Primary hypertrophic osteoarthropathy: an update

Abstract

Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary hypertrophic osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of hypertrophic osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis.

Keywords

digital clubbing / primary hypertrophic osteoarthropathy / prostaglandin E2 (PGE2)

Introduction

Primary hypertrophic osteoarthropathy (PHO; MIM 167100), or pachydermoperiostosis (PDP), is a rare genetic disease affecting both skin and bones. The major diagnostic criteria include digital clubbing, periostosis and pachydermia [1]. The report of the earliest patient with clubbing is probably attributed to Hippocrates (460 BC-370 BC); therefore, this finding is also referred to as “Hippocratic fingers.” The first scientific description of PHO was originally given by Friedreich (1868) in two affected brothers as “hyperostosis of the entire skeleton” [2]. In 1935, Touraine, Solente and Gole individualized PHO as the primary form of the hypertrophic osteoarthropathy, distinct from the more common secondary hypertrophic osteoarthropathy (SHO), which always associates with an underlying cause (e.g., pulmonary or cardiac disease) [3]. Although the disease is not present with high frequency in the general population, the precise incidence and prevalence are still unknown [4]. Both autosomal dominant and recessive inheritance of PHO have previously been suggested. Autosomal dominant transmission was confirmed in about half (54.4%) of the families, showing marked inter- and intrafamilial clinical variability [5,6]. The penetrance was incomplete (82.2%), with a minor but significant difference between sexes [1]. Autosomal recessive inheritance was suggested in pedigrees with consanguineous parents and single-generation families with two or more affected sibs [7-9].

Clinical manifestations

The age of disease onset has a bimodal distribution, peaking during the first year of life and at puberty. It is generally thought to be a self-limiting disease. After the active phase during adolescence, its manifestations may become stationary or even resolve spontaneously [10].

PHO predominantly affects soft connective tissue, skin and bone. Both digital clubbing and the swelling of periarticular tissue (arthralgia) reflect the involvement of soft connective tissue. Digital clubbing, the most common sign of PHO, is present in almost all cases (Fig. 1A). In mild cases, digital clubbing may be the only feature of the disease. Arthralgia or arthritis is present in 20%-40% of all cases. Major affected joints such as knees, ankles and wrists are usually affected. Synovial effusion may be evident in the knees. It may be more difficult to define the presence of effusion at the wrist or ankle level due to the surrounding soft-tissue swelling [11]. Synovial fluid examination reveals a thick viscous fluid with no inflammatory cell exudation [11]. The involvement of skin comprises two parts: dermal hypertrophy and glandular hypertrophy. Dermal hypertrophy is demonstrated as progressive thickening and furrowing of the skin on the face and the scalp (cutis verticis gyrata) (Fig. 1B). Glandular hypertrophy consists of sebaceous gland hypertrophy shown as seborrhoea, blepharoptosis and acne, and sweat gland hypertrophy as hyperhidrosis. The main concern of bone is shaggy periosteal new bone formation of the long bones (periostosis) (Fig. 1C). Radiologically, acro-osteolysis, periosteal changes of the short and flat bones and ossification of ligaments and interosseous membranes have been also reported. According to the range of the tissue involvement, three clinical subtypes have been proposed: (i) a complete form, presenting the full-blown phenotype, (ii) an incomplete form, with isolated bone involvement and limited skin changes and (iii) a fruste form, with pachydermia and minimal or absent periostosis [12]. According to the recent molecular findings, PHO is now categorized into hypertrophic osteoarthropathy, primary, autosomal recessive, type 1 (PHOAR1; OMIM 259100) due to 15-hydroxyprostaglandin dehydrogenase (HPGD) deficiency and hypertrophic osteoarthropathy, primary, autosomal recessive, type 2 (PHOAR2; OMIM 614441) due to solute carrier organic anion transporter family, member 2A1 (SLCO2A1) deficiency [13,14]. These two subtypes have different features and are clinically distinctive from each other. A review of all PHO patients who were molecularly diagnosed help to reveal several differences [1]: the age of onset of symptoms has a bimodal distribution, peaking during the first year of life in PHOAR1 with a high frequency of patent ductus arteriosus (PDA) and cranial suture defects, and at puberty in PHOAR2 [2]; remarkable difference of sex ratio between the two subtypes: male to female ratio is roughly 1:1 in PHOAR1, while SLCO2A1-deficient female patients do not present with any dermoskeletal manifestations [3]; it is notable that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis [15-22].

