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NORD is very grateful to Francine Blei, MD, MBA, Medical Director, Vascular Birthmark Institute of New York, Roosevelt Hospital; Michael T. Dellinger, PhD, Research Director, Lymphatic Malformation Institute; and Jack Kelly, Lymphangiomatosis & Gorham's Disease Alliance, for assistance in the preparation of this report.
Gorham-Stout syndrome (GSS), which is also known as vanishing bone disease, disappearing bone disease, massive osteolysis, and more than a half-dozen other terms in the medical literature, is a rare bone disorder characterized by progressive bone loss (osteolysis) associated with the overgrowth (proliferation) of lymphatic vessels. Affected individuals experience progressive destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected by GSS include the ribs, spine, pelvis, skull, collarbone (clavicle), and the jaws (maxillofacial area). Pain and swelling in the affected area may occur. Bones affected by GSS are prone to reduced bone mass (osteopenia) and fracture. The severity of GSS can vary from one person to another and the disorder can potentially cause disfigurement and functional disability of affected areas. The exact cause of GSS is unknown.
While GSS mainly involves the musculoskeletal system, it can involve the viscera, and is closely related to generalized lymphatic anomaly (GLA, also known as lymphangiomatosis). Patients with GLA have multifocal lymphatic malformations. These malformations can be present in bone but do not cause the loss of cortical bone. Lymphatic malformations are rare non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system, which includes lymph nodes, the small nodules where certain white blood cells (lymphocytes) and other cells participate in the immune regulatory system of the body. When fluid leaves arteries and enters the soft tissue and organs of the body, it does so without red or white blood cells. This thin watery fluid is known as lymph. The lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through the network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When lymphatic malformations are widespread in bone and soft tissue, the term “lymphangiomatosis” is used. However, definition of the term “lymphangiomatosis” is controversial – if it doesn’t involve bone or cortical bone is preserved it will be called GLA. However, if cortical bone is lost it will be called GSS.
GSS is sometimes classified as a form of lymphangiomatosis. GSS was first described in the medical literature in 1838. In 1954, L. Whittington Gorham, MD, and colleagues reported on two affected individuals and then, a year later, provided a comprehensive review of the disorder.
The specific symptoms and severity of Gorham-Stout syndrome are highly variable and depend, in part, on the specific areas of the body affected. GSS can be mild and manageable in some cases; in other cases, it can cause significant deformity and functional impairment. The most severe cases can progress to cause life-threatening complications. The course of GSS is also highly variable as the rate of progression of bone loss is unpredictable. Generally, GSS is a slowly progressive disorder, but the disease can stabilize without reason for years or, in rare cases, can resolve on its own (spontaneous remission). GSS can also progress until the affected bone is completely destroyed.
Bone is a dynamic system continuously engaged in a remodeling process of resorption and formation. Bone resorption refers to the breakdown of bone followed by the formation of new bone. This is a normal and continuous process in the body. In individuals with GSS, affected bone is broken down, but no new bone growth occurs. Basically, affected bone disintegrates and is replaced by a fibrous band of connective tissue.
It is not precisely known what drives bone loss (osteolysis) in GSS. Some research suggests that bone destroying cells known as osteoclasts rather than lymphatic vessels drive bone resorption. Osteolysis may result in progressive bone loss of all or a portion of affected bones.
The specific symptoms that develop depend upon the specific bones involved. In some cases, one bone may be involved; in other cases, several adjacent (contiguous) bones and nearby soft tissue may be affected. As noted above, the most common bones affected in individuals with GSS include those of the face and jaws (maxillofacial area) ribs, spine, pelvis, skull, and collarbone (clavicle). Virtually any bone can potentially be affected in GSS, however one study found that the extremities and pelvis were more frequently affected in GLA than GSS. Furthermore, patients with GSS tend to have more extensive and progressive bony involvement. In some cases, affected individuals may rapidly develop pain and swelling in the affected area. In other cases, affected individuals may experience a dull pain or ache or generalized weakness that builds over time. Bones affected by GSS are prone to pathological fractures. In some cases, surrounding soft tissue may slowly waste away (soft tissue atrophy).
When GSS affects the maxillofacial area, pain, loose teeth, fractures and facial deformity may develop. Some medical references have reported an association with meningitis in such cases. Meningitis is inflammation of the membranes (meninges) covering the brain and spinal cord, usually due to infection.
Involvement of the spine or skull base can be associated with neurological complications. Involvement of the spine can also potentially result in chronic or acute pain or paralysis (paraplegia).
