Hypertrophic Osteoarthropathy

Etiology

Hypertrophic osteoarthropathy (Pierre Marie–Bamberger syndrome) is characterized by digital clubbing and periosteal proliferation along the long tubular bones. It can be classified as either primary (idiopathic/hereditary) or secondary hypertrophic osteoarthropathy.

The primary form of the disease, also known as pachydermoperiostosis, idiopathic hypertrophic osteoarthropathy, or Touraine-Solente-Gole syndrome, is a familial disorder with autosomal dominant transmission and variable degrees of expression.

The secondary form of hypertrophic osteoarthropathy (HOA), formerly known as hypertrophic pulmonary osteoarthropathy, is related to any one of a large number of underlying conditions, of which bronchogenic carcinoma is the most common. It was first described in 1890 by Pierre Marie in patients with chronic lung disease. Multiple nonpulmonary causes of HOA have now been described, accounting for the change in nomenclature. A summary of the diseases associated with secondary HOA is presented in eBox 86-1 .

Prevalence and Epidemiology

Primary HOA is a rare disorder that most commonly presents in males by a ratio of 9 : 1. The onset of disease has a bimodal distribution, with one peak during the first year of life and a second peak around the age of puberty. The patient may present with the complete syndrome (pachyderma, periostitis, and cutis vertices gyrate) or an incomplete manifestation. More than one third of reported patients with pachydermoperiostosis have a relative with a similar illness.

Secondary HOA related to lung cancer is relatively common. One study found evidence of HOA in 17% of staging bone scintigrams performed on patients with lung cancer. On clinical examination, up to 30% of patients with lung cancer have evidence of digital clubbing. The presence of secondary HOA has no prognostic significance in patients with lung cancer. The age and sex distribution of secondary HOA follow that of the underlying condition. In addition to bronchogenic carcinoma, hypertrophic osteoarthropathy has been described with intrathoracic processes, such as mesothelioma, pulmonary abscess, bronchiectasis, emphysema, lipoid pneumonia, diaphragmatic tumors, and various lung metastases. Case reports of HOA secondary to pulmonary tuberculosis and sarcoidosis are documented in the literature. Nonpulmonary causes of HOA have been reported, such as cirrhosis or other chronic liver disease ; Crohn disease or other gastrointestinal inflammation ; primary nasopharyngeal, esophageal, gastric, or pancreatic neoplasms; acquired immunodeficiency syndrome (AIDS) ; arteriovenous malformation; polyposis ; endocarditis ; esophagitis ; voriconazole treatment ; and Erdheim-Chester disease.

HOA confined to one or both upper or lower extremities has been described secondary to vascular graft infection of the aorta or subclavian artery.

Secondary HOA may appear in childhood secondary to cystic fibrosis, cyanotic congenital heart disease, Hodgkin disease, metastasis, Crohn disease, prostaglandin therapy, and primary pulmonary neoplasms.

Clinical Presentation

Primary HOA is characterized by enlargement of the hands and feet with clubbing of the fingers and toes causing convexity of the nails. In the lower extremity, soft tissue swelling and bone enlargement can lead to a cylindrical appearance, with disruption of the normal extremity contours. Dramatic skin thickening in the face and scalp can result in deep furrows and transverse folds known as cutis verticis gyrata. Additional characteristic features of primary HOA include hyperhidrosis of the extremities and seborrhea of the face, nose, and scalp. Life expectancy is normal.

Secondary HOA may be the initial presentation of bronchogenic carcinoma. The presence of bilaterally symmetric periostosis and digital clubbing should alert the clinician to the possibility of underlying malignancy. Typically pain and tenderness occur at one or more articulations. The knees, ankles, wrists, elbows, and metacarpophalangeals joints are most commonly involved.

Pathophysiology

The pathogenesis of HOA remains uncertain. Many theories have been proposed, but none so far are entirely adequate. The importance of increased blood flow in hypertrophic osteoarthropathy has been emphasized. Periosteal reaction has been induced in dogs after the formation of a fistula between the left atrium and pulmonary arteries. Localized vascular proliferation and endothelial cell hyperplasia have been demonstrated histologically in the soft tissues of patients with HOA. These histologic findings are believed to be related to the presence of one or more growth factors in the systemic circulation that are normally inactivated in the lungs. Megakaryocytes and platelet clumps that are normally fragmented in the lungs reach the distal extremities and are thought to cause a local tissue reaction via release of cytokines. Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) have been proposed as having a role in clubbing and HOA. A neurogenic component may be contributory, as relief of signs and symptoms can occur after vagotomy. Many believe HOA to be a paraneoplastic syndrome caused by humoral factors, such as estrogen, adrenocorticotropin (ACTH), and growth hormone, which are known to be excreted by some pulmonary neoplasms.