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Gorham-Stout Disease

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Copyright 1991, 2002, 2005, 2013, 2014

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.

Synonyms of Gorham-Stout Disease

Disorder Subdivisions

General Discussion

Summary
Gorham-Stout disease (GSD), 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 GSD 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 GSD are prone to reduced bone mass (osteopenia) and fracture. The severity of GSD can vary from one person to another and the disorder can potentially cause disfigurement and functional disability of affected areas. The exact cause of GSD is unknown.

Introduction
While GSD 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 GSD.

GSD is sometimes classified as a form of lymphangiomatosis. GSD 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.

Symptoms

The specific symptoms and severity of Gorham-Stout disease are highly variable and depend, in part, on the specific areas of the body affected. GSD 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 GSD is also highly variable as the rate of progression of bone loss is unpredictable. Generally, GSD 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). GSD 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 GSD, 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 GSD. 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 GSD include those of the face and jaws (maxillofacial area) ribs, spine, pelvis, skull, and collarbone (clavicle). Virtually any bone can potentially be affected in GSD, however, one study found that the extremities and pelvis were more frequently affected in GLA than GSD. Furthermore, patients with GSD 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 GSD are prone to pathological fractures. In some cases, surrounding soft tissue may slowly waste away (soft tissue atrophy).

When GSD 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 GSD 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 GSD is variable, and the results are hardly predictable. The prognosis for GSD 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.

Causes

The exact cause of Gorham-Stout disease 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 GSD has not been identified. Most cases occur randomly for no known reason (sporadically).

Bone loss in GSD 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 GSD.

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 GSD, 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 GSD. 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 GSD. Additionally, abnormal osteoclast activity is not identifiable in everyone with GSD either.

The specific reason(s) that GSD 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 GSD.

Affected Populations

Gorham-Stout disease 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 GSD 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 GSD is so rare, many cases go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of Gorham-Stout disease. 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 GSD 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.)

Standard Therapies

Diagnosis
There is no specific test or procedure that definitively diagnoses Gorham-Stout disease, 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.

Treatment
There is no specific treatment of individuals with GSD 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 GSD. 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 GSD. 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 GSD.

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 GSD affecting the upper extremity.

Investigational Therapies

According to the medical literature some individuals with Gorham-Stout disease 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 GSD. 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 GSD. 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 GSD.

Additional medications that promote bone regeneration and decrease bone metabolism have been used to treat individuals with GSD include vitamin D, cisplatin, bleomycin, magnesium, estrogen, fluoride, calcium and the hormone calcitonin. The effectiveness of such therapies is highly variable and inconsistent.

Focused GSD 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 GSD 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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: http://www.clinicaltrailsregister.eu/

Organizations related to Gorham-Stout Disease

References

JOURNAL ARTICLES
Dellinger, M. T., Garg, N, Olsen, B.R., 2014. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 63C, 47-52.
http://www.ncbi.nlm.nih.gov/pubmed/24583233

Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation. Skeletal Radiology. 2013;42:917-24. http://www.ncbi.nlm.nih.gov/pubmed/23371338

Noda M, Endo C, Hoshikawa Y, Ishibashi N, Suzuki T, Okada Y, et al. Successful management of intractable chylothorax in Gorham-Stout disease by awake thoracoscopic surgery. Gen Thorac Cardiovasc Surg. 2013;61:356-8. http://www.ncbi.nlm.nih.gov/pubmed/22865280

Robinson HA, Kwon S, Hall MA, Rasmussen JC, Aldrich MB, Sevick-Muraca EM. Non-invasive optical imaging of the lymphatic vasculature of a mouse. J Visual Exper. 2013(73):e4326. http://www.ncbi.nlm.nih.gov/pubmed/23524658

Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, et al. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest. 2012;122:3101-13. http://www.ncbi.nlm.nih.gov/pubmed/3428080

Gordon KD, Mortimer PS. Progressive lymphangiomatosis and Gorham’s disease: care report and clinical implications. Lymphat Res Biol. 2011;9:201-204. http://www.ncbi.nlm.nih.gov/pubmed/22196286

Kiran DN, Anupama A. Vanishing bone disease: a review. J Oral Maxillofac Surg. 2011;69:199-203. http://www.ncbi.nlm.nih.gov/pubmed/21030127

Blei F. Lymphangiomatosis: clinical overview. Lymphat Res Biol. 2011;185-190. http://www.ncbi.nlm.nih.gov/pubmed/22196283

Garbers E, Reuther F, Delling G. Report of a rare case of Gorham-Stout disease of both shoulders: bisphosphonate treatment and shoulder replacement. Case Reports in Rheumatology. 2011;2011:565142. http://www.ncbi.nlm.nih.gov/pubmed/22937447

