A new paper (abstract available here) published online in the journal Nature Genetics demonstrates the power of traditional Mendelian genetics to reveal clues to the underlying mechanisms of more common diseases. Finger or digital clubbing, which is also known as hypertrophic osteoarthropathy, is one of the classic physical signs taught to medical students. Hippocrates is commonly thought to have been the first to recognize digital clubbing in the fifth century BC. The clubbing depicted in the figure below (from www.nail-disorders.com) is the hallmark of so-called pulmonary hypertrophic osteoarthropathy, a clinical sign that can develop in the context of a number of clinical conditions including intrathoracic neoplasms (i.e., cancers within the chest):
Some Clinical Conditions Associated with Digital Clubbing
- Lung Cancer
- Congenital Heart Disease
- Inflammatory Bowel Disease
Figure: Digital clubbing (aka hypertrophic osteoarthropathy). From www.nail-disorders.com.
Despite the fact that the form of hypertrophic osteoarthropathy secondary to lung cancer and other disorders has been recognized for many centuries, its actual cause has remained remarkably enigmatic. However, the new study in Nature Genetics breaks important new ground.
The authors, led by Dr. David Bonthron of the Leeds Institute of Molecular Medicine and Yorkshire Regional Genetics Service, studied several families with a rare inherited form of digital clubbing, known as "primary (idiopathic) hypertrophic osteoarthropathy (PHO)." They localized the gene responsible for PHO to the long arm of chromosome 4 and demonstrated that the responsible gene is HPGD, which provides the coding information to produce a protein called "15-hydroxyprostaglandin dehydrogenase." The affected individuals in these families had mutations in both of their copies of HPGD, suggesting that the inheritance pattern is autosomal recessive (i.e., similar to cystic fibrosis in that a mutation in both copies of the gene are necessary to get the clinical condition).
Importantly, 15-hydroxyprostaglandin dehydrogenase is the main enzyme responsible for breaking down prostaglandin E2 (PGE2, a lipid compound which has a number of functions in the lung, the GI tract, and in the uterus during pregnancy) and other prostaglandins and related compounds.
The authors measured PGE2 levels in the urine of the study subjects and showed that they were elevated in the individuals from the families with mutations in both copies of HPGD. Interestingly, intermediate elevations of urinary PGE2 levels were seen in some of the family members with one normal copy and one mutated copy of HPGD. Some of these individuals had mild, late-onset digital clubbing, which is consistent with the degree of elevation of prostaglandin levels within the body determining the severity and age of onset of the digital clubbing.
In hindsight, the identification of HPGD, the key enzyme in prostaglandin degradation, as a disease gene for PHO makes a great deal of sense. PGE2 is known to have a number of effects upon bone. The demonstration, in this rare disorder, that mutations in the key enzyme of prostaglandin degradation lead to PHO suggests that elevated prostaglandin levels are critical in causing the much more common clubbing seen in pulmonary hypertrophic osteoarthropathy (the clubbing seen in association with lung cancer and other disorders). As the lung is known to be a site of PGE2 clearance by HPGD, perhaps the lung diseases associated with pulmonary hypertrophic osteoarthropathy lead to decreased clearance and degradation of PGE2.
PGE2 is also known to be important in the context of a type of congenital heart disease known as "patent ductus arteriosus" (PDA). Normally, the ductus arteriosus is closed after birth when circulating PGE2 levels fall significantly (due to exposure of the blood to HPGD in the newborn's lung). One might expect that PGE2 levels would not drop as rapidly in individuals with mutations in HPGD, and, indeed, 4 of the 13 HPGD-deficient individuals in this study had patent ductus arteriosus. Although, this association was previously recognized, it now makes much more sense given the association with a disruption in the capacity to metabolize PGE2. It will be interesting to see if significant numbers of individuals with PDA have mutations in one or both copies of HPGD.
The authors point out that there were some previous clues to the involvement of prostaglandins in clubbing. For example, liver transplant patients who received prostaglandin E therapy developed clubbing. Nevertheless, this novel result suggests that PHO and the more common secondary pulmonary hypertrophic osteoarthropathy have a common cause: elevated prostaglandin levels.
There are two important clinical implications for the future:
- Strategies aimed at decreasing prostaglandin levels might be helpful in individuals with PHO.
- For middle-aged or elderly individuals presenting to a physician with clubbing in the future, it may be worthwhile considering whether there are HPGD mutations, as their presence could help the patient avoid an extensive work-up looking for other underlying causes including malignancy.
