[76] In 2008, King et al reported a case of hypertrophic osteoarthropathy–related limb pain that resulted from bronchogenic carcinoma and completely resolved following a single intravenous infusion of ZA (4 mg over 15 min). In 2012 Sonthalia et al reported painful hypertrophic osteoarthropathy associated with pulmonary metastasis secondary to nasopharyngeal carcinoma treated with 4 mg of ZA, which resulted in complete resolution of the pain and significant reduction in the swelling.[98]

Thompson and coworkers reported another case of hypertrophic osteoarthropathy associated with metastatic melanoma and the hypertrophic osteoarthropathy–associated pain was largely controlled by ZA and concomitant chemotherapy. Approximately 14 cases of hypertrophic osteoarthropathy were treated with bisphosphonates in the medical literature, with a case series containing 3 cases. Among the 14 patients, 10 were successfully treated with pamidronate, 3 with ZA, and 1 with risedronate.[99, 98]

Based on the above, ZA may be even more efficacious and longer lasting than pamidronate for management of the bone and joint pain associated with hypertrophic osteoarthropathy, irrespective of the underlying disorders.[76] The authors supported the theory that VEGF may play a role in the development of hypertrophic osteoarthropathy and noted that although the inhibitory effects of bisphosphonates on bone metabolism may be responsible for its benefits in hypertrophic osteoarthropathy, both pamidronate and ZAs have been shown to decrease levels of plasma VEGF in patients with cancer. Current use of bisphosphonates to treat hypertrophic osteoarthropathy–associated musculoskeletal pain is off-label rather than approved by the US Food and Drug Administration.[76]

An orally active selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) provided clinical antitumor activity in a case report in Tokyo[100] to induce disappearance of periostitis in a case of hypertrophic osteoarthropathy with advanced lung adenocarcinoma.[4]

Reduction of the serum estrogen level or tissue sensitivity to circulating sex steroids might become a therapeutic strategy for hypertrophic osteoarthropathy. Tamoxifen has been reported to improve arthralgia, sweating of hands, and gynecomastia.

TNF-alpha is an inflammatory cytokine found in high levels in hypertrophic osteoarthropathy and it is involved on the production of other inflammatory mediators, which increases osteoclastogenesis (increasing RANKL expression). Infliximab is a monoclonal antibody that binds to TNF preventing its biologic action. A case report has been defined showing improvement of hypertrophic osteoarthropathy symptoms with infliximab. The good response to the TNF-blocking agent in hypertrophic osteoarthropathy suggests that TNF-alpha can be involved in the pathogenesis of periostitis and arthritis in this condition.[41]

Reports described symptomatic relief following vagotomy, but this is not currently used. Along the same line, another neurogenic therapy for hypertrophic osteoarthropathy was proposed in 1976 by Readon et al. They reported fall in the thermographic index along with subjective improvement on combined adrenergic blockade with propranolol and phenoxybenzamine.[4]

Surgical Care

Hypertrophic osteoarthropathy improves and in many cases resolves with resection and/or treatment of the primary tumor. As early as 1976, Atkinson et al reported that chemotherapy treatment of primary malignancy, Hodgkin lymphoma, also leads to complete resolution of hypertrophic osteoarthropathy symptoms. By 1991 and 1992, 2 reported cases of resolved hypertrophic osteoarthropathy following surgical resection of lung tumor were noted. Similarly in 2009, Poanta et al reported complete resolution of hypertrophic osteoarthropathy symptoms following pneumonectomy for primary spinocellular lung cancer. Other treatment modalities of primary causes leading to alleviation of hypertrophic osteoarthropathy symptoms include cytoreduction of tumor by radiofrequency ablation, antibiotics treating recurrent infections in cystic fibrosis, and lung transplantation for cystic fibrosis.[4]

In most lung cancer patients, digital clubbing resolves after effective surgical treatment of the tumor, as can occur in patients with other conditions.[94] Joint and bone pains also resolve quickly after tumor resection, which confirms its paraneoplastic nature.[101]

Outside of primary pulmonary processes, treatment of primary liver condition, heart disease, and esophageal tumors have also been reported to alleviate symptoms of hypertrophic osteoarthropathy. In 1987, Huaux et al reported the first case of liver graft alleviating symptoms of hypertrophic osteoarthropathy associated with end-stage cholestatic cirrhosis related to non-Wilsonian copper overload. Since then, full liver transplantation has also led to resolution of hepatic hypertrophic osteoarthropathy.[4]

Correction of cyanotic heart malformation has also been found to be effective in relieving hypertrophic osteoarthropathy symptoms. In 1982, Frand et al reported two cases of hypertrophic osteoarthropathy–associated cyanotic heart disease corrected by surgery leading to complete resolution of hypertrophic osteoarthropathy symptoms both clinically and radiologically.

