Dysregulated miRNAs in bone cells of patients with Gorham-Stout disease.

Gorham-Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR-1246, miR-1-3p, and miR-137-3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR-1246 was also up-regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR-204a-5p, miR-615-3p and miR-378a-3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.

Complex Lymphatic Anomalies and Therapeutic Options.

Complex lymphatic anomalies include a variety of disorders with overlapping clinical, histological and imaging features. The often-confusing nomenclature used for lymphatic anomalies limits timely diagnosis and treatment. The updated 2018 classification of the International Society for the Study of Vascular Anomalies divides lymphatic anomalies into several subsets.1 Newer imaging techniques including intranodal and magnetic resonance lymphangiography have improved our understanding of anatomy and function of the lymphatic system. Advances in medical, interventional, and surgical treatments have opened a realm of new therapeutic options for patients with complex lymphatic disorders.

Gorham's disease: treatment with an autologous iliac bone graft and a reverse total shoulder arthroplasty.

BACKGROUND: Gorham's disease (GSD) is a rare osteolytic disease with unclear etiology, and no known prevention or effective treatment. Here we report a new surgical treatment for a case of GSD in September 2017. CASE PRESENTATION: We report GSD in a 52-year-old woman. She had disappearance of her humeral head and a defect of the glenoid bone in her left shoulder joint, which were serious obstacles to joint function. We used an autologous iliac bone graft to repair the glenoid bone defect and a reverse total shoulder arthroplasty. After surgery, humeral osteolysis did not continue, and her shoulder function recovered well. CONCLUSIONS: This case suggests that autologous bone grafting can still be used to treat GSD despite it being an osteolytic disease. The successful treatment suggests that this method could be used for GSD in other bones.

A Child with Early-Onset Gorham-Stout Disease Complicated by Chylothorax: Near-Complete Regression of Bone Lesions with Interferon and Bisphosphonate Treatment.

We report a case of Gorham-Stout disease (GSD) complicated by chylothorax and treated with a combination therapy with interferon and bisphosphonates. This treatment may be helpful in improving the usually unfavorable prognosis of GSD beginning with a chylothorax before 1 year of age, and in reducing bone lesions. Moreover, the use of bisphosphonates appears to be useful in treating pain.

An overview of the neurosurgical implications, pathophysiology, diagnosis and recent treatment strategies for Grade IV idiopathic osteolysis, also known as Gorham-Stout or phantom bone disease.

OBJECTIVE: Gorham-Stout disease (GSD), commonly referred as vanishing bone or phantom bone disease, is a rare disorder characterized by spontaneous bone osteolysis due to proliferation of lymphangiomatous tissue. This disease can involve multiple bones and cause pathologic fractures. The exact cause of GSD is unknown and its severity is unpredictable; the disorder can potentially cause disfigurement or functional disability. According to CARE guidelines, we studied a 46 years old lady with a progressive defect of the skull. Differential diagnosis included: benign and malignant diploic lesions (eosinophylic granuloma of the skull, myeloma, lytic metastasis from unknown primary tumour, etc) and osteomyelitis. A suspicion of GSD was raised by coupling information from laboratory and nuclear medicine investigations, and eventually confirmed histologically. CONCLUSION: We included early in the investigation protocols a total body fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan that was extremely helpful to promptly rule out malignant or infective nature of osteolysis. An update on the diagnostic and management options available for GSD, with particular reference to the role of nuclear medicine and the latest clinical trials from international patients registries and classification of idiopathic osteolysis is provided.

Intracranial hypotension and hypertension: reversible Chiari malformation due to dynamic cerebrospinal fluid abnormalities in Gorham-Stout disease. Case report.

Gorham-Stout disease (GSD) is an intractable disease characterized by massive osteolysis caused by abnormal lymphangiogenesis in bone. In rare cases of GSD, CSF abnormalities develop. The authors present the case of a 19-year-old woman with GSD presenting with orthostatic headache due to intracranial hypotension (5 cm H2O). The clinical course of this case was very unusual. Orthostatic headache was associated with a CSF leak from the thigh after pathological fractures of the femur and pelvis. The chronic CSF leak led to acquired Chiari malformation (CM) with syringomyelia. After an epidural blood patch, her neurological status improved; however, after the complete arrest of the CSF leak from the thigh, she presented with severe nonpostural headache and progressive visual acuity loss with optic papilledema. A ventriculoperitoneal shunt was placed to treat intracranial hypertension (50 cm H2O). Headache improved and optic papilledema decreased after shunt surgery. This case shows that dynamic CSF abnormalities may lead to reversible CM in patients with GSD. Sealing a CSF leak rather than performing suboccipital decompression is recommended for acquired CM resulting from a CSF leak.

