Cystic angiomatosis of bone/Gorham-Stout disease (GSD)

(OMIM phenotype number #123880)

Cystic angiomatosis of bone/Gorham-Stout disease (GSD), (also known as massive osteolysis, vanishing bone disease, and phantom bone disease) is a rare disease characterized by the proliferation of endothelial-lined vessels in bone, resulting in destruction of osseous matrix and absorption of bone and possible visceral involvement. GSD can present at any age, but is most commonly diagnosed in children and young adults (average age of diagnosis is 25 years). This disorder does not display a clear race, geographic distribution and sex predilection (1.6:1 male-to-female ratio) or inheritance pattern. More than 300 cases of GSD have been described in the literature. The etiology is unknown, although several theories exist. One or multiple bones can be affected, including the skull, the upper and lower extremities, the spine and pelvis. The clinical manifestations are, most frequently: pain, functional impairment and swelling of the affected region. Nevertheless, some asymptomatic cases have been described. The disease has a benign character, but its prognosis is unpredictable and there can be physical deformities, disabilities, and several possible serious complications (pleural effusion, chylothorax, hemangiomatosous cutaneous lesions, bone infection and subsequent septic shock, spinal cord involvement and paraplegia due to vertebral lesion and cerebrospinal fluid leakage and meningitis). The differential diagnosis of the GSD includes: hereditary multicentric osteolysis, osteolysis with nephropathy, osteomyelitis, rheumatoid arthritis, osteolysis due to intraosseous malignacies, hyperparathyroidism, eosinophilic granuloma and osteolysis due to diseases of central nervous system, like syringomyelia and tabes dorsalis.

The diagnosis of the syndrome is challenging. Laboratory findings are not indicative except alkaline phosphatase (ALP), which may be slightly high. Moreover, some studies have shown that VEGF-A and IL-6 concentrations can be high in the circulation of patients affected by GSD and that the level of these factors can decrease after some treatments. However, VEGF-A and IL-6 are not elevated in all GSD patients. Plain X-rays, initially, show radiolucent foci in the intramedullary or subcortical regions and, later, slowly progressive atrophy, dissolution, fracture, fragmentation and disappearance of a part of a bone. On the other side, bone scan and magnetic resonance imaging give variable results. The disease is confirmed by the histopathological analysis of the lesions, showing nonmalignant hyperproliferation of small vessels. Heffez et al suggested the following 8 diagnostic criteria of Gorham-Stout syndrome: (1) positive biopsy findings in terms of angiomatous tissue presence; (2) absence of cellular atypia; (3) minimal or no osteoclastic response and absence of dystrophic calcifications; (4) evidence of local bone progressive resorption; (5) non-expansive, non-ulcerative lesion; (6) absence of visceral involvement; (7) osteolytic radiographic pattern; and (8) negative hereditary, metabolic, neoplastic, immunologic and infectious etiology.

The therapeutic options for individuals with GSD are limited and include: medicine therapy (biphoshonates, interferon alfa-2b..), radiation and surgery (resection of the lesion and reconstruction by use of bone grafts and/or prostheses, pleurectomy, pleurodesis, thoracentesis...). Biphoshonates have been successfully used showing an antiosteolytic activity. Some individuals have been treated with interferon alfa-2b, which inhibits the formation of lymphatic vessels (anti-angiogenic). Besides, other pharmacologic agents, like vitamin D, calcium, adrenal extracts and androgens have been suggested. Further clinical trials are needed to test the efficacy of therapies against GSD.

Gene

GSD is a sporadic disease potentially caused by specific genetic risk factors or by mosaicism for a somatic mutation.

Phenotype

Inherited osteolysis disorder characterized by destruction and resorption of affected bones with subsequent skeletal deformities and functional impairment. Early-onset progressive osteolysis of one or more bones always associated with an angiomatosis of blood vessels and sometimes of lymphatics, history of fragility fractures, and vascular malformations in the affected bones or surrounding soft tissues, multiple dilated vascular spaces replacing normal bone marrow elements, disseminated multifocal vascular lesions of the skeleton with possible visceral involvement, bony deformities, muscular weakness and localized pain.

Main biochemical alterations

High IL-6 (not always), high serum fibrinogen, high serum D-dimer, high ESR, high CD105/endoglin, ALP slightly high.

Images

Fig. Radiographs show (a) the right hip of a 77-year-old woman ten weeks after a fall, with complete resorption of the proximal femur, (b) the right shoulder of a 83-year-old woman with massive osteolysis of the proximal humerus, and (c) the right shoulder of a 56-year-old woman with disappearance of the head of the right humerus leaving only bone fragments. 

Reproduced with permission and copyright © of the British Editorial Society of Bone and Joint Surgery [Möller G, Priemel M, Amling M, et al. The Gorham-Stout syndrome (Gorham's massive osteolysis). A report of six cases with histopathological findings. J Bone Joint Surg Br. 1999 May;81(3):501-6].

Other resource

Lymphangiomatosis & Gorham’s Disease Alliance, Inc. (LGDA)

References

  1. Dellinger MT, Garg N, Olsen BR. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 2014 Jun;63:47-52.
  2. Nikolaou VS, Chytas D, Korres D, et al. World J Orthop. 2014 Nov 18;5(5):694-8. Vanishing bone disease (Gorham-Stout syndrome): A review of a rare entity.
  3. Heffez L, Doku HC, Carter BL, et al. Perspectives on massive osteolysis. Report of a case and review of the literature. Oral Surg Oral Med Oral Pathol. 1983 Apr;55(4):331-43.
  4. Hardegger F, Simpson LA, Segmueller G. The syndrome of idiopathic osteolysis. Classification, review, and case report. J Bone Joint Surg Br. 1985 Jan;67(1):88-93.
  5. Devlin RD, Bone HG 3rd, Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease.
  6. J Clin Endocrinol Metab. 1996 May;81(5):1893-7.
  7. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  8. http://www.omim.org