Hypertrophic Osteoarthropathy

The clinical triad of digital clubbing, arthralgias, and ossifying periostitis that characterizes hypertrophic osteoarthropathy (HOA) has been recognized since the late 1800s and was previously known as hypertrophic pulmonary osteoarthropathy (HPOA). Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers. ^[4]

Observations made in modern times by Eugen von Bamberger (1889) ^[5]  and Pierre Marie (1890) ^[6]  led to the term Marie–Bamberger disease. ^[7]  Work by other investigators led to identification of various causes of this digital anomaly, which can be the first manifestation of a severe organic disorder such as chronic pulmonary and cardiac diseases, ^[8]  

Primary hypertrophic osteoarthropathy (PHO; 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 and proposed the following classification ^{[9, 10]} :

• Complete - Pachydermia, digital clubbing, and periostosis
• Incomplete - No pachydermia
• Forme fruste  - Prominent pachydermia with few skeletal manifestations

In some cases, the diagnosis of HOA as primary can be challenged with the development of a disease that is known to be associated with secondary HOA. This may occur as late as 6-20 years after the appearance of HOA. ^{[11, 12]}

The development of hypertrophic osteoarthropathy (HOA) has been linked to several mechanisms, including excessive collagen deposition, endothelial hyperplasia, edema, and new bone formation. ^[13]  It has been hypothesized that these mechanisims are driven by paraneoplastic growth factors, ^[14]  such as prostaglandin E and other cytokines; and neurologic, hormonal, ^[15]  and immune mechanisms. ^{[16, 17]}  All, or at least many, likely contribute to its development in different clinical situations. A popular theory involves the interaction between activated platelets and the endothelium, which is discussed further below. ^{[14, 16, 18]}  Primary and secondary HOA have distinct pathophysiologies despite similar clinical presentations.

Primary HOA involves mutations in the HPGD or SLCO2A1 gene (see Etiology), which code for enzymes involved in prostaglandin metabolism. The mutations result in elevated levels of prostaglandin E2 (PGE2), with decreases in the level of its metabolites. Under normal conditions, PGE2 is degraded into unstable 13, 14-dihydro-15-keto PGE2 and then into stable 13, 14-dihydro-15-keto PGA2, with 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as a key enzyme in the catabolic pathway. ^[19]  Increased PGE2 levels have been shown to stimulate activity of both osteoclasts and osteoblasts, which may contribute to the skeletal manifestations of primary HOA, including periostosis and acro-osteolysis. ^{[20, 21]} The exact effects of PGE2 on the skin are not completely understood.

Kozak et al tested the hypothesis that elevated systemic levels of PGE2 was 2.3-fold higher in patients with clubbing than in patients without clubbing. ^[22] Several other pathophysiologic mechanisms have also been observed in HOA. The most important of these mechanisms involve circulating signaling molecules and growth factors that are normally cleared from the blood by the pulmonary endothelium. ^[23]  

Secondary HOA is most often associated with an underlying pulmonary disease, mainly bronchogenic carcinoma; hence the older term hypertrophic pulmonary osteoarthropathy. HOA has been observed in up to 17% of bronchogenic carcinoma patients. ^[24] Secondary HOA can also be associated with non-pulmonary conditions, including cardiovascular, gastrointestinal, hepatobilliary, and endocrine diseases. ^[24]

Normally, megakaryoctes released from bone marrow into the general circulation travel to the pulmonary microvasculature, where they fragment into platelets. ^[25] If that fails to occur, the platelet precursors can become trapped in the peripheral vasculature, where they release platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), which promote vascularity. ^[26] This has been demonstrated in patients with cyanotic heart diseases, in which large circulating platelets with abnormal, and at times bizarre, morphology have been found. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves. ^{[27, 16]}

Several physiologic and anatomic processes have been defined in which these large particles reach the fingertip capillaries and impact release of growth factors. Megakaryocytes or megakaryocyte fragments have been observed bypassing the lung capillary network (eg, in patients with 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) and forming 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, in chronic inflammatory bowel disease). ^[28]

For the reasons above, cyanotic heart diseases are an excellent model for studying HOA pathogenesis because more than one third of patients with lifelong clubbing secondary to cyanotic heart disease eventually display the full HOA syndrome. ^[29] HOA caused by intrapulmonary shunting of blood becomes 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.