Finally, multiple case reports describe patients with hypertrophic osteoarthropathy secondary to esophageal leiomyoma or esophageal squamous cell carcinoma whose hypertrophic osteoarthropathy symptoms resolved with total esophagectomy. Pallecaros et al also reported that total esophagogastrectomy of a patient with crippling hypertrophic osteoarthropathy secondary to an inflammatory fibroid polyp led to resolution of pain. However, the author noted that vagotomy unavoidable during esophagogastrectomy, may have led to the resolution of the patient's hypertrophic osteoarthropathy.

In patients with secondary hypertrophic osteoarthropathy, tumor resection results in spontaneous improvement within 2-4 weeks. In fact, hypertrophic osteoarthropathy may disappear completely by 3-6 months.[39] Thus, in cases where the primary cause can be treated, symptoms of hypertrophic osteoarthropathy most likely improves or resolves. The challenge lies in symptomatic treatment of hypertrophic osteoarthropathy when the primary cause cannot be eliminated.[4]

In patients with primary hypertrophic osteoarthropathy, plastic surgery may be necessary to remove excess facial skin. The treatment of pachydermia is usually centered on improving the cosmetic appearance through plastic surgery. Surgical management of pachydermia includes bilateral blepharoplasties, tarsal wedge resections, excision of skin furrows, and facial rhytidectomy and scalp-reduction techniques.[55] More recently, forehead lifting and direct excision of the dermal folds have been described. A reported case described an approach using endotines in combination with mask subperiosteal and lateral SMASectomy facelifts.

Patients with the rare condition of PDP with secondary ptosis and floppy eyelid was successfully treated with a combination of levator advancement and an upper eyelid tarsal strip.[65]

In the 1950s, thoracic surgeon Dr. Geoffrey Flavell discovered that unilateral vagotomy on the side of the lung cancer lead to symptomatic relief of hypertrophic osteoarthropathy symptoms in some severe cases. Flavell observed that patients with failed dissection, inoperable tumor, or disseminated disease had complete resolution of pain with dissection of the vagus nerve.

In 1962 and 1964, Dr. Magdi Yacoub further justified Dr. Flavell’s hypothesis by performing vagotomy on 2 patients with severe hypertrophic osteoarthropathy, effectively relieving their pain symptoms. It should be noted that these patients had both physical and radiological regression of symptoms, negating the placebo effect. Despite varying success with vagotomy, the vagal mechanism has largely been deemed implausible given that it does not fit with physiological mechanisms accepted in current practices.

However, Ooi et al revived the old vagus nerve hypothesis in their report of a 50-year-old woman with disabling hypertrophic osteoarthropathy and inoperable lung cancer who experienced effective pain relief after video-assisted thoracoscopic truncal vagotomy.[4] Vagotomy improved the associated articular pain and swelling. Surgical correction of digital clubbing has also been reported.

Medication Summary

No drug effectively treats hypertrophic osteoarthropathy (HOA). Drugs such as NSAIDs may be used for symptomatic relief. Beta-blockers may be used for the treatment of hyperhidrosis of primary hypertrophic osteoarthropathy.

Ibuprofen (Motrin, Advil, Ibu, Caldolor)

Clinical Context:  DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. Most common toxicities are nausea, dyspepsia, peptic ulcer disease, and renal and central nervous system toxicity.

Piroxicam (Feldene)

Clinical Context:  For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of COX, which is responsible for prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Anaprox, Aleve)

Clinical Context:  For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of COX, which is responsible for prostaglandin synthesis.

Celecoxib (Celebrex)

Clinical Context:  Inhibits primarily COX-2, which is considered an inducible isoenzyme induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek lowest effective dose for each patient.

Diclofenac (Voltaren XR, Cataflam, Cambia)

Clinical Context:  This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. The main mechanism of action is inhibition of COX activity and prostaglandin synthesis. These agents may also have other mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. NSAIDs such as ibuprofen, naproxen, indomethacin, piroxicam, diclofenac, and others are reasonable alternatives.

Propranolol (Inderal LA, InnoPran XL)

Clinical Context:  Opposes multisystemic effects of excessive adrenergic tone.

