Gorham and others speculated that such a change in the bone chemistry might cause an imbalance in the rate of osteoclast to osteoblast activity such that more bone is dissolved than is replaced. Beginning in the 1990s, elevated levels of a protein called interleukin-6 (IL-6) being detected in people with the disease were reported, leading some to suggest that increased levels of IL-6 and vascular endothelial growth factor (VEGF) may contribute to the chemical changes Gorham and others believed were the cause of this type of osteolysis.In 1999, Möller and colleagues concluded, "The Gorham-Stout syndrome may be, essentially, a monocentric bone disease with a focally increased bone resorption due to an increased number of paracrine – or autocrine – stimulated hyperactive osteoclasts. The resorbed bone is replaced by a markedly vascularized  fibrous tissue. The apparent contradiction concerning the presence or absence or the number of osteoclasts, may be explained by the different phases of the syndrome." They further stated that their histopathological study provided good evidence that osteolytic changes seen in Gorhams disease are the result of hyperactive osteoclastic bone. However, others have concluded that lymphangiomatosis and Gorhams disease should be considered as a spectrum of disease rather than separate diseases.While a consensus exists that Gorhams is caused by deranged osteoclastic activity, no conclusive evidence has been found as to what causes this behavior to begin.
Though several reports of similar cases were published in the interim, more than 80 years passed before another significant report of the condition appeared in the medical literature.Both born in 1885, Lemuel Whittington Gorham, MD, and Arthur Purdy Stout, MD, had long, distinguished careers in medicine and shared a lifelong interest in pathology. Dr. Gorham practiced and taught medicine and oncology and from the mid-1950s through the early 1960s conducted and reported the classical clinicopathological investigations of pulmonary embolism. During this time, he also authored several case series on osteolysis of bone. Dr. Stout began his career as a surgeon and became a pioneer in tumor pathology, publishing Human Cancer in 1932. This work became the model for the Atlas of Tumor Pathology project, which Stout oversaw as chairman of the National Research Council in the 1950s. In his later years, Dr. Stout embarked on a systematic study of soft tissue tumors in children and was among the first to link cigarette smoking to lung cancer.In 1954, Gorham and three others published a two case series, with a brief review of 16 similar cases from the medical literature, that advanced the hypothesis that angiomatosis was responsible for this unusual form of massive osteolysis. That same year, Gorham and Stout presented to the American Association of Physicians their paper (in abstract form), "Massive Osteolysis (Acute Spontaneous Absorption of Bone, Phantom Bone, Disappearing Bone): Its Relation to Hemangiomatosis".