The major complications of PHO include anemia, myelofibrosis, hypoalbuminemia and gastrointestinal abnormalities (i.e., peptic ulcer, chronic gastritis, gastric carcinoma, Ménétrier’s disease and Crohn’s disease). A number of occasional findings, including compressive neuropathy, corneal leukoma, hypoplastic internal genitalia, gynaecomastia and periodontal and alveolar bone abnormalities, have been reported in single patients [23-25]. The mechanism of anemia associated with PHO is multifactorial including blood loss from the GI tract, bone marrow failure by myelofibrosis or narrowing of the medullary spaces, and possibly, the presence of an inhibitor for erythropoiesis [26]. Of these underlying factors, myelofibrosis is of particular concern due to the difficulty in treatment. Moreover, when skin and bone manifestations resolve with aging, myelofibrosis continues to develop. The pathomechanism of myelofibrosis deserves further investigation.

Differential diagnosis

Digital clubbing is a clear-cut unambiguous clinical sign easily recognized by medical students and physicians alike [27]. Its presence sets apart hypertrophic osteoarthropathy from other types of bone diseases such as acromegaly. When confronting a patient with digital clubbing, of utmost importance is to differentiate the more common secondary hypertrophic osteoarthropathy due to pulmonary disease or other conditions from the rarer PHO. Special attention must be directed to the chest. Nowadays, most cases of hypertrophic osteoarthropathy are secondary to intrathoracic diseases. Bone lesions in the secondary form are more painful and progress more rapidly while the skin changes are slight to moderate. As well as clinical considerations, periosteal apposition differs between the conditions; it is exuberant and irregular in the primary disorder, whereas it has a smooth undulating appearance in secondary hypertrophic osteoarthropathy [28].

Etiology and pathogenesis

Great efforts have been made to gain a better understanding of hypertrophic osteoarthropathy in recent decades. Primary and secondary hypertrophic osteoarthropathy have similar clinical and pathological features. Histological studies have shown vascular hyperplasia, endothelial cell activation, edema and periosteal proliferation [29]. Therefore, it is proposed that primary and secondary hypertrophic osteoarthropathy may share similar pathogenic mechanisms. On the basis of clinical investigations, a unifying hypothesis was proposed in 1987 stating that hypertrophic osteoarthropathy appears when the lung fails to inactivate a single clubbing-promoting growth factor [30]. In the meantime, Dickinson and Martin proposed a mechanism for hypertrophic osteoarthropathy that centers on abnormal platelet production [31]. Fragmentation of megakaryocytes into platelets takes place, at least in part, in the pulmonary circulation. Interaction of these megakaryocyte fragments with endothelial cells could result in local release of inflammatory and growth-promoting factors. One of such growth-promoting factors is vascular endothelial growth factor (VEGF). Different authors observed that patients with PHO and those with secondary hypertrophic osteoarthropathy have increased circulating levels of VEGF [32-34]. VEGF induces vascular hyperplasia, new bone formation, and edema [35,36]; these features characterize hypertrophic osteoarthropathy [29]. Therefore, VEGF is postulated as the prototypical osteogenic-angiogenic coupling factor in the pathogenesis of hypertrophic osteoarthropathy [34,37]. Furthermore, the authors showed high circulating VEGF levels in a patient with pulmonary hypertrophic osteoarthropathy and removal of the lung tumor led to a dramatic disappearance of the skeletal abnormalities and to reduction of circulating VEGF levels [38]. Studies of patients with SHO associated with cyanotic heart diseases are consistent with these explanations [39]. These studies contributed greatly to our understanding of its pathogenesis. However, the purported factor responsible for PHO remained to be established.

