Última actualización:
February 07, 2017
Años publicados: 1991, 2002, 2005, 2013, 2014, 2017
NORD gratefully acknowledges Francine Blei, MD, MBA, Medical Director, Vascular Anomalies Program, Lenox Hill Hospital of Northwell Health; 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.
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) and 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 jaw. 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
The lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph is fluid that contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through a 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. GSD is a rare disease that is thought to be caused by an error in the development of the lymphatic system. In individuals with GSD, bones become infiltrated with lymphatic vessels and are broken down and replaced by a fibrous band of connective tissue.
The symptoms of GSD depend upon the specific bones involved. The ribs, spine, pelvis, skull, collarbone (clavicle), and jaw are the most commonly affect bones in GSD. 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. Trauma is often a trigger of the initial presentation of the disease. Bones affected by GSD are prone to pathological fractures.
When GSD affects the maxillofacial area, pain, loose teeth, fractures and facial deformity may develop.
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). 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 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 fat. 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 also occur in patients with GSD.
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 prognosis for GSD patients is uncertain and variable and depends 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 of time.
The exact cause of GSD is unknown. No environmental, immunological or genetic risk factors have 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. 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 investigators have speculated that circulation issues lead to a deficiency of oxygen being delivered to affected areas, which, in turn, causes changes in pH and promotes the activity of specific enzymes that ultimately cause the destruction of bone.
Osteoclasts are large cells that degrade bone. Several reports suggest that osteoclasts play a role in the resorption of bone in GSD. Active osteoclasts have been observed in histological samples from some patients with GSD. Additionally, CTX-1 (a circulating marker of osteoclast activity) has been reported to be elevated in several GSD patients. It has been suggested that osteoclast precursors in GSD patients are more sensitive to osteoclast-inducing factors than osteoclasts precursors in unaffected individuals. Also, interleukin-6 (a factor that induces osteoclast formation) has been reported to be elevated in some patients with GSD. More recently, a basic science study revealed that lymphatic endothelial cells (LECs) express a high level of macrophage colony stimulating factor (M-CSF), a factor that induces the development of osteoclasts. Interestingly, LECs were found to induce osteoclast formation and activity in an M-CSF dependent manner. More work is required to elucidate the role of osteoclasts in GSD.
Taken together, the specific reason that GSD develops is simply not well understood. More research is necessary to determine the exact cause and underlying mechanisms that ultimately result in GSD.
GSD 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 300 affected individuals 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.
There is no specific test or procedure that definitively diagnoses GSD, 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 the extent of the disease and in detecting soft tissue involvement. In the finding of the presence of bone loss, full-body skeletal scans are useful in the differential diagnosis – especially related to the closely related, multifocal GLA disorder. Newer imaging techniques provide anatomic clarity, such as non-contrast magnetic resonance (MR) lymphangiogram, dynamic contrast MR lymphangiography and intranodal lymphangiogram are available at some institutions.
Treatment
GSD (and GLA) can present at any age. Diagnosis, treatment, and care generally require a multidisciplinary team. Access to care is available through the worldwide Vascular Anomalies Clinical Network. For more information on expertise and consult, contact the Lymphangiomatosis & Gorham’s Disease Alliance.
There is no consensus in the medical literature as to what is the most effective treatment for GSD. Treatment is usually directed toward the specific symptoms that are apparent in each individual.
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, positive results were achieved using a total dose of 15 Gy in an individual with GSD affecting the upper extremity.
Some individuals with GSD have been treated with medications that inhibit bone resorption (bisphosphonates) such as pamidronate or zoledronic acid. Some individuals have also been treated with interferon alfa-2b, which inhibits the formation of blood and lymphatic vessels. These treatments have led to the improvement of symptoms (e.g., pain), but individual response is highly variable. In some cases, bisphosphates and interferon alfa-2b have been used concurrently to treat affected individuals.
Additional medications that promote bone regeneration and decrease bone metabolism that 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.
Sirolimus, an mTOR inhibitor, is a novel therapy increasingly being used to treat GSD. However, clinical trials involving larger numbers of patients are required to determine the effective dose, duration of treatment, and effectiveness of such a therapy for GSD. In the future, the International Patient Registry by the Lymphangiomatosis & Gorham’s Disease Alliance (https://www.lgdalliance.org/registry) will assist in the development of future clinical trials.
Supported by the Lymphatic Malformation Institute, and others, the Vascular Anomalies Center (VAC) at Boston Children’s Hospital has established a data registry for patients with rare, complicated lymphatic conditions. The Lymphatic Anomalies Registry is seeking to collect clinical data from patients to improve the understanding of these diseases – including GSD and GLA.
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, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
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:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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