Grunewald TG, Damke L, Maschan M, et al. First report of effective and feasible treatment of multifocal lymphangiomatosis (Gorham-Stout) with bevacizumab in a child. Ann Oncol. 2010;21:1733-1734. http://www.ncbi.nlm.nih.gov/pubmed/20605931

Kuriyama DK, McElligott SC, Glaser DW, Thompson KS. Treatment of Gorham-Stout disease with zoledronic acid and interferon-alfa: a case report and literature review. J Pediatr Hematol Oncol. 2010;32:579-584. http://www.ncbi.nlm.nih.gov/pubmed/20962674

Kose M, Pekcan S, Dogru D, et al. Gorham-Stout syndrome with chylothorax: successful remission by interferon alpha-2b. Pediatr Pulmonol. 2009;44:613-615. http://www.ncbi.nlm.nih.gov/pubmed/19434689

Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol. 2008;52:799-806. http://www.ncbi.nlm.nih.gov/pubmed/18755341

Radhakrishnan K, Rockson SG. Gorham’s disease: an osseous disease of lymphangiogenesis? Ann NY Acad Sci. 2008;1131:203-205. http://www.ncbi.nlm.nih.gov/pubmed/18519972

Papadakis SA, Khaldi L, Babourda EC, et al. Vanishing bone disease: review and case reports. Orthopedics. 2008;31:278. http://www.ncbi.nlm.nih.gov/pubmed/19292231

Parihar V, Yaday YR, Sharma D. Gorham’s disease involving the left parietal bone: a case report. Cases J. 2008;1:258. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580766/

Underwood J, Buckley J, Manning B. Gorham disease: an intraoperative case study. AANA J. 2006;74:45-48. http://www.ncbi.nlm.nih.gov/pubmed/16483068

Hagendoorn J, Padera TP, Yock TI, et al. Platelet-derived growth factor receptor-beta in Gorham’s disease. Nat Clin Pract Oncol. 2006;3:693-697. http://www.ncbi.nlm.nih.gov/pubmed/17139320

Takahashi A, Ogawa C, Kanazawa T, Watanabe H, Suzuki M, Suzuki N, et al. Remission induced by interferon alfa in a patient with massive osteolysis and extension of lymph-hemangiomatosis:a severe case of Gorham-Stout syndrome. J Pediatr Surg. 2005 Mar;40(3):E47-50. http://www.ncbi.nlm.nih.gov/pubmed/15793714

Leite, Hernandez-Martin, Colmenero, Lopez-Gutierrez, Torrelo, Invasive lymphatic malformation (gorham-stout) of the pelvis with prominent skin involvement. Pediatr Dermatol. 2013 May-Jun;30(3):374-8. doi: 10.1111/j.1525-1470.2012.01814.x. Epub 2012 Jul 24.]
http://www.ncbi.nlm.nih.gov/pubmed/22823281

Trenor,C. Clinical Features of Generalized Lymphatic Anomaly And Gorham-Stout Disease, 1st International Conference on Generalized Lymphatic Anomaly and Gorham-Stout Syndrome, Bethesda, MD, USA, 7-8 June 2013

Hammer F, Kenn W, Wesselmann U, Hofbauer LC, Delling G, Allolio B, et al. Gorham-Stout disease--stabilization during bisphosphonate treatment. J Bone Miner Res. 2005 Feb;20(2):350-3. http://www.ncbi.nlm.nih.gov/pubmed/15647829

Malde R, Agrawal HM, Ghosh SL, Dinshaw KA. Vanishing bone disease involving the pelvis. J Cancer Res Ther. 2005;1:227-228. http://www.ncbi.nlm.nih.gov/pubmed/17998658

Patel DV. Gorham’s disease or massive osteolysis. Clin Med Res. 2005;2:65-74. http://www.clinmedres.org/cgi/content/full/3/2/65

Duffy BM, Manon R, Patel RR, Welsh JS. A case of Gorham’s disease with chylothorax treated curatively with radiation therapy. Clin Med Res. 2005;3:83-86. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183437/

Fontanesi J. Radiation therapy in the treatment of Gorham disease. J Pediatr Hematol Oncol. 2003;25:816-817. http://www.ncbi.nlm.nih.gov/pubmed/14528108

Devlin RD, Bone HG 3rd, Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease. J Clin Endocrinol Metab. 1996;81:1893-1897. http://jcem.endojournals.org/content/81/5/1893.short

Heyden G, Kindblom LG, Nielsen JM. Disappearing bone disease. A clinical and histological study. The Journal of bone and joint surgery American volume. 1977 Jan;59(1):57-61. http://www.ncbi.nlm.nih.gov/pubmed/833176

Report last updated: 2014/10/09 00:00:00 GMT+0