Class Summary

Beta-blockers are useful for treating hyperhidrosis, which may occur in primary hypertrophic osteoarthropathy.

Further Inpatient Care

Hypertrophic osteoarthropathy (HOA) itself does not require inpatient care; however, inpatient care may be required for associated conditions.

Further Outpatient Care

With specific curative treatment for the associated conditions, hypertrophic osteoarthropathy may remit with only analgesic and anti-inflammatory supportive treatment. Similarly, the symptomatic recurrences of hypertrophic osteoarthropathy in persons with cystic fibrosis are usually associated with pulmonary superinfections and can be controlled and prevented with appropriate curative or prophylactic antibiotic therapy. A re-emergence of symptoms often heralds disease relapse and may precede symptoms from the primary tumour.

Inpatient & Outpatient Medications

Any of the classic NSAIDs or the newer COX-2 inhibitors can be used at their usual dose as needed. These drugs do not influence the evolution of hypertrophic osteoarthropathy, but they are useful to control symptoms. Other analgesic medications (eg, acetaminophen, opioid analgesics) may be used.

Complications

The only complication of hypertrophic osteoarthropathy is secondary osteoarthritis observed in patients with long-standing hypertrophic osteoarthropathy.

Prognosis

At times, hypertrophic osteoarthropathy may be an ominous syndrome, but it does not add significantly to the mortality or morbidity of the associated diseases.

Author

Mehwish Amir Khan, MD, Fellow in Rheumatology, Louisiana State University Health Science Center at Shreveport

Disclosure: Nothing to disclose.

Coauthor(s)

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport

Disclosure: Nothing to disclose.

Specialty Editors

Bryan L Martin, DO, Associate Dean for Graduate Medical Education, Designated Institutional Official, Associate Medical Director, Director, Allergy Immunology Program, Professor of Medicine and Pediatrics, Ohio State University College of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD, Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Disclosure: AbbVie Honoraria Speaking and teaching; Genentech Honoraria Speaking and teaching; GSK Honoraria Speaking and teaching; Janssen Consulting fee Consulting

Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Mohammed Mubashir Ahmed, MD Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine

Mohammed Mubashir Ahmed, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Federation for Medical Research

Disclosure: Nothing to disclose.

Henri Andre Menard, MD, FRCPC Professor of Medicine, Director of Rheumatology, Department of Medicine, Division of Rheumatology, McGill University Health Center (MUHC) and McGill University Faculty of Medicine; Director, The McGill Arthritis Center; Senior Physician, Shriner's Hospital for Crippled Children, Montreal; Leader, MSK Research Axis, MUHC Research Institute

Henri Andre Menard, MD, FRCPC is a member of the following medical societies: American College of Rheumatology, Canadian Medical Association, Canadian Rheumatology Association, and Quebec Medical Association

Disclosure: Nothing to disclose.

Fahd Saeed, MD Rheumatology Fellow, Louisiana State University Health Sciences Center, Shreveport

Disclosure: Nothing to disclose.

