Gene discovery should help diagnose incontinentia pigmenti

Press Release regarding IP mutation discovery, May 24, 2000

HOUSTON--The discovery of the gene that causes a rare disorder affecting the skin, hair, nails, teeth, eyes and nervous system in females should help prevent it from being mistaken for illnesses with similar features.

Researchers at Baylor College of Medicine in Houston, in collaboration with an international team, identified the gene on the X chromosome that causes incontinentia pigmenti (IP). Their findings are published in the May 25 issue of the journal Nature.

The characteristics of IP and their severity vary. Newborn and infant girls with IP often develop a blistering rash similar to chicken pox or herpes. The blisters can become wart-like, and problems with pigmentation due to damaged skin cells can result in brown swirls resembling a marble cake.

Delay of primary teeth, abnormally shaped or spaced teeth, bald patches on the scalp, missing or deformed nails, permanent visual defects, blindness, strokes and seizures are among the other possible features of IP.

"If there's no family history of the disease, it's not uncommon for a girl born with IP to go down a funnel of misdiagnosis", said Dr. Richard Lewis, Baylor professor of ophthalmology and a co-author of the Nature paper. "The child might be treated for herpes, a blood infection known as sepsis or other disorders characterized by the same feature as IP."

By studying more than 150 families, the researchers traced the cause of IP to a defect on a gene called NEMO on the X chromosome. Skin cells with the mutated X chromosome are killed around the time of birth. As a result, the dying cells in the skin create dramatic rashes and blisters. Unlike females, who have two X chromosomes, males have an X and a Y chromosome. Males don't have a "backup" copy of the X chromosome; consequently, if they have a NEMO defect, they usually die before birth.

Most affected patients with IP are female. Because IP is lethal in males, affected women can have multiple spontaneous abortions if they conceive affected males.

"About 70 percent of the families with IP that we studied have a single alteration in the NEMO gene, so it's likely that we can screen for this genetic defect prenatally," said Dr. David Nelson, Baylor professor of molecular and human genetics and a co-author of the paper.

Testing for the mutation can also speed diagnosis of the disease so that physicians don't suggest treatments for misdiagnosed illnesses in newborns.

IP could serve as a model for other human diseases because NEMO activates a key cellular pathway that influences growth, development, immune responses and other functions in the body. Shutting down this pathway results in a variety of problems seen in patients with IP.

"By studying the functions of this highly complex pathway, scientists hope to understand the biological processes it controls," Nelson said. "Perhaps this will help explain the disease process of IP and similar disorders."

The incidence of IP is estimated to be between one in 10,000 and one in 100,000. There is no known cure yet, and treatment is based on problems as they develop.

The Baylor team collaborated with scientists in France, Germany, Italy and the United Kingdom. Their study was funded by the National Incontinentia Pigmenti Foundation, headed by Susanne Emmerich, along with grants from the National Institutes of Health, Research To Prevent Blindness Inc., the Foundation Fighting Blindness and several organizations overseas.

Other co-authors at Baylor were graduate student Swaroop Aradhya, Dr. Moise Levy, professor of dermatology, and Dr. Takanori Yamagata, a visiting scientist from Jiichi Medical School in Tochigi, Japan.