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Hypertrophic osteoarthropathy (HOA) syndrome comprises the combined presence of digital clubbing, periostosis, and joint swelling.
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HOA is divided into primary and secondary forms. Primary HOA is also known as pachydermoperiostosis. The secondary form of HOA has been associated with a wide variety of medical conditions, including malignancies.
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Involvement of vascular endothelial growth factor, platelet-derived growth factor, platelets, and genetically determined increased prostaglandin E2 levels
Hypertrophic Osteoarthropathy: What a Rheumatologist Should Know About this Uncommon Condition
Section snippets
Key points
Definition
Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of the skin and osseous tissues at the distal parts of the extremities. Three features are typically present: a peculiar bulbous deformity of the tips of the digits conventionally described as clubbing, periostosis of the tubular bones, and synovial effusions.1
Historical overview
Digital clubbing is one of the oldest clinical signs in medicine. Its original recognition has been attributed to Hippocrates (circa 450 bc).2 He described a patient with empyema and curved nails. Marie, in 1890,3 and Bamberger, in 1891,4 described the fully developed syndrome. Marie distinguished it from acromegaly and suggested the term pulmonary HOA. Paleopathologic studies have shown changes consistent with HOA in human skeletal remains from both pre-Hispanic Mesoamerica5 and in a medieval
Epidemiology
There are no systematic studies on the prevalence of digital clubbing in the general population. A retrospective study of 1226 patients with lung cancer showed that 4.5% of these had findings suggestive of periostosis by bone scintigraphy and only 0.8% displayed clubbing and joint pain.7 In another study,8 clubbing was present in 1% of 1511 patients admitted over 1-year period to a general internal medicine department.
Clubbing is usually associated with a variety of internal illnesses. Thus,
Nomenclature
The term acropachy is etymologically the most appropriate and has been used to describe either clubbing or the fully developed syndrome. Synonyms for clubbing include drumstick, pendulum, and Hippocratic fingers. Primary HOA is also known as pachydermoperiostosis.
There is evidence to sustain the belief that clubbing and HOA represent different stages of the same disease process.10 In most cases, the finger deformity is the first manifestation and, as the syndrome progresses, periostosis becomes
Pathology
An excessive soft tissue deposit of collagen fibers and interstitial edema are responsible for the bulbous deformity of the digits. Furthermore, small blood vessels are dilated and the number of arteriovenous anastomoses is increased. In addition, there is vascular hyperplasia and thickening of the vessel walls, with perivascular infiltration of lymphocytes.11
Electron microscopic studies have confirmed the structural vessel damage shown by the presence of Weibel-Palade bodies, the prominence of
Classification
As shown in Table 1, HOA is divided into primary and secondary forms. Primary HOA is also known as pachydermoperiostosis (MIM numbers 259100 and 167100), or Touraine-Solente-Golé syndrome. It is a rare hereditary condition with variable expressivity. According to several reports, from 33% up to 73% of patients with primary HOA have a close relative with the same illness.15 The male/female ratio is 9:1. Primary cases are prone to displaying a more disseminated skin hypertrophy, hence the term
Cause and pathogenesis
Significant advances in the understanding of HOA have been made in recent decades.18 Any valid theory attempting to unravel its pathogenesis must explain the peculiarities of the syndrome, namely, how such different diseases can induce so unique a deformity. It must also explain the reason for the acropachy: why the syndrome begins at the most distal parts of the extremities and evolves in a centripetal fashion. It must also account for the pathologic features of edema, localized endothelial
Signs and symptoms
In HOA, there is a continuum of signs and symptoms. At one end of the spectrum, patients may be asymptomatic and unaware of the deformity of their digits. On the other end, some patients, in particular those with lung malignancies, complain of a burning sensation of the fingertips and may also suffer from excruciating bone pain. Characteristically, this pain is deep seated, more prominent in the lower extremities, and aggravated by the dependency of the limbs.
Physical examination is of utmost
Laboratory Studies
There are no useful serologic tests for HOA. However, an array of biochemical abnormalities may be found, reflecting the pathophysiologic process of underlying disease. Isolated reports have shown increased bone-formation marker levels, such as total alkaline phosphatase, bone alkaline phosphatase, the amino terminal propeptide of type I procollagen, and osteocalcin. Also, bone resorption markers including the serum carboxy terminal telopeptide of type I collagen, and the urinary amino terminal
Differential diagnosis
When HOA is fully expressed, the drumstick fingers are unique to such a degree that its recognition poses no dilemma. However, there are borderline cases in which neither careful examination nor the Digital Index clarify the situation.20 The most appropriate approach for such cases is to assume the presence of clubbing and to search for an underlying disease.11
Diagnostic criteria for HOA include the combined presence of clubbing and radiographic evidence of periostosis of the tubular bones.
Rheumatic diseases associated with HOA
As shown in Table 3, a variety of the more common rheumatic diseases have been associated with or coexist either with clubbing, periostosis or, less frequently, with the fully developed HOA syndrome.
Treatment
Aside from its unsightliness, clubbing is usually asymptomatic and does not require treatment. For patients with painful osteoarthropathy, pharmacologic treatment with analgesics and NSAIDs is effective in relieving pain in most patients. There are isolated case reports from different parts of the world stating that intravenous infusions of bisphosphonates are effective in cases of HOA with refractory bone pain.79, 80 Bisphosphonates are not only osteoclastic bone resorption antagonists but
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