References

  1. Fauci AS et al, eds. Harrison's Principles of Internal Medicine. New York, NY: McGraw-Hill Medical; 2008.
  2. Martínez-Lavín M, Matucci-Cerinic M, Jajic I, Pineda C. Hypertrophic osteoarthropathy: consensus on its definition, classification, assessment and diagnostic criteria. J Rheumatol. Aug 1993;20(8):1386-7. [View Abstract]
  3. Hippocrene Books. Hippocrates: Prognostic: Regimen in Acute Diseases, Sacred Disease, Art, Breaths, Law, Decorum, Physician, Dentition (Loeb Classical Library). Vol 1. London, UK: Harvard University Press; 1849.
  4. Nguyen S, Hojjati M. Review of current therapies for secondary hypertrophic pulmonary osteoarthropathy. Clin Rheumatol. Jan 2011;30(1):7-13. [View Abstract]
  5. Manger B, Lindner A, Manger K, Wacker J, Schett G. [Hypertrophic osteoarthropathy. Bamberger-Marie disease]. Z Rheumatol. Sep 2011;70(7):554-60. [View Abstract]
  6. Touraine A, Solente G, Gole L. Un syndrome osteodermopathique: La pachydermie plicaturee avec pachyperiostose des extremites. Presse Med. 1935;43:1820-4.
  7. Karnan S, Krishnamoorthy V, Ethiraj P, Sathyanathan BP. Touraine-Solente-Gole syndrome: The complete form needs to be recognized. Indian J Nucl Med. Jul 2012;27(3):201-4. [View Abstract]
  8. Martinez-Lavin M, Vargas A, Rivera-Vinas M. Hypertrophic osteoarthropathy: a palindrome with a pathogenic connotation. Curr Opin Rheumatol. Jan 2008;20(1):88-91. [View Abstract]
  9. Narayanan S, Mohamed Gani VM, Sundararaju V. Primary hypertrophic osteoarthropathy with hypertrophic gastropathy. J Clin Rheumatol. Jun 2010;16(4):190-2. [View Abstract]
  10. Toovey OT, Eisenhauer HJ. A new hypothesis on the mechanism of digital clubbing secondary to pulmonary pathologies. Med Hypotheses. Dec 2010;75(6):511-3. [View Abstract]
  11. Padula SJ, Broketa G, Sampieri A, et al. Increased collagen synthesis in skin fibroblasts from patients with primary hypertrophic osteoarthropathy. Evidence for trans-activational regulation of collagen transcription. Arthritis Rheum. Sep 1994;37(9):1386-94. [View Abstract]
  12. Bigler FC. The morphology of clubbing. Am J Pathol. Mar-Apr 1958;34(2):237-61. [View Abstract]
  13. Altman RD, Tenenbaum J. Hypertrophic osteoarthropathy. In: Kelley W, Harris ED Jr, Ruddy S, Sledge C, eds. Textbook of Rheumatology. 5th ed. Philadelphia, Pa: WB Saunders; 1997:1514-20.
  14. Rothschild BM, Rothschild C. Recognition of hypertrophic osteoarthropathy in skeletal remains. J Rheumatol. Nov 1998;25(11):2221-7. [View Abstract]
  15. Rosenthall L, Kirsh J. Observations of radionuclide imaging in hypertrophic pulmonary osteoarthropathy. Radiology. Aug 1976;120(2):359-62. [View Abstract]
  16. Altman RD. Hypertrophic osteoarthropathy. In: McCarty JD, Koopman WJ, eds. Arthritis and Allied Conditions. 12th ed. Philadelphia, Pa: Lea & Febiger; 1993:1511-7.
  17. Pineda C, Fonseca C, Martinez-Lavin M. The spectrum of soft tissue and skeletal abnormalities of hypertrophic osteoarthropathy. J Rheumatol. May 1990;17(5):626-32. [View Abstract]
  18. Pineda CJ, Guerra J Jr, Weisman MH, Resnick D, Martinez-Lavin M. The skeletal manifestations of clubbing: a study in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy. Semin Arthritis Rheum. May 1985;14(4):263-73. [View Abstract]
  19. Fam AG, Chin-Sang H, Ramsay CA. Pachydermoperiostosis: scintigraphic, thermographic, plethysmographic, and capillaroscopic observations. Ann Rheum Dis. Feb 1983;42(1):98-102. [View Abstract]
  20. Schumacher HR Jr. Articular manifestations of hypertrophic pulmonary osteoarthropathy in bronchogenic carcinoma. Arthritis Rheum. May-Jun 1976;19(3):629-36. [View Abstract]
  21. Vidal AF, Altman RD, Pardo D, et al. Structural and immunologic changes of synovium of hypertrophic osteoarthropathy. Arthritis Rheum. 1977;20:139.
  22. Lauter SA, Vasey FB, Hüttner I, Osterland CK. Pachydermoperiostosis: studies on the synovium. J Rheumatol. Spring 1978;5(1):85-95. [View Abstract]
