[citation needed] Mutations in the cathepsin C gene (CTSC), located at human chromosome 11q14.1-q14.3, are the cause of PLS.

[8] A diagnosis can be made by a urine analysis for low/no activity of the enzyme cathepsin C.[8] A full patient history and identification of characteristic physical symptoms is another way to identify this syndrome.

However, often the symptoms are visually similar to other, milder, conditions, and it is only with the eruption of infant teeth that tissue degeneration or inflammation become apparent, often in conjunction with a sudden abnormality of skin colour.

[8] Genetic testing at the molecular level can look for alterations in the CTSC gene which are known to cause Papillon–Lefèvre syndrome, however this diagnostic service is only available at specialized laboratories.

[citation needed] An alternative to rehabilitation with conventional dental prothesis after total loss of the natural teeth was proposed by Drs.