Megakaryocytes or megakaryocyte fragments impacted at distal sites release growth factors that include bradykinin, slow-reacting substance of anaphylaxis, transforming growth factor–β1 (TGF-β1), VEGF, and PDGF stored in the platelet alpha granules. Those 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. ^{[16, 18]}

Increased circulating growth factor levels thus would explain all of the features of HOA. PDGF and VEGF are thought to contribute significantly to the development of HOA. VEGF is a platelet-derived factor whose 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 PDGF and VEGF induce vascular hyperplasia, new bone formation, and edema. ^[30]

In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated levels of von Willebrand factor antigen (vWF:Ag) in persons with primary HOA and those with HOA secondary to cyanotic heart disease. ^[16] vWF:Ag is a surrogate marker of endothelial activation and damage, as shown by the fact that high plasma levels of vWF:Ag are also found in the vasculitides, myocardial infarction, diabetic microangiopathy, and scleroderma. ^[16] Other substances that are found at increased levels in the plasma of patients with HOA and could have a role in disease progression and periosteal proliferation include endothelin-1 and β-thromboglobulin. ^[31]

Thus, a common pathogenetic pathway for HOA possibly involves localized activation of endothelial cells by an abnormal platelet population. Macrothrombocyte and endothelial cell activation can also be present in cases of HOA associated with other disease entities such as liver cirrhosis, in which a prominent intrapulmonary shunting of blood occurs. ^[18]

Stimulation of fibroblasts by PDGF, epidermal growth factor (EGF) and TGF-β along with overexpression of VEGF have also been linked to the extensive myelofibrosis seen in a few cases of pachydermoperiostosis. ^[32]

A second proposed mechanism for the development of HOA 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 HOA, suggesting a role for reflex vagal stimulation. ^[33] Bazaar et al proposed that sympathetic override of the normal protective function of vagal innervation is the basis of HOA. ^[34] 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, kidney failure, and tumor-induced hypoxia. Reversal of those conditions with removal of the associated lung neoplasm or correction of a cyanotic heart malformation suggests that alteration of lung function plays an important role. ^[14]

A third mechanism is the possibility of ectopic production of hormonelike substances (such as 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. Elevated circulating concentrations of VEGF and evidence of tumor production of VEGF have been found in lung cancer. ^[35] Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement. Increased levels of VEGF and IL-6 caused by the genetic mutation of K-ras might play a role in the pathogenesis of HOA with lung cancer. ^[36]

Diverse types of cancers produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is also known to occur in non-neoplastic diseases associated with HOA, such as Graves disease and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy. In HOA related to vascular prosthesis infection, Alonso-Bartolome et al suggested involvement of the humoral pathway giving rise to graft infection–associated HOA syndrome by endotoxin or vasoactive compound activated or released by bacteria adherent to the graft. ^[8]

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. ^[37]

The role of different cytokines and cell receptors, including IL-6 and the osteoprotegerin or RANKL (receptor activator of nuclear factor kappa-Β ligand) 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 HOA is characterized by increased bone resorption, probably mediated by IL-6 and RANKL. ^[38]

The pathogenesis underlying the higher risk of HOA in males, as proposed by Bianchi et al, relates to the high levels of nuclear steroid receptors, increased cytosolic estrogen receptors, and absence of detectable progesterone and androgen cytosolic receptors in HOA. Those suggest increased tissue sensitivity to different circulating sex steroids, which could enhance tissue epidermal growth factor or transforming growth factor alpha production and use. ^[39]

HOA 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 HOA by enhancing dermal fibroblast functions. ^[40] 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) complex 12 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. ^[40]

Various rare associations have been described, including hypertrophic gastropathy, peptic ulcers, gynecomastia, acro-osteolysis of fingers and toes, Crohn disease, atherothrombotic brain infarction, ^[41]  renal amyloid A (AA) amyloidosis, and bone marrow failure due to myelofibrosis. Only six cases of myelofibrosis in primary HOA have been described to date. The development of myelofibrosis makes primary HOA a disease with unfavorable outcome. ^[42]  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. ^[43]

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 without clubbed nails appears to be rare and few cases have been reported.