  23. Kabashima K, Sakabe J, Yoshiki R, Tabata Y, Kohno K, Tokura Y. Involvement of Wnt signaling in dermal fibroblasts. Am J Pathol. Feb 2010;176(2):721-32. [View Abstract]
  24. Alves AP, Holanda Filha JG, Jerônimo FT. [Eyelid ptosis associated with pachydermoperiostosis: case report]. Arq Bras Oftalmol. May-Jun 2005;68(3):401-4. [View Abstract]
  25. Kumar S, Sidhu S, Mahajan BB. Touraine-soulente-golé syndrome: a rare case report and review of the literature. Ann Dermatol. Aug 2013;25(3):352-5. [View Abstract]
  26. Martínez-Lavín M. Digital clubbing and hypertrophic osteoarthropathy: a unifying hypothesis. J Rheumatol. Feb 1987;14(1):6-8. [View Abstract]
  27. Ginsburg J, Brown JB. Increased oestrogen excretion in hypertrophic pulmonary osteoarthropathy. Lancet. Dec 9 1961;2(7215):1274-6. [View Abstract]
  28. Matucci-Cerinic M, Martinez-Lavin M, Rojo F, Fonseca C, Kahaleh BM. von Willebrand factor antigen in hypertrophic osteoarthropathy. J Rheumatol. May 1992;19(5):765-7. [View Abstract]
  29. Martinez-Lavin M. Hypertrophic osteoarthropathy. Curr Opin Rheumatol. Jan 1997;9(1):83-6. [View Abstract]
  30. McGuire MM, Demehri S, Kim HB, Kamin D. Hypertrophic osteoarthropathy in intestinal transplant recipients. J Pediatr Surg. Nov 2010;45(11):e19-22. [View Abstract]
  31. Vazquez-Abad D, Martinez-Lavin M. Macrothrombocytes in the peripheral circulation of patients with cardiogenic hypertrophic osteoarthropathy. Clin Exp Rheumatol. Jan-Feb 1991;9(1):59-62. [View Abstract]
  32. Wiedermann CJ, Kob M, Benvenuti S, et al. Digital clubbing in primary intestinal lymphangiectasia: a case report. Wien Med Wochenschr. Aug 2010;160(15-16):431-6. [View Abstract]
  33. Shin KC, Chung WJ, Lee KY, et al. Pachydermoperiostosis accompanied by heart failure. J Cardiovasc Ultrasound. Dec 2009;17(4):135-7. [View Abstract]
  34. Miller RE, Illing RO, Whelan JS. Lung carcinoma with hypertrophic osteoarthropathy in a teenager. Rare Tumors. Mar 30 2011;3(1):e8. [View Abstract]
  35. Arikan S, Sen I, Bahceci M, Tuzcu A, Ayli M. An interesting case of pachydermoperiostosis with idiopathic myelofibrosis associated with monosomy 22. Int J Dermatol. Aug 2009;48(8):882-5. [View Abstract]
  36. Kozak KR, Milne GL, Bentzen SM, Yock TI. Elevation of prostaglandin E2 in lung cancer patients with digital clubbing. J Thorac Oncol. Dec 2012;7(12):1877-8. [View Abstract]
  37. Yacoub MH. Cervical Vagotomy for Pulmonary Osteoarthropathy. Br J Dis Chest. Jan 1965;59:28-31. [View Abstract]
  38. Bazar KA, Yun AJ, Lee PY. Hypertrophic osteoarthropathy may be a marker of underlying sympathetic bias. Med Hypotheses. 2004;63(2):357-61. [View Abstract]
  39. Hara Y, Matsuura Y, Takiguchi H, et al. [Reversal of pulmonary hypertrophic osteoarthropathy in surgically treated lung cancer]. Nihon Kokyuki Gakkai Zasshi. Dec 2010;48(12):966-71. [View Abstract]
  40. Toovey OT, Eisenhauer HJ. A new hypothesis on the mechanism of digital clubbing secondary to pulmonary pathologies. Med Hypotheses. Dec 2010;75(6):511-3. [View Abstract]
  41. da Costa FV, de Magalhaes Souza Fialho SC, et al. Infliximab treatment in pachydermoperiostosis: a rare disease without an effective therapeutic option. J Clin Rheumatol. Jun 2010;16(4):183-4. [View Abstract]
  42. Sasaki T, Niizeki H, Shimizu A, et al. Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. J Dermatol Sci. Oct 2012;68(1):36-44. [View Abstract]
  43. Zhang Z, He JW, Fu WZ, Zhang CQ, Zhang ZL. Two novel mutations in the SLCO2A1 gene in a Chinese patient with primary hypertrophic osteoarthropathy. Gene. Jan 25 2014;534(2):421-3. [View Abstract]
  44. Cheng R, Li M, Guo Y, Yao Y, Gao C, Yao Z. Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy. Eur J Dermatol. Sep-Oct 2013;23(5):636-9. [View Abstract]
  45. Martinez-Lavin M, Pineda C, Valdez T, et al. Primary hypertrophic osteoarthropathy. Semin Arthritis Rheum. Feb 1988;17(3):156-62. [View Abstract]
