Gorham-Stout syndrome is a rare condition of unknown aetiology that is thought to result from a localised endothelial proliferation of lymphatic vessels resulting in destruction and absorption of bone.
The disease has been described in patients as young as 1 month to as old as 75 years. It was first reported by Jackson in 1838 in a 12-year-old boy with complete osteolysis of the humerus. In 1955, Gorham and Stout further characterized the main pathologic features of this rare disease as nonmalignant intraosseous proliferation of vascular tissue that caused massive osteolysis. Imaging features of Gorham disease at conventional radiography, CT, MR, and scintigraphy have been reported elsewhere in the literature and most of the cases failed to show the vasculature entity of the lesion, an important pathologic feature of the disease. Moreover, because of a lack of specific findings on conventional images, including those of conventional radiography and CT, the diagnosis of Gorham disease can be difficult. Other diseases such as Paget disease and metastases may have similar appearance. Although the disease is quite well described, it does not occur often enough to be recognised readily. It often takes many years for the condition to be recognized. Because of this rarity it is most unusual for a case of Gorhams disease to be known from the beginning of an incident and for ancillary treatment to be commenced at once. Yet because of the nature of the disease, repeat fracture might be expected to be common. In most instances, the condition is not recognised until a fracture
occurs and bone healing is delayed or subverted. The condition affects both sexes equally and has been noted to be posttraumatic in many cases. Clinical onset has been reported to occur anytime from childhood to adulthood; it usually manifests unilaterally and includes focal lymphatic proliferation involving one bone or contiguous bones (such as vertebrae). Adjacent soft tissue can also be involved, producing diffuse muscle atrophy .Any part of the skeleton can be affected. Involvement of the thoracic cage is progressive and life-threatening. The pathological process is the replacement of normal bone by an aggressively expanding lymphatic tissue. It is unknown what stimulus sets off this change in bone and also whether all bones of the affected individual are equally likely to react in this adverse fashion. Since it is most commonly seen in trauma it is reasonable to deduce that the traumatic episode initiates the sequence of events. Since neovasularisation of the blood clot that forms in between fragments of a fracture is the first step in bone healing it is tempting to speculate that some error in this process, or in the control of this process, is the root cause of Gorham's Disease. Wildly proliferating neovascular tissue appears to be the agent of the massive bone loss in this condition.


There is an useful list of factors to help distinguish Gorham disease from other destructive bone disorders:
They include a biopsy sample indicating the presence of lymphatic tissue (D2-40 positivity on inmunohistochemistry).

Absence of cellular atypia.

Little or no osteoblastic response or dystrophic calcification.

Local progressive osseous resorption.

A nonexpansile, nonulcerative lesion.

An osteolytic radiographic pattern.

And no hereditary, metabolic, neoplastic, immunological, or infectious cause.
The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity.

This bone disorder is largely attributed to focal lymphatic endothelial proliferation, whereby the bone is progressively destroyed and resorbed. The expected course of events after a fracture in a bone affected by Gorhams Disease is failure of healing followed by progressive reabsorption of bone around the fracture site. Progression of the disease has been observed to cease without treatment in many cases, but regeneration of the destroyed bone is not expected. The self-limited course correlates well with two phases of evolution of the histopathological lesions with neoplastic-like proliferation of lymphatic endothelial cells corresponding to the rapid and massive bone destruction, and a later

differentiation of the cells in mature vascular structures, but still with accelerated bone resorption which is partly compensated by appositional activity.
The criteria for what is and is not Gorham's Disease are not well worked out. The most easily separable group is that of multicentric osteolysis of which the great majority primarily affect the hands and feet, so-called acro-osteolysis. A subset has been described which is clearly inherited and two syndromes are recognised. Yet another group of multicentric osteolysis patients has an associated nephropathy.


A rapid review of the literature led to the conclusion that there is no consensus about the most efficacious treatment.

Apart from standard orthopaedic treatment for fractures, non unions and deformities the medical treatment for Gorhams Disease falls into three groups :

1. Surgical intervention has been suggested as the method of choice when feasible and involves local resection of the affected bone, with or without replacement prostheses or bone grafts.

2. Anti-osteoclastic medication (biphosphonates) and interferon. Synergistic action of Zoledronic acid and Interferon is a powerful antiangiogenic therapy which is giving currently the best results.

3. Radiotherapy : Radiotherapy acts by accelerating sclerosis of the proliferating blood vessels and prevents regrowth of these vessels. Although the use of total doses from 30 to 45 Gy have been reported to be effective. Some authors showed excellent results using a total dose of 15 Gy in a case that involved the upper extremity. Others reported rapid relief of symptoms and prevention of further osseous destruction during a 6-year follow-up period with a total dose of 3000 rads. Regrowth of bone after radiation therapy is unusual but has been reported in some cases. There is a significant risk of long term sarcoma development in children.
Of course, the usefulness of all these treatments is also shaped by the severity of the disease (for example, surgery would be impractical in patients with widespread vertebral involvement) and the urgency of the patient's condition.

The prognosis varies from slight disability to death by involvement of vital skeletal structures. It has been reported that >15% of patients die as a result of their disease. Severe disability results from involvement of the pelvis, thorax, and cervical spine.

Neurological complications increase the mortality to 33.3%. However, the disease usually remains localized within a skeletal region and undergoes eventual spontaneous arrest.

Studies on genetic mechanisms are just beginning. A vascular endothelial growth factor receptor (VEGFr3) that is specific for lymphatics has been identified. Three genes associated with inherited lymphedema (generalized swelling due to lymphatic abnormality) have been identified. Animal models simulating lymphedema are currently being studied. It is possible that the pathogenesis of lymphangiomatosis and Gorham disease is different; lymphatic malformations that arise during early childhood might stem from aberrant sequestrations of lymphatic vessels, while the acquired proliferation of small lymphatics observed in Gorham's disease might be driven by lymphangiogenic growth factors. IL-6, in particular, appears to be a mediator of the massive osteolysis in patients with the Gorham-Stout syndrome.

We highlight the need to tailor therapy based on both the presence of therapeutic targets and the complications those therapies might induce in the individual patient.
1. Any child or adult with sudden progressive osteolysis should be considered as a potential Gorham disease patient.

2. We encourage patients and physicians to contact, as soon as the diagnosis is suspected, centers with multidisciplinary teams involved in the treatment of the disease with large experience and active protocols.

3. After analysis of the clinical presentation, imaging findings and histology specimens available they have to be classified in one of the following 5 groups considering characteristics of the bone and soft tissue involvement:
> Focal osteolysis without soft tissue lymphatic anomaly (noticeable on MRI).

> Multifocal osteolysis without soft tissue lymphatic anomaly.

> Focal osteolysis with soft tissue lymphatic anomaly.

> Multifocal osteolysis with soft tissue lymphatic anomaly.

> Lymphatic Osteolysis in the context of vascular tumors or syndromes.
In summary, what action should be taken regarding Gorham´s disease treatment? Answer: there is no universal answer. Each child suffering from lymphatic osteolysis is unique and each treatment decision must be made individually.

Dr Juan Carlos López-Gutiérrez
Vascular Anomalies Center
Hospital Infantil La Paz
Madrid, Spain