Mandibular Gorham-Stout disease: A case report and literature review.

RATIONALE: Gorham-Stout disease (GSD) is characterized by aggressive bone resorption, proliferation of vascular or lymphatic vessels, and soft-tissue swelling. Bones that initially appear normal start to resorb, partially or completely. However, the etiology of GSD is unknown. PATIENT CONCERNS: A 29-year-old man with a chief complaint of toothache and mobility in the lower right mandible for the previous 1 year. DIAGNOSES: Gorham-Stout disease (GSD). INTERVENTIONS: The RANK-ligand inhibitor denosumab was suggested to use to inhibit the development of osteoclasts and slow mandibular resorption. In addition, we proposed resection of the remaining mandible and reconstruction via vascularized bone graft, after resorption of the mandible had become stationary. OUTCOMES: Regular follow-ups were advised to this patient to monitor the stability of bone resorption prior to any surgical intervention. LESSONS: We strongly recommend that every attempt should be made for early diagnosis and prompt effective medical and surgical management. The failure to do so results in further complications and poor prognosis.

Sirolimus on Gorham-Stout disease. Case report / Sirolimus en la enfermedad de Gorham-Stout. Caso clínico

Abstract Background: Gorham-Stout disease (GSD) is a rare disease of unknown etiology characterized by vascular proliferation that produces destruction of bone matrix. Case description: This case is about 43 year old woman who begins with pain in sternum, dyspnea, abdominal mass and, serous-hematic pleural effusion. Imaging tests were performed showing lesions on 6th and 10th left ribs archs. Later, a thoracotomy was performed observed absence of the end of the 6th and lung, pleural and costal biopsy was token. The histologic features described lymphatic vascular proliferation in bone tissue of chest wall. Other pathologies were excluded and in view of the findings, GSD diagnosis was made. Treatment and outcome: treatment was initiated with sirolimus achieving remission of the disease after the first month; however, because the presence of metrorrhagia the treatment was discontinued, reappearing symptoms afterwards. For that reason the treatment was restarted getting disappearance of the symptoms again, 4 weeks later. Clinical relevance: we present the first clinical cases of EGS with pleural effusion with response to sirolimus treatment that could be an alternative to the current therapy.

Resumen Antecedentes: La enfermedad de Gorham-Stout (EGS), es una enfermedad poco común, de etiología desconocida, caracterizada por la proliferación vascular que produce destrucción de la matriz ósea. Caso clínico: Se presenta el caso de mujer de 43 años que comienza con dolor en el esternón, disnea y tumoración abdominal junto con derrame pleural izquierdo de características serohemáticas como forma de presentación de una EGS. En pruebas de imagen que mostraron lesiones líticas en el 6º y 10º arcos costales izquierdos. Posteriormente se realizó toracotomía con biopsia pulmonar, pleural y costal observándose ausencia del extremo de la 6ª costilla. En el estudio histopatológico se describe proliferación vascular linfática en tejido óseo de pared costal. Se excluyeron otras patologías y se diagnosticó EGS. Tratamiento y resultado: Se inició tratamiento con sirolimus consiguiendo remisión completa desde el primer mes. Sin embargo, tras la suspensión del tratamiento por metrorragias, presentó reaparición de los síntomas. Se decide entonces reiniciar el tratamiento, consiguiendo nuevamente desaparición de los síntomas, tras 4 semanas de tratamiento. Relevancia clínica: Se presenta el primer caso clínico de EGS en edad adulta con derrame pleural asociado y con respuesta clínica a sirolimus, fármaco que podría ser una alternativa a la terapéutica actual.

Gorham-Stout Disease of the Skull Base With Hearing Loss: Dramatic Recovery and Antiangiogenic Therapy.

Gorham-Stout disease (GSD) is a rare disorder of unknown etiology. We present a 6-year-old male with GSD involving the skull base who presented with recurrent cerebrospinal fluid (CSF) rhinorrhea, severe hearing loss, and facial palsy secondary to cerebellar herniation into the internal auditory canal. After 2 months of treatment with pegylated interferon (IFN) α-2b (50 µg/week), his hearing recovered dramatically. Two years later, new bone formation appeared radiologically and IFN was switched to sirolimus. One year after the switch, CSF rhinorrhea disappeared. Antiangiogenic therapy might inhibit proliferation of vascular endothelial cells in osteolytic lesions and lead to new bone formation.