Genetic studies provided the breakthrough. Rare cases of PHO, clustered in families, have been documented in the absence of systemic disease. In such families, Uppal et al. [13] identified mutations in HPGD gene, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin E2 (PGE2) catabolizing enzyme, and Zhang et al. [14] recently identified mutations in the SLCO2A1 gene, which encodes prostaglandin transporter (PGT) responsible for uptake of PGE2. Both two genetic studies point the blame at the same factor — PGE2. PGE2 is a ubiquitous lipid mediator generated from membrane stores of arachidonic acid by the sequential actions of a number of enzymes, including cyclooxgenase (COX)-1 and COX-2. PGE2 has been implicated as a mediator in a plethora of physiological systems, and PGE2 production is often elevated in regions of inflammation. Therefore, not surprisingly, circulating levels are very low in healthy individuals. Degradation of PGE2 involves a two-step process: a carrier-mediated uptake across the plasma membrane followed by cytoplasmic oxidation in the lung [40-42]. Both HPGD-deficient and SLCO2A1-deficient patients had much higher urinary levels of PGE2 than their healthy relatives and normal controls. There have been previous clinical clues to the involvement of prostaglandins in hypertrophic osteoarthropathy. In patients with hypertrophic osteoarthropathy secondary to pulmonary neoplasms, the urinary levels of PGE2 were elevated. Individuals chronically treated with PGE2 develop typical signs of hypertrophic osteoarthropathy, and these symptoms resolve when the therapy is discontinued [43]. Both Hpgd^-/- mice and Slco2a1^-/- mice die in the perinatal period with PDA, a condition in which the ductus arteriosus, a large artery that connects the pulmonary trunk with the aorta allowing fetal blood to bypass the lung in utero, fails to close [44,45]. An increased risk for PDA is observed in individuals with PHO. PDA is observed in about 0.05% of full-term births; PDA was observed in 25% of individuals with PHO [46]. All these observations support the idea that impaired metabolism of PGE2 is critical in pathogenesis of hypertrophic osteoarthropathy.

Osteogenesis is strongly dependent on angiogenesis. Stimulation of VEGF expression by prostaglandins and its suppression by glucocorticoids respectively stimulate and suppress bone formation [47]. Studies have shown that even modest increases in PGE2 can increase platelet activation through the prostaglandin E receptor subtype 3 (EP3) receptor [48]. Most probably, the effect of PGE2 on bone formation is mediated by VEGF and/or abnormal platelet activation.

Treatment

A key question raised by the recent breakthrough is whether the progression of hypertrophic osteoarthropathy can be attenuated in individuals with PHO by treatment with non-steroid anti-inflammatory drugs (NSAIDs) which block PGE2 synthesis. NSAIDs are effective at relieving pain and swelling of joints, as well as reducing sweating and sebaceous gland secretion. However, further investigations on their side effects due to long-term medication, such as stomach ache and decreased libido, are needed. Newer proposed symptomatic treatment of hypertrophic osteoarthropathy involves the use of bisphosphonates, which is a potent inhibitor of osteoclastic bone resorption [49]. It is unclear how bisphosphonates fit in the scheme of suggested pathogenesis mechanism of hypertrophic osteoarthropathy, but there have been various case reports of symptomatic relief of hypertrophic osteoarthropathy with use of IV pamidronate or zoledronic acid [49,50]. For its complications, myelofibrosis is the most severe one. It is difficult to treat, and the affected patient may finally become transfusion-dependent. Some authors advised to use glucocorticoid in this condition [51,52]. Plastic surgery has been attempted for cosmetic purpose to improve rough facial features [53].

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