  46. Castori M, Sinibaldi L, Mingarelli R, Lachman RS, Rimoin DL, Dallapiccola B. Pachydermoperiostosis: an update. Clin Genet. Dec 2005;68(6):477-86. [View Abstract]
  47. Swartz MH. Textbook of Physical Diagnosis: History and Examination. 2nd ed. Philadelphia, Pa: WB Saunders; 1994:76-8.
  48. Branwood AW. Clubbing of the fingers. Edinb Med J. Mar 1949;56(3):105-20. [View Abstract]
  49. Kaditis AG, Nelson AM, Driscoll DJ. Takayasu's arteritis presenting with unilateral digital clubbing. J Rheumatol. Dec 1995;22(12):2346-8. [View Abstract]
  50. Vazquez-Abad D, Pineda C, Martinez-Lavin M. Digital clubbing: a numerical assessment of the deformity. J Rheumatol. Apr 1989;16(4):518-20. [View Abstract]
  51. Pallares-Sanmartin A, Leiro-Fernandez V, Cebreiro TL, Botana-Rial M, Fernandez-Villar A. Validity and reliability of the Schamroth sign for the diagnosis of clubbing. JAMA. Jul 14 2010;304(2):159-61. [View Abstract]
  52. Martinez-Lavin M. Hypertrophic osteoarthropathy. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. London, UK: Mosby; 1998:8.46.1-4.
  53. Resnick D. Enostosis, hyperostosis, and periostitis. In: Resnick D, Kransdorf MJ, eds. Bone and Joint Imaging. 3rd ed. Philadelphia, Pa: Elsevier Saunders; 2005:1433-35.
  54. Poormoghim H, Hosseynian A, Javadi A. Primary hypertrophic osteoarthropathy. Rheumatol Int. Mar 2012;32(3):607-10. [View Abstract]
  55. Ghosn S, Uthman I, Dahdah M, Kibbi AG, Rubeiz N. Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A. J Am Acad Dermatol. Dec 2010;63(6):1036-41. [View Abstract]
  56. Rastogi R, Suma GN, Prakash R, Rastogi UC, Bhargava S, Rastogi V. Pachydermoperiostosis or primary hypertrophic osteoarthropathy: A rare clinicoradiologic case. Indian J Radiol Imaging. Apr-Jun 2009;19(2):123-6. [View Abstract]
  57. Girisha KM, Mandal K, Phadke SR. Milder form of pachydermoperiostosis: a report of four cases. Clin Dysmorphol. Apr 2009;18(2):85-9. [View Abstract]
  58. Diggle CP, Carr IM, Zitt E, et al. Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. Rheumatology (Oxford). Jun 2010;49(6):1056-62. [View Abstract]
  59. Neufeld KR, Price K, Woodward JA. Massive eyelid thickening in pachydermoperiostosis with myelofibrosis. Ophthal Plast Reconstr Surg. Jul-Aug 2009;25(4):316-8. [View Abstract]
  60. Poanta L, Parasca I, Fazakas E, Porojan M, Pais R, Boian L. Paraneoplastic hypertrophic osteoarthropathy: evaluation at 25 years after pneumectomy. Pol Arch Med Wewn. Sep 2009;119(9):603-6. [View Abstract]
  61. Martinez-Ferrer A, Peris P, Alos L, Morales-Ruiz M, Guanabens N. Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report. Clin Rheumatol. Oct 2009;28(10):1229-33. [View Abstract]
  62. Sinibaldi L, Harifi G, Bottillo I, et al. A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy. Clin Exp Rheumatol. Mar-Apr 2010;28(2):153-7. [View Abstract]
  63. Kumar U, Bhatt SP, Misra A. Unusual associations of pachydermoperiostosis: a case report. Indian J Med Sci. Feb 2008;62(2):65-8. [View Abstract]
  64. Nakajima M, Hirano T, Itoh K, Uchino M. Atherothrombotic brain infarction in a patient with pachydermoperiostosis. Mod Rheumatol. 2008;18(3):281-4. [View Abstract]
  65. Bleyen I, White VA, Dolman PJ. Floppy eyelid syndrome and ptosis in a patient with pachydermoperiostosis. Ophthal Plast Reconstr Surg. Jul-Aug 2010;26(4):293-5. [View Abstract]
  66. Bergmann C, Wobser M, Morbach H, et al. Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD/HPGD loss-of-function mutations. Exp Dermatol. Jun 2011;20(6):531-3. [View Abstract]
  67. Saghafi M, Azarian A, Nohesara N. Primary hypertrophic osteoarthropathy with myelofibrosis. Rheumatol Int. Apr 2008;28(6):597-600. [View Abstract]
  68. Chen X, Zou CC, Dong GP, Liang L, Zhao ZY. Cranio-osteoarthropathy: a rare variant of hypertrophic osteoarthropathy. Ir J Med Sci. Jun 2012;181(2):257-61. [View Abstract]