Sirolimus on Gorham-Stout disease. Case report.

BACKGROUND: Gorham-Stout disease (GSD) is a rare disease of unknown etiology characterized by vascular proliferation that produces destruction of bone matrix. CASE DESCRIPTION: This case is about 43 year old woman who begins with pain in sternum, dyspnea, abdominal mass and, serous-hematic pleural effusion. Imaging tests were performed showing lesions on 6th and 10th left ribs archs. Later, a thoracotomy was performed observed absence of the end of the 6th and lung, pleural and costal biopsy was token. The histologic features described lymphatic vascular proliferation in bone tissue of chest wall. Other pathologies were excluded and in view of the findings, GSD diagnosis was made. TREATMENT AND OUTCOME: treatment was initiated with sirolimus achieving remission of the disease after the first month; however, because the presence of metrorrhagia the treatment was discontinued, reappearing symptoms afterwards. For that reason the treatment was restarted getting disappearance of the symptoms again, 4 weeks later. CLINICAL RELEVANCE: we present the first clinical cases of EGS with pleural effusion with response to sirolimus treatment that could be an alternative to the current therapy.

ANTECEDENTES: La enfermedad de Gorham-Stout (EGS), es una enfermedad poco común, de etiología desconocida, caracterizada por la proliferación vascular que produce destrucción de la matriz ósea. CASO CLÍNICO: Se presenta el caso de mujer de 43 años que comienza con dolor en el esternón, disnea y tumoración abdominal junto con derrame pleural izquierdo de características serohemáticas como forma de presentación de una EGS. En pruebas de imagen que mostraron lesiones líticas en el 6º y 10º arcos costales izquierdos. Posteriormente se realizó toracotomía con biopsia pulmonar, pleural y costal observándose ausencia del extremo de la 6ª costilla. En el estudio histopatológico se describe proliferación vascular linfática en tejido óseo de pared costal. Se excluyeron otras patologías y se diagnosticó EGS. TRATAMIENTO Y RESULTADO: Se inició tratamiento con sirolimus consiguiendo remisión completa desde el primer mes. Sin embargo, tras la suspensión del tratamiento por metrorragias, presentó reaparición de los síntomas. Se decide entonces reiniciar el tratamiento, consiguiendo nuevamente desaparición de los síntomas, tras 4 semanas de tratamiento. RELEVANCIA CLÍNICA: Se presenta el primer caso clínico de EGS en edad adulta con derrame pleural asociado y con respuesta clínica a sirolimus, fármaco que podría ser una alternativa a la terapéutica actual.

Viewpoints on vessels and vanishing bones in Gorham-Stout disease.

Gorham-Stout disease (GSD) is a rare disorder characterized by the proliferation of endothelial-lined vessels in bone and the progressive destruction of bone. Although Jackson described the first case of GSD in 1838, the clinical and histological features of GSD were not defined until Gorham and Stout published their report on massive osteolysis in 1955. In the years since Gorham and Stout's groundbreaking publication, more than 300 cases of GSD have been described in the literature. These reports have revealed that the progressive resorption of bone in GSD causes severe physical deformities, disabilities, and life-threatening complications. Unfortunately, the underlying cause of GSD remains unknown and, as a result, the therapeutic options for individuals with GSD are limited. Here we review the latest advances in GSD research and present strategies to address basic and clinical research questions related to GSD.

Gorham-Stout syndrome of the facial bones: a review of pathogenesis and treatment modalities and report of a case with a rare cutaneous manifestations.

Gorham disease is a very rare condition associated with spontaneous destruction and resorption of 1 or more bones anywhere in the body. Many authors have suggested and/or implicated trauma as the initiating factor in the majority of the reported cases. It can affect almost all bones, and a combination of bones has been reported. In the maxillofacial skeleton, the first facial case was reported by Romer in 1928. Until now, only a few cases of Gorham disease affecting the maxillofacial bones, including this case report, have been reported. We present a brief review of the pathogenesis and treatment modalities of the disease and report a very rare clinical picture of the disease affecting a young and otherwise healthy patient with massive osteolysis of the mandibular bone and extensive involvement of the mouth floor and skin of the chin, which to our knowledge, is the only case report with skin manifestation affecting the maxillofacial region. Such skin manifestations play an important role for the diagnosis and add a clue for management of such condition.

Gorham-Stout disease.