Clubbed digits

Clubbing is characterized by 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. ^[44] 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. ^[45] Vast numbers of arteriovenous anastomoses may also be seen in the nail bed. ^[46]

Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic. ^[47]  Hypertrophy or bony overgrowth predominates in patients with HOA secondary to lung cancer, whereas acro-osteolysis predominates in patients with HOA secondary to cyanotic congenital heart disease. ^[48] The type of bone remodeling process depends on the age when clubbing develops. ^[47] 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. ^[47]

Periosteum

Periosteal new bone formation is a hallmark of hypertrophic osteoarthropathy. It mostly affects the appendicular skeleton, usually bilaterally and symmetrically along the metadiaphyseal regions of the bones. ^[49]

Neoangiogenesis, edema, and osteoblast proliferation in distal tubular bones lead to subperiosteal new bone formation in HOA. Subperiosteal new bone formation occurs 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 metacarpals, metatarsals, tibia, fibula, radius, ulna, femur, humerus, and clavicle are involved. The tibia is almost invariably involved. ^{[17, 50]} Involvement of the epiphysis distinguishes it from the secondary form, which typically spares the epiphysis.

Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum. ^[17] 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. ^[51]

Synovium

Synovial involvement may occur with subperiosteal changes. ^[17] Thickening of the subsynovial blood vessels and mild lining-layer hyperplasia may occur. ^{[23, 17]} The edematous synovium becomes mildly infiltrated with lymphocytes, plasma cells, and occasional polymorphonuclear leukocytes, but the results of immunohistologic studies are negative. Electron-dense subendothelial deposits are present in vessel walls. ^{[52, 53, 54]} In a study of a patient with primary HOA and chronic arthritis, Lauter et al found multilayered basement laminae around small subsynovial blood vessels consistent with the late stages of vascular injury. ^[54] Synovial fluid is usually noninflammatory with low leukocyte counts and few neutrophils. ^{[52, 54]}

Skin

Skin changes are more evident in primary HOA and are caused by dysregulation of mesenchymal cells. ^[40] Characteristic cutaneous manifestations include pachydermia (thickening of the skin) of the face and the scalp, cutis verticis gyrata, and bilateral ptosis over the eyes resulting in blepharoptosis. ^[55] These changes yield a characteristic leonine or “bulldog” appearance. ^[56]

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

Hypertrophic osteoarthropathy (HOA) may be either primary (hereditary or idiopathic) or secondary to a variety of malignant and nonmalignant conditions. Primary HOA comprises about 3-5% of all cases of hypertrophic osteoarthropathy. ^[57]

Primary hypertrophic osteoarthropathy

Primary HOA is also known as pachydermoperiostosis (PDP). Primary HOA has been linked to mutations in two genes: 15-hydroxyprostaglandin dehydrogenase (HPGD) ^[58] and solute carrier organic anion transporter family, member 2A1 (SLCO2A1). ^[59]  Both autosomal dominant inheritance with incomplete penetrance and recessive inheritance have been reported. ^[2] Hereditary primary HOA consists of three subtypes based on inheritance pattern and genetic mutation ^[60] :

• Primary hypertrophic osteoarthropathy, autosomal recessive 1 (PHOAR1) caused by HPGD mutation
• Primary hypertrophic osteoarthropathy, autosomal recessive 2 (PHOAR2) caused by  SLCO2A1 mutation
• Primary hypertrophic osteoarthropathy, autosomal dominant (PHOAD) caused by  SLCO2A1 mutation

A family history of the disease can be traced in only about 25-38% of primary HOA cases. Familial recurrence of PDP has been reported in 33-100% of pedigrees.