Involvement of the thoracic cage can lead to chylothorax, which is the accumulation of chyle in the space between the membranes (pleura) that line the lungs and chest cavity. Chyle is a milky fluid that consists of lymph and emulsified fats. Chyle accumulation is associated with abnormalities affecting lymphatic vessels. Chylothorax can cause difficulty breathing (dyspnea), rapid breathing (tachypnea), chest pain or respiratory compromise. Chylothorax can eventually progress to cause life-threatening respiratory complications. Chylous ascites (accumulation of chyle in the abdominal cavity) can occur due to lymphangiomatosis in the thorax or gastrointestinal tract.
Some individuals with GSS may develop abnormal fluid accumulation around the heart (pericardial effusion). Specifically, the fluid accumulates in the pericardium, the sac-like structure that surrounds the heart.
Clinical Course – Outcomes
The clinical course for GSS is variable, and the results are hardly predictable. The prognosis for GSS patients is variable depending on the extent of the disease, the part of the body involved, and underlying proliferative progressiveness of the disease. Pulmonary involvement with chylothorax or spinal involvement may confer a poor prognosis, sometimes leading to death. In other cases, lesions may remain stable for long periods, however, new bone growth often does not occur. When just the limbs or pelvic girdle are affected, there generally is no apparent threat to life.
The exact cause of Gorham-Stout syndrome is unknown. No environmental, immunological or genetic risk factors that may play a role in the development of a lymphatic malformation have been identified. A genetic mutation for GSS has not been identified. Most cases occur randomly for no known reason (sporadically).
Bone loss in GSS is accompanied by the uncontrolled growth (proliferation) of lymphatic tissue. Affected bone is slowly destroyed and replaced by vascular fibrous connective tissue. The signal that stimulates this abnormal proliferation of vascular and lymphatic tissue is unknown. However, laboratory research has implicated specific growth factors (e.g. vascular endothelial growth factor [VEGF]) in modulating lymphatic vessel growth and bone development and destruction. Future investigations will reveal the role these growth factors serve in promoting GSS.
Some authors have speculated that circulation issues lead to a deficiency of oxygen (hypoxia) being delivered to affected areas, which, in turn, causes changes in pH and promotes the activity of specific enzymes that ultimately cause the characteristic bone loss of GSS, proposing that sluggish blood flow might trigger hypoxia, lower tissue pH and favor the activity of acid hydrolases (which in turn lead to bony destruction).
Additional theories point toward other factors that may be associated with the development of GSS. Some researchers conjecture that, as a result of a trauma, the blood supply to a bone or bones is affected, upsetting the balance between bone building cells (osteoblasts) and bone destroying cells (osteoclasts). The bone destroying cells predominate, and thus bone loss (resorption) outpaces bone production. Investigations have identified elevated interleukin-6 in some individuals. Interleukin-6 is a protein which may play a role in bone resorption by mediating osteoclast activity. However, a precipitating traumatic event cannot be identified in all people with GSS. Additionally, abnormal osteoclast activity is not identifiable in everyone with GSS either.
The specific reason(s) that GSS develops is simply not well understood. The underlying cause of abnormal vascular and lymphatic tissue growth is also not understood. More research is necessary to determine the exact cause and underlying mechanisms that ultimately result in GSS.
Gorham-Stout syndrome usually affects children and young adults under the age of 40. However, the disorder has been reported in an infant less than one month old and an adult more than 70, suggesting GSS can potentially affect individuals of any age. Some medical sources state that males are affected more often than females. Other medical sources state that the ratio is even (1:1). More than 200 cases have been reported in the medical literature. Because GSS is so rare, many cases go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.
Symptoms of the following disorders can be similar to those of Gorham-Stout syndrome. Comparisons may be useful for a differential diagnosis.
Bone loss (osteolysis) can be caused by several different conditions including infection, inflammation, cancer and certain endocrine disorders. Several different disorders have been noted in the differential diagnosis of GSS including Hajdu-Cheney syndrome, Paget’s disease, rheumatoid arthritis, fibrous dysplasia, Langerhans cell histiocytosis, Winchester syndrome, carpal tarsal osteolysis, idiopathic multicentric osteolysis, multicentric osteolysis with nephropathy, and eosinophilic granulomatosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Diffuse pulmonary lymphangiomatosis (DPL) is a disease in which the overgrowth (proliferation) of lymphatic vessels (GLA, lymphangiomatosis) occurs in the lungs, pleura and typically the surrounding soft tissue of the chest (mediastinum). Lymphangiomatosis (generalized lymphatic anomaly – GLA) can potentially affect any part of the body except the brain. The involvement can be widespread, affecting multiple areas simultaneously (GLA) or be isolated to one area, as in the lungs and chest (pulmonary lymphangiomatosis). The specific symptoms and severity vary, depending in part upon the size and the specific location of the abnormalities. Diffuse pulmonary lymphangiomatosis causes functional impairment of the lungs. The exact cause of diffuse pulmonary lymphangiomatosis is unknown. (For more information on this disorder, choose “diffuse pulmonary lymphangiomatosis” as your search term in the Rare Disease Database.)
