The “Hippocratic fingers”
The ancient clinical sign of finger clubbing is often accompanied by hypertrophic osteoarthropathy (HO). Clubbing can portend any of a wide range of serious diseases, but intrathoracic pathologies, particularly lung cancer and chronic pulmonary infection, are especially notable (hence the term, “pulmonary osteoarthropathy”). Curiously, though, circulatory anomalies, e.g. right-to-left shunting in cyanotic congenital heart disease, can also lead to progressive clubbing.
Primary hypertrophic osteoarthropathy
Like many disease processes, pulmonary osteoarthropathy has a Mendelian mimic, a “primary” form (PHO) that shows all the same features, but in the absence of underlying malignancy or other serious pathology.
Right: Radiograph showing thickened, columnar diaphyses and erosion of the terminal phalangeal tufts in PHO.
By autozygosity mapping, we localized the PHO gene to Chromosome 4q34, and identified mutations in the HPGD gene, encoding 15-hydroxyprostaglandin dehydrogenase, the major enzyme that degrades prostaglandin (particularly prostaglandin E2—PGE2).
Left: Structural model of PGE2 bound to HPGD (Colin Fishwick, School of Chemistry, Leeds), showing the predicted effect of the PHO mutation A140P, displacing the substrate and preventing coordination of its 15-OH group to serine 138.
PHO patients have chronically elevated levels of circulating PGE2, which explains a number of features of PHO. For example, the association of PHO with persistent patent ductus arteriosus (PDA) can be understood, since an HPGD-mediated postnatal fall in PGE2 is required for closure of the ductus.
The genetic basis of PHO also illuminates the pathophysiology of secondary finger clubbing. Several diseases, such as lung cancer, that commonly cause clubbing, are known to result in overproduction of PGE2. Also, pulmonary HPGD normally plays a major role in degrading circulating PGE2; consequently, chronic lung disease (e.g. cystic fibrosis) or right-to-left cardiac shunt (bypassing the pulmonary circulation) both result in failure of this degradative process, leading to clubbing.
Uppal S, Diggle CP, Carr IM, Fishwick CWG, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SEV, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nature Genet 40:789–783 (doi:10.1038/ng.153).
