Hypertrophic Osteoarthropathy Clinical Presentation

Updated: Jan 13, 2021
  • Author: Vishnuteja Devalla, MD; Chief Editor: Herbert S Diamond, MD  more...
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Presentation

History

The clinical presentation of hypertrophic osteoarthropathy (HOA; pachydermoperiostosis [PDP]) varies according to the rapidity of onset and the evolution of the underlying disease. Primary HOA and slowly progressive secondary HOA are insidious and essentially asymptomatic.

Primary PDP usually begins after puberty. Some changes may start early in childhood. Skin and bone changes become progressively more severe for 5–10 years and then usually remain unchanged throughout life. Sometimes, disease may continue to progress.

Such patients rarely voluntarily report symptoms, because the clubbing and skin manifestations have developed slowly, over many years, and have become part of the patient's body image; the patient usually considers them more or less normal. Instead, these patients initially seek medical help for minor pains in the shoulders or hands, or recurrent swelling of a mechanical nature (effusions) in the knees (hydroarthrosis) or ankles (osteoarthritis), [12] They may be surprised by the physician’s interest in their clubbed fingers.

 Because of autonomic dysfunction (sympathetic hyperactivity), patients may have hyperhidrosis of the palms and soles. [58]  With HOA secondary to neoplastic or inflammatory pulmonary conditions, patients report pain and swelling in joints and long bones. These rheumatic symptoms follow a mechanical diurnal pattern.

This picture can precede the appearance of constitutional signs and symptoms (eg, fatigue, fever, weight loss) or respiratory signs and symptoms (eg, cough, hemoptysis, chest pain, dyspnea) by several months.

In secondary HOA, which occurs predominantly in men aged 30–70 years, the bone changes are the most obvious feature, develop more rapidly, and are often more painful than in primary form. The skin changes are absent or relatively mild. 

Although secondary HOA usually appears after the underlying disease is established, it can precede manifestation of the underlying disorder by more than a year; hence, follow-up of patients is essential.

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Physical

The diagnostic criteria for hypertrophic osteoarthropathy (HOA) include clubbing and periostosis of the tubular bones. [59]  Three incomplete forms of hypertrophic osteoarthropathy are described:

  • Clubbing alone
  • Periostosis without clubbing in the setting of an illness known to be associated with HOA
  • Pachydermia associated with minor manifestations (eg, synovial effusion, seborrhea, hyperhidrosis, hypertrophic gastropathy, acroosteolysis)

The presence of periostitis and limb pain/swelling, even without clubbing, can suffice for a diagnosis of an incomplete form of HOA. For the complete form of HOA, the major diagnostic criteria are the triad of digital clubbing, hypertrophic skin changes (pachydermia), and painful swelling of the limbs (from periostosis of long bones). [54, 7]  Hypertrophy of soft tissues can also be seen, resulting in coarse facial features, cylindrical calves (elephant feet), ptosis of the eyelids, and cutis verticis gyrata or prominent frontal cerebroid wrinkles.

Earliest manifestations of primary HOA include delayed closure of the cranial sutures and patent ductus arteriosus. The most common clinical features of primary HOA include the following:

  • Clubbing (89%)
  • Swelling of periarticular tissue (with 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%)

Clubbing

Clubbing usually progresses through the following 4 phases [18] :

  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 angle (Lovibond angle [60] ) formed by the dorsal surface of the distal phalanx and the nail plate; in healthy fingers, the Lovibond angle is approximately 165°; however, with clubbing the angle 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 skin creases and appearance of longitudinal striation of the nail

Clubbing can be classified into 3 topographical groups [61, 62] :

  • Symmetrical: All the fingers and toes are involved, as depicted in the image below
    Clubbing associated with hypertrophic osteoarthrop 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.
  • Unilateral: The fingers or toes of 1 hand or foot are involved
  • Unidigital: Only 1 finger or toe is involved

Clubbing can also be classified into 3 color groups .

  • Normal skin color: This occurs with insidious onset of mildly symptomatic clubbing, evolving over years, that is usually associated with chronic low-grade inflammatory and infectious diseases or primary .

  • Red skin color: This occurs with recent onset, rapid progression, and fairly severe bone and joint symptoms that are usually associated with malignant diseases or chronic severe infections, such as miliary tuberculosis.

  • Blue skin color: This occurs with chronic clubbing associated with cyanotic cardiopulmonary conditions.

Five clinical signs can be used to describe clubbing.

  • The profile sign: On lateral views, a loss of the normal 165° angle between the nail bed and the cuticle is visible. The hyponychial angle can also be measured.

  • The nail sign (rocking): The base of the nail bed can be palpated for sponginess.

  • The apposition (Schamroth) sign: When the dorsal surfaces of the left and right index fingers are placed in apposition, with the distal interphalangeal (DIP) joints and the nail beds touching, an oblong diamond-shaped aperture is normally visible between the two juxtaposed nail beds; with clubbing, this space is obliterated. [63, 64]

  • The digital index: The circumference of each finger at the nail bed and DIP joint are measured. The mean ratio of the nail bed circumference to the DIP joint circumference should be less than 1. Alternatively, the ratio of each finger's nail bed and DIP joint can be added. If the sum is greater than 10, clubbing is present; if the sum is greater than 11, advanced clubbing is present. [65, 33]

Clubbing can be quantified using instruments to determine the nail bed angles or the phalangeal depth ratio (PDR). However, this is not performed routinely. 