There is no specific test or procedure that definitively diagnoses Gorham-Stout syndrome, which is partly a diagnosis of exclusion. A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including biopsies and specialized imaging techniques.
Clinical Testing and Work-Up
A biopsy, which is the surgical removal and microscopic study of affected tissue, can reveal the presence of abnormal lymphatic tissue and characteristic bony changes. There is a caution reported in taking biopsies of rib lesions whenever possible since these biopsies may lead to chronic pleural effusions.
Imaging techniques including plain x-rays, ultrasound, radioisotope bone scans, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI) may be used to aid in obtaining a diagnosis. The findings for these exams may be variable, but can show dissolution, fragmentation and fracture of bones. These tests can also be useful in showing increased vascularity, the extent of the disease and to detect soft tissue involvement. “Disappearing” or missing bones may also be detected through imaging techniques. Newer techniques are using near infrared technologies.
There is no specific treatment of individuals with GSS and no consensus in the medical literature as to what is the most effective therapeutic option. Treatment is directed toward the specific symptoms that are apparent in each individual. Although there is no standard protocol for these patients, clinical trials are under development. Surgery and radiation therapy either individually or in combination are the two most commonly used therapeutic options.
Surgery to remove the affect areas of bone has been performed to treat individuals with GSS. In some cases, a bone graft, which stimulates or augments the formation of new bone, may be used in conjunction with the surgical removal of affected bone. However, bone grafts can only be used after stabilization of the osteolytic process. Consequently, some physicians prefer the use of artificial (prosthetic) bone to replace bone removed by surgery.
Radiation therapy, sometimes in conjunction with surgery, has also been used to treat individuals with GSS. Radiation therapy has proven effective in treating some affected individuals, achieving pain relief and arresting the spread of osteolysis. Radiation therapy has also been effective in treating chylothorax, which is sometimes associated with GSS.
According to cases reported in the medical literature, positive results have been achieved with a total dose of 30 to 45 Gy. In one reported case (Fontanesi et al.) positive results were achieved using a total dose of 15 Gy in an individual with GSS affecting the upper extremity.
According to the medical literature some individuals with Gorham-Stout syndrome have been treated with medications that inhibit bone resorption including bisphosphates such as pamidronate or zoledronic acid. Some individuals have been treated with interferon alfa-2b, which inhibits the formation of lymphatic vessels (anti-angiogenic). These treatments have led to the improvement of symptoms (e.g., pain), but individual response is highly variable. Interferon alfa-2b has also proven effective in treating chylothorax associated with GSS. In some cases, bisphosphates and interferon alfa-2b have been used concurrently to treat affected individuals.
There is one case report describing the effective use of a drug known as bevacizumab for the treatment of a patient with GSS. Bevacizumab is a drug that blocks the formation of new blood vessels (anti-angiogenesis) and is used to treat some forms of cancer. However, clinical trials involving larger numbers of patients are required to determine the long-term safety and effectiveness of such a therapy for GSS.
Additional medications that promote bone regeneration and decrease bone metabolism have been used to treat individuals with GSS include vitamin D, cisplatin, bleomycin, magnesium, estrogen, fluoride, calcium and the hormone calcitonin. The effectiveness of such therapies is highly variable and inconsistent.
Focused GSS research has just begun via the Lymphatic Malformation Institute (LMI) to determine the cause. Further research – beyond cause – will be the development of clinical trials. Important resources in new trials will be identifying targets, developing animal models, identifying compounds, the recently developed International Patient Registry by the Lymphangiomatosis & Gorham’s Disease Alliance, the basic and translational research funded by the Lymphatic Malformation Institute, and the Biobank at NDRI for tissue donated from patients with GSS and generalized lymphatic anomaly (lymphangiomatosis).
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD:
NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: http://www.clinicaltrailsregister.eu/
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Report last updated: 2013/10/25 00:00:00 GMT+0