Gorham-Stout disease is a rare disease of unknown etiology. It is characterized by spontaneous excessive replacement of bone by proliferative non-neoplastic thin-walled lymphatic and/or blood vessels. Histology shows positive stain for the lymphatic endothelial marker LYVE-1 (lymphatic vascular endothelial hyaluronan receptor-1) and many lymphatic growth factors (PDGF-BB, VEGF-C, VEGFR-3). Patients may present with localized pain and/or weakness and radiographic evidence of massive osteolysis involving contiguous bone structures. The disease usually progresses and complications may occur with significant morbidity and mortality. Close monitoring of these patients is recommended. Treatment remains challenging. Surgical treatment has been combined with pre- and postoperative radiation therapy. Drug regimes including bisphosphonates and vitamin D have been used with various results. Currently, the most effective agent is INF-alpha due to its anti-angiogenic effect. The effect of the newer immunomodulatory agents such as the OK-432 remains to be proved.

Neuropathic arthropathy of the shoulder associated with syringomyelia: a report of six cases.

Here, we report a series of 5 patients (6 shoulders) diagnosed with neuropathic arthropathy of the shoulder joint in our clinic between 2005 and 2008. Initial diagnosis, previous treatment, and radiological and clinical follow-up findings were reviewed. The mean age at diagnosis was 44.2 years. Four patients had unilateral and 1 patient had bilateral involvement. The presenting symptoms were pain, swelling, and loss in range of motion. Active forward flexion and abduction ranged from 0° to 90°. Hypoesthesia and loss of temperature sense was evident in 3 patients. Radiographs showed massive osteolysis of humeral head and glenoid process, and magnetic resonance imaging showed periarticular fluid collection, and degeneration at the rotator cuff and shoulder joint, resembling chronic septic arthritis or sarcoma. Biopsy was performed in 4 patients before definitive diagnosis, and synovial hypertrophy and necrotic bone was found. Two patients had a history of operated cervical syringomyelia, and the remaining 3 patients were later diagnosed to have syringomyelia and referred to neurosurgery clinic, where 2 of those were operated. Four patients were followed-up with symptomatic therapy, and 1 patient underwent an unsuccessful shoulder arthroplasty in another clinic. As a conclusion, neuropathic arthropathy of the shoulder is rare, and correct diagnosis is possible by careful physical and neurological examination and pathologic evaluation when needed.

Gorham's disease of the fibula: a case report.

UNLABELLED: Gorham's disease, or massive osteolysis, is a rare condition characterized by the spontaneous onset of osteolysis in an otherwise healthy individual. Such osteolysis is related to localized endothelial proliferation of lymphatic vessels (lymphangiomatous osteolysis) resulting in destruction and absorption of bone, and is commonly thought to affect primarily cancellous bone. In this article, we describe a case of Gorham's disease involving the fibula in a 13-year-old boy with a 2-year history of pain and a 1-year history of muscle atrophy. The patient was treated with analgesics and anti-inflammatory drugs, and a period of immobilization. At the 3-year follow-up visit, the patient was ambulating without restrictions, although he experienced occasional episodes of pain and swelling localized to the left ankle; and follow-up radiographs revealed no further progression of the disease. Current literature suggests that the fibula, being primarily cortical bone, is not likely to be affected by Gorham's disease and that fibular grafts may be used in the treatment of the disorder. However, since this case depicts the disorder localizing to the distal fibula, we believe further studies are needed to validate the usefulness of fibular grafts in the treatment of the condition. Because the course of the disease is unpredictable and may arrest spontaneously, and based on the results observed in the patient described in this article, conservative treatment may be appropriate for Gorham's disease localized to the distal fibula. LEVEL OF CLINICAL EVIDENCE: 4.

Gorham's disease of skull base and cervical spine--confusing picture in a two year old.

The unusual presentation of Gorham's disease of skull base and cervical spine in a two-year-old female child with radiological signs mimicking those of raised intracranial pressure is discussed. The differential diagnosis consists of skull base tumours, meningitis, osteomyelitis of the base of skull, congenital hydrocephalaus and congenital syndromes involving the skull base. Pathologically it can be very difficult to differentiate it from lymphangioma of the bone. Difficulty in establishing the diagnosis is discussed along with failure of radiotherapy and palmidronate therapy to cause arrest of the disease process and failure of surgery to provide stabilisation. We describe the course of the disease in this child over the period of last eight years. To the best of our knowledge this is the youngest case of Gorham's described so far.