  69. Vogl A, Blumenfeld S, Gutner LB. Diagnostic significance of pulmonary hypertrophic osteoarthropathy. Am J Med. Jan 1955;18(1):51-65. [View Abstract]
  70. Ito T, Goto K, Yoh K, et al. Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. J Thorac Oncol. Jul 2010;5(7):976-80. [View Abstract]
  71. Izumi M, Takayama K, Yabuuchi H, Abe K, Nakanishi Y. Incidence of hypertrophic pulmonary osteoarthropathy associated with primary lung cancer. Respirology. Jul 2010;15(5):809-12. [View Abstract]
  72. Moralidis E, Gerasimou G, Theodoridou A, Hilidis I, Mylonaki E, Gotzamani-Psarrakou A. Hypertrophic osteoarthropathy manifested with isolated calcaneal periostitis in bone scintigraphy. Ann Nucl Med. May 2010;24(4):313-7. [View Abstract]
  73. Yao Q, Altman RD, Brahn E. Periostitis and hypertrophic pulmonary osteoarthropathy: report of 2 cases and review of the literature. Semin Arthritis Rheum. Jun 2009;38(6):458-66. [View Abstract]
  74. Izumi M, Takayama K, Yabuuchi H, Abe K, Nakanishi Y. Incidence of hypertrophic pulmonary osteoarthropathy associated with primary lung cancer. Respirology. Jul 2010;15(5):809-12. [View Abstract]
  75. Aissa I, Messadi A, Boudaya S, El Mezni F, Kilani T, Ghedira H. [Hypertrophic osteoarthropathy associated with pulmonary tuberculosis]. Rev Pneumol Clin. Apr 2011;67(2):101-4. [View Abstract]
  76. Jayakar BA, Abelson AG, Yao Q. Treatment of hypertrophic osteoarthropathy with zoledronic acid: case report and review of the literature. Semin Arthritis Rheum. Oct 2011;41(2):291-6. [View Abstract]
  77. McGuire MM, Demehri S, Kim HB, Kamin D. Hypertrophic osteoarthropathy in intestinal transplant recipients. J Pediatr Surg. Nov 2010;45(11):e19-22. [View Abstract]
  78. Suppiah R, McQueen F. Hypertrophic osteoarthropathy associated with a left ventricular tumour. Rheumatology (Oxford). Sep 2008;47(9):1277. [View Abstract]
  79. Murphy C, Syahizul Nuhairy Mohd Sharial M, Brennan N, Lee G, Moylan E, O' Reilly S. Hypertrophic osteoarthropathy leading to the diagnosis of primitive neuroectodermal tumour (PNET). Acta Oncol. 2008;47(5):983-6. [View Abstract]
  80. Chen L, Mulligan ME. Medication-induced periostitis in lung transplant patients: periostitis deformans revisited. Skeletal Radiol. Feb 2011;40(2):143-8. [View Abstract]
  81. Ayub A, Kenney CV, McKiernan FE. Multifocal nodular periostitis associated with prolonged voriconazole therapy in a lung transplant recipient. J Clin Rheumatol. Mar 2011;17(2):73-5. [View Abstract]
  82. Pracht M, Le Roux C, Kerjouan M, Boucher E, Audrain O, Raoul JL. Clubbing and hypertrophic osteoarthropathy in two patients taking long-term bevacizumab for metastatic colorectal cancer. J Gastrointest Cancer. Sep 2011;42(3):176-8. [View Abstract]
  83. Ede K, McCurdy D, Garcia-Lloret M. Hypertrophic osteoarthropathy in the hepatopulmonary syndrome. J Clin Rheumatol. Aug 2008;14(4):230-3. [View Abstract]
  84. Shah NN, Price MR, Loeb DM. Cardiac metastasis and hypertrophic osteoarthropathy in recurrent infantile fibrosarcoma. Pediatr Blood Cancer. Jul 15 2012;59(1):179-81. [View Abstract]
  85. Utine EG, Yalcin B, Karnak I, et al. Childhood intrathoracic Hodgkin lymphoma with hypertrophic pulmonary osteoarthropathy: a case report and review of the literature. Eur J Pediatr. Apr 2008;167(4):419-23. [View Abstract]
  86. Mauricio O, Francis L, Athar U, Shah C, Chaudhary M, Gajra A. Hypertrophic osteoarthropathy masquerading as lower extremity cellulitis and response to bisphosphonates. J Thorac Oncol. Feb 2009;4(2):260-2. [View Abstract]
  87. Cathebras P, Gaultier JB, Charmion S, Guichard I. Hypertrophic osteoarthropathy of the lower limbs. J Rheumatol. Apr 2011;38(4):775-6. [View Abstract]
  88. Moule B, Grant MC, Boyle IT, May H. Thyroid acropachy. Clin Radiol. Jul 1970;21(3):329-33. [View Abstract]
  89. Kinsella RA Jr, Back DK. Thyroid acropachy. Med Clin North Am. Mar 1968;52(2):393-8. [View Abstract]
