Genetics Sheds Light on Lentiginosis Syndromes

CC patients have “very distinct and purer labial macules, and some have no distinct pigmentation of the face,” except for a particular distribution and a few blue nevi on the saddle of the nose, which would be unusual for the general population, according to Dr. Stratakis.

Multiple genital macules are present in CC patients, in contrast to one or two at most in the general population. Ear and outer canthal pigmentation is present in about one-third of CC patients but also occurs infrequently in Peutz-Jeghers patients.

CC patients have mutations in the PRKAR1A gene; PRKAR1A is a regulator of protein kinase A and mutations cause dysregulation of the catalytic subunit of the enzyme. A mouse model confirmed that the mutated gene could cause a variety of tumors. Subsequent experiments showed chromosomal instability and other features caused by PRKAR1A gene mutations in human and mouse cells.

If very different genes that do not seem to have a “functional connection” cause all of these inherited lentinginosis syndromes, “then they must have a common mediator of tumorigenesis,” Dr. Stratakis said. “It turns out that the common mediator is mTOR,” which is the mammalian target of rapamycin. Indeed, it appears that all of these conditions are associated with dysregulation of mTOR activity, which normally regulates other tumor suppressor genes and oncogenes. Rapamycin and its analogues are being tested in clinical trials of cancer patients, Dr. Stratakis noted.

This patient with Carney's complex shows lentigines on the eyelids as well as a small, red myxoma on the upper lid. Courtesy Dr. Constantine Stratakis