Researchers at the National Institutes of Health (NIH) worked with 15 patients from around the world to solve the genetic basis of a rare bone disorder’s origins. The rare disorder, known as melorheostosis (or “dripping candle wax” bone disease) causes excess bone formation that resembles dripping candle wax on x-rays. The results offer potential treatment targets for this rare disease, provide important clues about bone development, and may lead to insights about fracture healing and osteoporosis.
Melorheostosis is an fatal condition characterized by the formation of excess unmineralized bone tissue, called osteoid, on one side of the body – typically a lower limb – that resembles dripping candle wax on an X-ray. The bone lesions begin to grow during childhood or early adulthood and continue throughout an affected individual’s life, leading to visible deformity and loss of function, accompanied by pain.
Though there are only about 400 known cases of this disorder worldwide, 15 unrelated adults with the condition from around the globe volunteered to come to the NIH Clinical Center to undergo biopsies of both affected and unaffected bones. The condition causes pain and bone deformity, which can limit the function of bones.
“Scientists previously assumed that the genetic mutations responsible for melorheostosis occurred in all cells of a person with the disorder,” said co-senior author Timothy Bhattacharyya, M.D., head of the Clinical and Investigative Orthopaedics Surgery Unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at NIH. “Our team hypothesized that mutations might only occur in the affected bone tissue.”
Researchers compared samples of healthy and affected bone from each participant to look for differences in the exome, the portion of the genome that codes for proteins. Comparing genetic information from both samples in each patient allowed the team to pinpoint even low levels of the mutations. Experts from NIAMS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) worked together on this study.
The analysis revealed that 8 of the 15 participants had mutations in the MAP2K1 gene in the affected bone only. MAP2K1 produces the protein MEK1. The gene MAP2K1 has previously been linked to some types of cancerous growths as well as to conditions that lead to abnormal blood vessel formation in the head, face or neck.
The study was supported by the NIH Intramural Research Program (ZIDAR041180 and Z1AHD000408) and the Melorheostosis Association. The Ludwig Boltzmann Institute of Osteology in Austria worked with the NIH on this study. The study is registered at ClinicalTrials.gov as NCT02504879. A link to the NIH article, can be found here.