PHOAR1 involves homozygous and compound heterozygous germline mutations in HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase, an NAD+ dependent enzyme that catalyzes prostaglandins. ^[60]  Homozygous HPGD mutations have so far been reported in 10 families; all but one displayed parental consanguinity. Only two of those families were of European origin. The c.175_176delCT frameshift mutation appears to be recurrent and to be the most common HPGD mutation in White families. ^[61]

So far, seven HPGD alterations are known. The allelic spectrum of the HPGD gene includes 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.

Secondary hypertrophic osteoarthropathy

Secondary HOA is also called Pierre Marie-Bamberger syndrome. In adulthood, 90% of generalized hypertrophic osteoarthropathy is associated with an intrathoracic infectious or neoplastic condition. The association with malignancy is relatively common in adults. ^{[62, 63]} HOA may precede the diagnosis of the underlying disease. ^[64]

Conditions underlying secondary hypertrophic osteoarthropathy can be easily separated into malignant and nonmalignant diseases. Paraneoplastic HOA is more common in subjects aged 50–70 years. ^[64]  Among malignancy-related hypertrophic osteoarthropathy, pulmonary malignancies compose 80% of reported 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 HOA. ^[30]  However, in a Japanese study of 1226 patients with lung cancer patients, 54.5% demonstrated abnormally high uptake on bone scintigraphy, suggesting possible HPO, but only 0.8% had clubbed fingers and joint pain and were eventually confirmed as having pulmonary HOA. Of the patients with confirmed lung cancer and HOA, most were males and heavy smokers and had advanced disease. ^[65]  

Lung cancer accounts for almost 20% of isolated digital clubbing and over 60% of HOA in adults. ^[8]  These data suggest that the development of HOA or simple digital clubbing in adults should prompt lung cancer screening, even in the absence of detectable respiratory symptoms. This would allow earlier diagnosis and so permit early treatment, leading to better outcome.

Other malignancies reported in the literature to be associated with HOA include the following ^[8]  :

• Nasopharyngeal cancer
• Mesothelioma
• Renal cell carcinoma
• Esophageal cancer
• Gastric tumor
• Pancreatic cancer
• Breast phyllodes tumor
• Melanoma
• Thymic cancer
• Hodgkin lymphoma

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, chronic obstructive pulmonary disease, pulmonary tuberculosis, ^[66] pulmonary primary intestinal lymphangiectasia (Waldmann disease), pulmonary epithelioid hemangioendothelioma, bronchiectasis, diffuse inflammatory lung disease, pulmonary arteriovenous malformations, and chronic hypoxemia. HOA has been reported in association with chronic rejection of a lung transplant. ^[51] A case report describes HOA in a patient who had undergone bilateral lung transplantation because of severe pulmonary sarcoidosis. ^[67]

Inflammatory bowel disease (Crohn disease and ulcerative colitis), celiac sprue, gastric hypertrophy, laxative abuse, polyposis, intestinal acute cellular rejection, primary intestinal lymphoma, juvenile polyps of the stomach, and gastric adenocarcinoma are associated with HOA. Chronic enteropathy has been reported in patients with primary HOA due to SLCO2A1 mutation. ^[68]

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. ^[8]  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. Hypertrophic osteoarthropathy has been associated with organ transplant in one isolated liver transplant recipient with chronic liver rejection. ^[69] No association with transplant medications has been noted. ^[70]

Congenital cyanotic congenital heart diseases, rheumatic diseases, and left ventricular tumors have been implicated as well. ^[71]

Neurologic causes include primitive neuroectodermal tumors (PNETs). ^[72]

Other causes include chronic infections associated with cystic fibrosis, HIV, ^[70]  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:

• Graves disease
• Thalassemia
• Diverse malignancies
• Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome
• Metastatic phyllodes tumor of breast
• Epithelioid hemangioendothelioma
• Nasopharyngeal carcinoma with lung metastasis
• Thymic carcinoma
• Renal cell carcinoma with lung metastasis
• Osler-Weber-Rendu syndrome
• Deep infections such as vascular graft infection and perianal abscess

