Study suggests link between gene variant and Proteus syndrome

Orthopaedic surgeons from Children's National Medical Center are part of a team of researchers that has identified the genetic mutation causing Proteus syndrome, a rare disorder in which tissue and bone grow massively out of proportion. The discovery appears in the July 27, 2011, online edition of the New England Journal of Medicine. The study, led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), may have larger implications in both the identification and treatment of Proteus syndrome, as well as for certain types of cancer.

The NIH-based research team found that a point mutation - a single-letter misspelling in the DNA of the genetic code - in the AKT1 gene activates the sporadic tissue growth associated with Proteus syndrome. This particular genetic mutation in AKT1 is almost always undetectable in simple blood samples, making it necessary for surgical teams to collect and contribute deep tissues, including bone, cartilage, and growth plates, while patients with Proteus syndrome are undergoing necessary surgical procedures as part of their standard care.

"Proteus syndrome is an extremely rare disorder, making tissue sample collection especially challenging," said Laura L. Tosi, MD, of the Division of Orthopaedic Surgery and Sports Medicine at Children's National. "Given the importance of this research, we stepped up to the plate and, over the last decade, Children's National surgeons have collected more than one third of the study's tissue samples while Proteus syndrome patients underwent necessary procedures here at Children's National and at NIH."

Dr. Tosi, as well as the Chief of Orthopaedics and Sports Medicine, Laurel Blakemore, MD, and Kurt D. Newman, MD, Senior Vice President of the Joseph E. Robert, Jr., Center for Surgical Care, contributed tissue samples from Proteus patients treated at Children's National to help fuel the NIH-based genetic research.

"Proteus syndrome can be a complex disease to treat, as it manifests differently in every patient," said Dr. Blakemore. "It is our job to treat the needs of our patients with complex spine and bone disorders, and also contribute our knowledge and expertise in caring for these children to studies, like this one, that aim to identify the causes, and hopefully, one day, find a cure."

The gene variant that triggers Proteus occurs spontaneously in affected individuals during embryonic development, but symptoms only appear in the child's first two years. This mutation in AKT1 alters the ability of affected cells to regulate their own growth, leading some parts of the patient's body to grow to abnormal sizes, while other parts of the body remain normal.

Clinical diagnosis is typically based on the observation of patient features, which include limb overgrowth, a variety of skin lesions, and thickening of the soles of the feet. A well known unconfirmed case of Proteus syndrome gained attention in 1980 through the movie "The Elephant Man," about a 19th century Londoner, Joseph Merrick, whom experts believe may have suffered from the disease.

"Children's National has a vision that surgery might be less painful and more precise for pediatric patients, especially those who require multiple surgeries and lifelong support, as in the case of Proteus syndrome," said Dr. Newman, who was recently named the incoming president and CEO of Children's National. "This study and similar studies underway in systems biology programs around the world, including our own Sheikh Zayed Institute for Pediatric Surgical Innovation, all share one common goal: identifying these disorders and their causes as early as possible and finding better treatments."