Vanishing bone disease better understood

Gorham-Stout disease (GSD), also known as vanishing bone disease, is a rare lymphatic disorder, in which progressive bone destruction occurs due to the proliferation of lymphatic vessels inside the bones. Patients gradually lose bone and may suffer from pain, fractures and functional disability of the affected area. They can have life-threatening complications, such as chylothorax, a serious condition in which lymph from the digestive system accumulates in the chest cavity. Current treatments for this disease are inadequate for most patients.

The exact cause of GSD was unknown. Recent research by the group of Miikka Vikkula brings the understanding of the underlying mechanisms to a new level. Nassim Homayun-Sepehr, a PhD-student in the Vikkula lab, performed genetic analysis on tissues from a patient with severe GSD. She discovered a mutation in the KRAS gene. The same mutation is often seen in cancers, and it leads to hyperactivity of KRAS.

To further explore the pathogenesis of GSD, they developed a mouse model of the disease. With this model, they were able to show that hyperactive KRAS expression led to the development of lymphatics in bone, which is a hallmark of GSD. They also found that the development of lymphatic valves was impaired and caused chylothorax in the model which is another characteristic of the disease.

The researchers then analyzed the effect of a drug called “trametinib” on their disease model. Trametinib is an FDA-approved drug, used in the treatment of various cancers, which inhibits the KRAS pathway. They showed that trametinib could suppress the disintegration of lymphatic valves and the severity of the GSD phenotype in their disease model. These findings suggest that trametinib could be an effective treatment for GSD in patients.

This work was performed in collaboration with UT Southwestern Medical Center in Dallas (USA) and recently published in JCI Insight.

Article describing the research:

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib.
Homayun-Sepehr N, McCarter AL, Helaers R, Galant C, Boon LM, Brouillard P, Vikkula M, Dellinger MT.
JCI Insight (2021) 6(15):e149831.