NIH News Release
National Institute of Dental
and Craniofacial Research

Tuesday, December 7, 1999
7:00 p.m. EST

Wayne Little
(301) 496-4261

Gene Found for Papillon-Lefevre Syndrome — A Disorder Affecting Skin and Gums

An international team of scientists has tracked down the gene responsible for Papillon-Lefevre syndrome (PLS), a rare but devastating condition that produces areas of thick, cracked skin and causes people to lose all their teeth by the time they are young adults. The rapid loss of both baby and permanent teeth mirrors the most severe forms of periodontal (gum) disease. The investigators feel that identification of the gene for PLS may help determine the process by which periodontal disease attacks the general population.

Dr. Thomas Hart of the University of Pittsburgh directed the study that examined the DNA from five Turkish families that had both normal and PLS-affected members. By following the inheritance pattern of known DNA markers, the responsible gene was narrowed to a small region of chromosome 11. A detailed analysis of this region found mutations in the gene that codes for an enzyme called cathepsin C. The study, which was supported by the National Institute of Dental and Craniofacial Research, appears in the December issue of the Journal of Medical Genetics.

"The identification of cathepsin C mutations in PLS will help scientists to better understand both normal and abnormal development of the skin and gums," said Dr. Hart. "Understanding how defective cathepsin C causes destruction of the gums in PLS may help us understand what causes more common forms of periodontal disease. We are currently evaluating this gene as a possible indicator of periodontal disease susceptibility. Also, because of the easy access to skin and gingival tissues, cathepsin C gene therapy may prove valuable for treating PLS and similar conditions."

Periodontal disease is usually considered a disease of adults, but some forms do occur soon after the baby teeth appear in the mouth. The causes of all variations of the disease are complex and thought to have genetic, bacterial, and immune system components. The type of gum disease associated with PLS is unusual in that it begins very early in life - usually before age 3 - is very severe, and is generally unresponsive to standard periodontal and antibiotic treatments. Patients who suffer from this condition lose all of their baby teeth prematurely, and by age 5, are usually completely toothless. The disease also affects permanent teeth, with most patients losing all of their teeth by age 20. People with PLS also tend to have an overproduction of skin cells in their hands and feet causing flaky, scaly skin.

First described by Drs. Papillon and Lefevre in 1924, PLS is an extremely rare disorder, with a single case occurring in every 1 - 4 million people. The syndrome has been observed in different ethnic groups and geographic regions, and is a recessive disorder requiring a mutated gene inherited from each parent. Although Hart and colleagues found a different mutation in each of the five Turkish families, each of the observed mutations would likely result in an inactive cathepsin C.

Although it remains to be resolved exactly how the absence of a functional cathepsin C enzyme leads to PLS, the investigators know that the normal gene is active in skin and gingival tissues and also white blood cells of the immune system. "It is possible that the absence of a functioning cathepsin C affects the structural integrity of the protective barriers formed by skin cells and cells lining the gums, and may also cause the immune cells to operate less efficiently," according to Hart. "Such a 'double-whammy' effect would make the periodontal pocket particularly ripe for bacterial infection and resulting tooth loss."

Collaborating with Dr. Hart were Drs. Suzanne Hart, Donald Bowden, Michael Michaelec, Scott Callison, and Steve Walker from Wake Forest University; Dr. Yingze Zhang from the University of Pittsburgh; and Dr. Erhan Firatli from the University of Istanbul School of Dentistry, Istanbul, Turkey. The study was supported by the National Institute of Dental and Craniofacial Research, one of the federal National Institutes of Health located in Bethesda, Maryland.