Bone and joint findings

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. [18] In some cases, dysesthesia of the fingers is present, with accompanying heat, sweating, clumsiness, and stiffness of the hands. [18] Adults with primary hypertrophic osteoarthropathy are asymptomatic. [57]

Joint symptoms range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. [18] 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). [64] The effusions are more likely a sympathetic reaction to nearby periostosis; arthrocentesis in such cases reveals a very thick noninflammatory fluid, with a cell count of less than 500 cells/µL. [23]

Inflammation and reduction of the joint space may be present, and contractures may develop in later stages. Rarely, periarticular erosions can occur. [28, 66] In the axial skeleton, changes are spondylolisthesis, with narrowing of intervertebral disk spaces and foramina, ligamentous ossification and laxity. [28, 66]

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. [67]   

Symmetrical cylindrical thickening of long bones has also been observed because of periosteal proliferation and subperiosteal new bone formation. It may appear as elephant foot in one fourth of 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. 

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.   [68]

Cutaneous findings

These are more prominent in, but not exclusive to, primary HOA. 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. [69]  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 pachydermoperiostosis (PDP). 

Other skin manifestations include seborrheic dermatitis, as eczematoid dermatitis of hands and feet, and also acne vulgaris.  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 primary HOA. [70]

These cutaneous features cause the patient to look prematurely aged. Thickened ears and lips may appear. Hyperhidrosis and overactivity 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. [58]  The skin of palms and soles is also thickened and rough, and the thenar and hypothenar areas become prominent.

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Causes

Primary or idiopathic hypertrophic osteoarthropathy (HOA; pachydermoperiostosis [PDP]) comprises about 3-5% of all cases of hypertrophic osteoarthropathy. [67] PDP is considered to be hereditary, although a family history of the disease can be traced in only about 25-38% of cases. Familial recurrence of PDP has been reported in 33–100% of pedigrees. Inheritance is autosomal dominant inheritance, although autosomal recessive and X-linked inheritance has been suggested. [12]  It occurs predominantly in males (male-to-female ratio of 9:1), and males usually show a more severe phenotype. [52] PDP is more common in African Americans. [69]

PDP has been 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. [69] 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. [71]

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. [26]

Various rare associations like hypertrophic gastropathy, peptic ulcers, gynecomastia, acro-osteolysis of fingers and toes, Crohn disease, atherothrombotic brain infarction, [58] renal amyloid A (AA) amyloidosis, and bone marrow failure due to myelofibrosis have been described. Only 6 cases of myelofibrosis in primary HOA have been described so far. The development of myelofibrosis makes primary HOA a disease with unfavorable outcome. [68]  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. [72] An increase in human leukocyte antigen (HLA) B12 has been shown in one study of this syndrome. [47] 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. [70]

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.

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. [18, 73] 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. [74, 75]

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. 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. [76]  

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. [77] 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. [46]  Lung cancer accounts for almost 20% of isolated digital clubbing and over 60% of hypertrophic osteoarthropathy in adults. [8] 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. [77]

However, patients with HOA 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. [78] Other malignancies reported in the literature to be associated with HOA include the following:

  • Nasopharyngeal cancer
  • Mesothelioma, renal cell carcinoma, esophageal cancer, gastric tumor, pancreatic cancer, breast phyllodes tumor, melanoma, thymic cancer and Hodgkin’s lymphoma. [8]  

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, [21] 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. [79] An association of sarcoidosis with hypertrophic osteoarthropathy has been reported and nodular periostitis by roentgenography has been reported in 1 case. [80]

Inflammatory bowel disease (Crohn disease and ulcerative colitis), celiac sprue, [57] 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.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. [81]   No association with transplant medications has been noted. [82]

Congenital cyanotic congenital heart diseases, rheumatic diseases, and left ventricular tumors have been implicated as well. [83]

Neurologic causes include primitive neuroectodermal tumors (PNETs). [84]

Other causes include chronic infections associated with cystic fibrosis, HIV, [82] 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.

 

ther 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. [62] 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. [62, 33] 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. [85] Therefore, unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet. [62]

Thomas first described thyroid acropachy in 1933. [86] 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. [87] It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid. [64]

Various medications including prostaglandin, vitamin A, and fluoride can produce periostitis and bony changes resembling hypertrophic osteoarthropathy. [88] The association between finger clubbing and senna misuse and the reversibility of finger clubbing, were reported in 1975.

Voriconazole has been reported to probably induce periostitis, but no apparent inflammatory arthritis was present in the case series report. [46] 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. [88] 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. [89]

Hypertrophic osteoarthropathy was also noted in one case after a long-term use of bevacizumab metastatic colorectal cancer. [90]

 

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. [91]

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. [46] 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. [46] A case report has described hypertrophic osteoarthropathy presenting as the first symptom of recurrent infantile fibrosarcoma. [92]

The authors did not identify any reported cases of hypertrophic osteoarthropathy associated with lung carcinoma in children or young adults in the literature. [46] 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. [93, 92]

An atypical form of hypertrophic osteoarthropathy has presentation limited to lower extremities. [94]

 

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