Although the pathogenesis of<unk>  is still not fully understood, two theories have been suggested: * The neurogenic theory proposes that stimulation of the vagus nerve leads to vasodilation, increased blood flow and<unk> . * The humoral theory proposes that mediators such as growth factors or inflammatory mediators are increased, leading to fibroblast proliferation and<unk> . This theory is explained in the next sections. Role of PGE2 Recently, it has been suggested that the locally acting mediator prostaglandin E2 (PGE2) plays a role in the pathogenesis of<unk> . In<unk>  patients, high levels of PGE2 and decreased levels of PGE-M (the metabolite of PGE2) were observed. PGE2 can mimic the activity of osteoblasts and osteoclasts (respectively building and breaking down bone tissue). This is why acroosteolysis and periosteal bone formation can be explained by the action of PGE2. Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing. Elevated levels of PGE2 in<unk>  patients are associated with mutations of HPGD gene. These patients showed typical<unk>  symptoms such as digital clubbing and periostosis. The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase). This enzyme catalyzes the first step in the degradation of PGE2 and related eicosanoids. So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in<unk>  patients. Due to these mutations, the binding of the substrate PGE2 to HPGD is disrupted. As a result of this, PGE2 cannot be transferred into PGE-M down and remain present at high concentrations. Role of other mediators Apart from elevated PGE2 levels, studies in patients with hypertrophic osteoarthropathy also showed increased plasma levels of several other mediators, such as Von Willebrand factor and vascular endothelial growth factor (VEGF). These substances could also have a role in<unk>  progression and proliferation. In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet. Von Willebrand factor is a marker of platelet and endothelial activation. This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of<unk> . VEGF promotes angiogenesis (growth of new blood vessels) and differentiation of osteoblasts, which can explain the clubbing and excessive fibroblast formation in<unk>  patients. Other mediators found in increased concentrations in<unk>  patients, include osteocalcin, endothelin-1, b-thromboglobulin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). It has not been described yet what role these mediators have in<unk> .
Pachydermoperiostosis
Acromegaly
Craniosynostosis
Melorheostosis
Buccal exostosis
Subungual exostosis
Achondroplasia
Pseudoachondroplasia