A rare bone disorder’s murky genetic origins have been clarified somewhat thanks to a study led by the US National Institute of Health (NIH).

Melorheostosis is an incurable 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.

Although very few people are affected by this debilitating condition, understanding its underlying mechanism can help scientists develop better treatments for bone disorders such as osteoporosis and improved methods for healing fractures.

Since it was first described by medical researchers in 1922, only about 400 cases have been reported worldwide. Without a known molecular cause, physicians have been unsure how to properly diagnose melorheostosis and treatment traditionally required surgical removal of overgrowth and, ultimately, limb amputation.

To remedy the gap in knowledge, the NIH team took samples of healthy and abnormal bone tissue from 15 unrelated patients and sequenced the exomes – the part of the genome that encodes protein – of each.

According to their results, published in Nature Communications, abnormal bone cells from eight affected subjects showed mutations in the important cell signaling gene MAP2K1. Normal bone cells from the subjects had normal copies of MAP2K1, suggesting the condition may arise from a random mutation in early development.

The findings also support previous research suggesting that the two heritable diseases with similar features, osteopoikilosis and Buschke-Ollendorff syndrome, are caused by different genes than melorheostosis. Both are linked to autosomal dominant mutations in the LEMD3 gene, yet none of this study’s subjects had LEMD3 mutations.

When the authors cultured the cells taken from the subjects’ lesions, they found that the osteoblasts – the cells that create osteoid – with MAP2K1 mutations were overactive, but their ability to mineralize was impaired. This is not totally surprising considering that drip-like formations of osteoid are the disease’s hallmark, but it is puzzling in light of recent evidence that the class of drugs developed to treat osteoporosis help slow progression of melorheostosis.

“Most adults have the problem of weakening bones as they grow older. These patients have the opposite problem as some of their bones are rock hard and still growing,” said co-senior author Dr Timothy Bhattacharyya in a statement.

“The prospect that we could somehow harness this pathway in the future is so exciting.”