The discovery, which has implications for potential drug therapies and even cancer, appears in the July 27, 2011, early online edition of the New England Journal of Medicine.
David Bick, MD, professor of pediatrics at the Medical College and medical director of genetics at Children’s Hospital of Wisconsin, is one of the authors of the study, which was led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH).
Proteus syndrome gained wide public attention in 1980, through the movie “The Elephant Man,’’ about a 19th century Londoner whom experts believe may have suffered from the disease.
Researchers discovered a single-letter misspelling in the DNA of a gene called “AKT1” that activates the sporadic tissue growth seen in patients with Proteus syndrome. There are fewer than 500 people with the disease in the developed world, where it can be tracked.
Affected patients appear normal at birth, but symptoms occur in the first two years of life. Some parts of the patient’s body grow to abnormal sizes, while other parts of the body remain normal. The overgrowth worsens with age, and makes patients more susceptible to tumors.
Until now, diagnosis has been based on observation of patient features. Besides overgrowth of limbs, the condition is characterized by a variety of skin lesions and thickening of the soles of the feet. Some patients have neurological complications, such as behavioral and cognitive disabilities, seizures and vision loss.
Finding the single-letter misspelling in the 3 billion letters that comprise the human genome was the literal “needle in a haystack.” Researchers performed whole-exome sequencing on the DNA of seven patients with Proteus syndrome. Whole-exome sequencing looks at the DNA responsible for protein-coding genes, which is about 1-2 percent of the genome. The researchers then analyzed an additional 13 patients and found the same gene variant in more than 90 percent of them. Researchers suspect the patients in which the mutation was not detected may actually have the mutation at low levels or in different tissues than those sampled in the initial biopsy.
“This study will offer hope for patients with Proteus syndrome, because now we can start to look for pharmaceutical therapies,” said Dr. Bick. “Up until this point, we haven’t been able to offer patients and their families much information beyond a clinical diagnosis.”
As follow up to this study, NHGRI researchers plan to test DNA from the skeleton of the original “Elephant Man,” Joseph Merrick, to determine whether Proteus syndrome caused his disfigurement.
In addition to patients seen at NIH, the study included the collaborators from eight community hospitals and five university medical centers in four countries. Contributors to the study also included investigators from the NIH Intramural Sequencing Center, administered by NHGRI, and from the National Cancer Institute and the National Institute of Dental and Craniofacial Research. In addition to the hospitals and medical centers, the study authors also included representatives from two independent research groups and the Proteus Syndrome Foundations of the United States and the United Kingdom.