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

The 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. ^[73]  In patients with patent ductus arteriosus, pulmonary hypertension causes right-to-left shunting of blood, which may cause HOA of the toes and fingers on the left side. ^{[73, 18]}  Development of hypertrophic osteoarthropathy localized to areas distal to a vascular prosthesis may allow early diagnosis of graft infection. 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. ^[74]  Therefore, unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet. ^[73]

Thomas first described thyroid acropachy in 1933. ^[75]  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. ^[76]  It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid. ^[77]

Medication

Various medications, including prostaglandin, vitamin A, and fluoride, can produce periostitis and bony changes resembling hypertrophic osteoarthropathy. ^[78] An association between senna misuse and finger clubbing (reversible with cessation of senna) has been reported.

Voriconazole has been reported to probably induce periostitis, but no apparent inflammatory arthritis was noted in the case series report. ^[30]  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. ^[78]  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. ^[79]

Hypertrophic osteoarthropathy was also noted in one case after a long-term use of bevacizumab for metastatic colorectal cancer. ^[80]

Pediatric cases

Hypertrophic osteoarthropathy is an uncommon disease in the pediatric age group. ^[30] It is characterized by noninflammatory joint effusions, terminal digit clubbing, and radiographic evidence of periosteal new bone formation affecting the hands, feet, and distal limbs.

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. ^[30] 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.

Case reports have described an association with biliary atresia, including an adolescent patient with a history of liver transplantation at 4 months for biliary atresia who was initially diagnosed with juvenile rheumatoid arthritis. This patient was also found to have hepatopulmonary syndrome. ^[81]

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. ^[30]  A case report has described hypertrophic osteoarthropathy presenting as the first symptom of recurrent infantile fibrosarcoma. ^[82]

The authors did not identify any reported cases of hypertrophic osteoarthropathy associated with lung carcinoma in children or young adults in the literature. ^[30]  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, to date only 34 cases of hypertrophic osteoarthropathy have been reported in pediatric patients with neoplastic diseases. Of those, 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. ^{[83, 82]}

An atypical form of hypertrophic osteoarthropathy has presentation limited to lower extremities. ^[84]

Primary hypertrophic osteoarthropathy (HOA) is a rare condition. The precise incidence of this syndrome is unknown. According to one study, it has an estimated prevalence of 0.16%. ^[85]

No systematic prevalence studies have been performed for secondary HOA, but cases are associated with many illnesses. According to Rassam et al, HOA occurred in about 3% (9 of 280) of consecutive lung cancer cases seen between 1970-1975. Other literature has described higher rates in primary lung cancer, ranging from about 4% to 32%. ^[8]

In a study of consecutive patients with congenital cardiac disease, Martínez-Lavín et al identified HOA in 10 of 32 patients (31%). ^[86] HOA associated with respiratory failure is reported to occur in 2–7% of patients.

HOA affects persons of all races but is more common in African Americans. Primary HOA due to HPGD mutation has no sexual predominance. Primary HOA due toSLCO2A1 mutation has a marked predominance in males, with a male-to-female ratio of 9:1, and males usually show a more severe phenotype. ^[2] Secondary osteoarthropathy has the same sex ratio as the associated illnesses.

 Onset of primary HOA due to HPGD mutation is more common in children. Onset of cases due to SLCO2A1 mutation is more likely during puberty. ^{[60, 87]} Secondary HOA is rarely encountered in children and adolescents; it most commonly affects individuals aged 55-75 years. ^[8]

Primary HOA has a self-limiting course, with progression stopping at the end of adolescence. There is no cure for the skeletal abnormalities. ^[12] The mortality and morbidity of secondary HOA vary with the associated illness. Secondary osteoarthritis may complicate long-standing HOA.

Patients first diagnosed with hypertrophic osteoarthropathy should be reassured regarding its good prognosis as a musculoskeletal condition. That being established, they should be informed of its significance and the need for further investigation to rule out any treatable associated disease. These investigations are guided by results from thorough clinical evaluations, including questions specifically targeting intrathoracic diseases.