  90. Diggle CP, Carr IM, Zitt E, et al. Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy. Rheumatology (Oxford). Jun 2010;49(6):1056-62. [View Abstract]
  91. Moreira AL, Porto NS, Moreira JS, Ulbrich-Kulczynski JM, Irion KL. Clubbed fingers: radiological evaluation of the nail bed thickness. Clin Anat. May 2008;21(4):314-8. [View Abstract]
  92. Jajic I, Pecina M, Krstulovic B, Kovacevic D, Pavicic F, Spaventi S. Primary hypertrophic osteoarthropathy (PHO) and changes in the joints. Clinical, X-ray, scintigraphic, arteriographic and histologic examination of 19 patients. Scand J Rheumatol. 1980;9(2):89-96. [View Abstract]
  93. Marino WD, Harigopalan JA, Bangar M. A 49-year-old smoker with a lung mass and diffuse bone pain. Chest. Feb 2011;139(2):460-3. [View Abstract]
  94. Cerny J, Licho R, Simkin P, Walsh WV. Hypertrophic pulmonary osteoarthropathy disappearance despite lung cancer relapse. South Med J. Sep 2008;101(9):970-1. [View Abstract]
  95. Angel-Moreno Maroto A, Martinez-Quintana E, Suarez-Castellano L, Perez-Arellano JL. Painful hypertrophic osteoarthropathy successfully treated with octreotide. The pathogenetic role of vascular endothelial growth factor (VEGF). Rheumatology (Oxford). Oct 2005;44(10):1326-7. [View Abstract]
  96. Langer CJ. Role of zoledronic acid in the setting of bone metastases from non-small-cell lung cancer. Clin Lung Cancer. Mar 2005;6(5):314-6. [View Abstract]
  97. King MM, Nelson DA. Hypertrophic osteoarthropathy effectively treated with zoledronic acid. Clin Lung Cancer. May 2008;9(3):179-82. [View Abstract]
  98. Sonthalia N, Mukherjee K, Saha A, Talukdar A. Treatment of hypertrophic osteoarthropathy in the case of pulmonary metastasis secondary-to-nasopharyngeal carcinoma with zoledronic acid: an enlightening experience. BMJ Case Rep. Nov 11 2012;2012:[View Abstract]
  99. Bernardo SG, Emer JJ, Burnett ME, Gordon M. Hypertrophic osteoarthropathy presenting as unilateral cellulitis with successful treatment using pamidronate disodium. J Clin Aesthet Dermatol. Sep 2012;5(9):37-46. [View Abstract]
  100. Hayashi M, Sekikawa A, Saijo A, Takada W, Yamawaki I, Ohkawa S. Successful treatment of hypertrophic osteoarthropathy by gefitinib in a case with lung adenocarcinoma. Anticancer Res. May-Jun 2005;25(3c):2435-8. [View Abstract]
  101. Poanta L, Parasca I, Fazakas E, Porojan M, Pais R, Boian L. Paraneoplastic hypertrophic osteoarthropathy: evaluation at 25 years after pneumectomy. Pol Arch Med Wewn. Sep 2009;119(9):603-6. [View Abstract]
  102. Bamberger E. Uber knochenveranderugen bei chronishen lungen und herzkrankheiten. Z Klin Med. 1891;18:193-217.
  103. Ito T, Goto K, Yoh K, et al. Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. J Thorac Oncol. Jul 2010;5(7):976-80. [View Abstract]
  104. Marie P. De l'osteo-arthropathie hypertrophiante pneumique. Rev Med. 1890;4:146-8.

Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This is symmetrical clubbing; it involves all the fingers.

Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints (eg, knees, ankles, wrists).

In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition.

Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This is symmetrical clubbing; it involves all the fingers.

Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints (eg, knees, ankles, wrists).

For hypertrophic osteoarthropathy diagnosis, radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. These findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies.

Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This is symmetrical clubbing; it involves all the fingers.

Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints (eg, knees, ankles, wrists).

For hypertrophic osteoarthropathy diagnosis, radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. These findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies.

In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition.