Gorham-Stout Disease Research Articles

Effective Use of ALK Inhibitors in EML4::ALK-Positive Lymphatic Malformations.

Genetically targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK-positive LMs, one with Gorham Stout disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly targeted therapies for LMs.

Gorham-Stout disease and multiple cervical lymphangiomas: case report.

Gorham-Stout disease is a rare condition characterized by extensive bone loss due to the proliferation of new vascular and lymphatic structures. It can occur in any bone and cause pathologic fractures with poor bone healing. Complications such as effusions and lymphangiomas can also develop. Gorham-Stout disease pathogenesis is still being studied, and treatment options are limited, but sirolimus has shown promise in stabilizing or reducing symptoms. We present a case of a 19-year-old male with Gorham-Stout disease, multiple cervical lymphangiomas, and several thoracic complications successfully treated with sirolimus. Rare lymphatic diseases should be considered as a potential cause in adult patients with bone involvement and multiple cystic lesions in the neck, axillary, or abdominal regions after excluding more common causes. The complexity of diagnosing Gorham-Stout disease should be emphasized.

Symposium Highlight: PULMONARY LYMPHATICS HISTORY, ANATOMY, AND PATHOPHYSIOLOGY: EMERGING KNOWLEDGE AND A LOOK TO THE FUTURE

Central lymphatic disorders of the lung have not received intense investigation. Lymphatic system physiology is presented in the context of historical developments and basic lung lymphatic anatomy is reviewed followed by emerging characteristics of primary and secondary pathophysiological disturbances of lymphatic involvement in a number of pulmonary diseases including Gorham-Stout disease, pulmonary edema and infections and inflammatory conditions including lymphangioleiomyomatosis (LAM). The future includes potential molecular targeting of lymphangiogenesis or lymphatic vessels for interventional occlusion. This article is an amalgamation of presentations at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease and as part of a Special Symposium on the Lymphatic system of the Heart and Lung in Health and Disease at the 26th International Congress of Lymphology meeting held in Barcelona, Spain, September 2017, which has been updated to 2024.

Erratum to “Gorham–Stout disease started with recurrent bilateral exudative pleuritis: case description and literature review” (doi: 10.17816/RFD625565)

The editorial board regret that in the published version of “Gorham–Stout disease started with recurrent bilateral exudative pleuritis: case description and literature review” institution (place of work) of the authors North-Western State Medical University named after I.I. Mechnikov was indicated incorrectly. The authors’ institutions are: Olga M. Lesnyak — North Western State Medical University named after I.I. Mechnikov, Clinical Rheumatological Hospital No. 25, Saint Petersburg; Vadim G. Pischik — Saint Petersburg State University, City Clinical Oncological Clinic, Saint Petersburg; Olga N. Tkach — Clinical Rheumatological Hospital No. 25, Saint Petersburg; Elena S. Kunitsina — Clinical Rheumatological Hospital No. 25, Saint Petersburg. The editorial board is confident that the error could not significantly affect the perception of the work and the interpretation of information by readers. The error has been corrected online, the file of the article and the issue have been updated.

Gorham–Stout disease started with recurrent bilateral exudative pleuritis: case description and literature review

Gorham–Stout disease is an extremely rare skeletal disorder of unknown etiology manifested by multiple foci of osteolysis (“vanishing bone disease”) and lymphangiomatosis. Osteolysis can occur in any part of the skeleton (skull, facial skeleton, ribs, clavicula, spine, pelvic bones, bones of the upper and lower extremities). Approximately half of the patients develop pleural effusion, accompanied by respiratory abnormalities. We describe a case of Gorham-Stout disease with recurrent bilateral exudative pleuritis as a first and most prominent sign, while the bone lesions at the vertebral bodies, ribs and sternum proceeded without active complaints and were an accidental finding during chest computer tomography. Timely diagnosis of the disease depends on the awareness of doctors of various specialties and careful reading of imaging results.

Chylothorax Associated with the Syndrome of Idiopathic Osteolysis Including Gorham-Stout Disease: Spontaneous Remission Without Treatment.

Chylothorax Associated with the Syndrome of Idiopathic Osteolysis Including Gorham-Stout Disease: Spontaneous Remission Without Treatment.

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.

Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs. This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration. Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable. Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Mandibular Gorham-Stout Disease With Implanted Fibular Resorption.

Gorham-Stout disease is an extremely rare disease characterized by progressive massive osteolysis with different clinical manifestations. The pathology is characterized by vascular proliferation, leading to destruction and resorption of the bone matrix, but the exact etiology is unknown. It can occur in any part of the body, with few reports of cases involving the maxillofacial region. Herein, the authors report a case of Gorham-Stout disease of the mandible, which started by affecting the alveolar bone and progressed to the mandibular marginal branches and even to the implanted vascularized free fibula.

Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model.

Gorham-Stout disease (GSD) is a sporadic chronic disease characterized by progressive bone dissolution, absorption, and disappearance along with lymphatic vessel infiltration in bone-marrow cavities. Although the osteolytic mechanism of GSD has been widely studied, the cause of lymphatic hyperplasia in GSD is rarely investigated. In this study, by comparing the RNA expression profile of osteoclasts (OCs) with that of OC precursors (OCPs) by RNA sequencing, we identified a new factor, semaphorin 3A (Sema3A), which is an osteoprotective factor involved in the lymphatic expansion of GSD. Compared to OCPs, OCs enhanced the growth, migration, and tube formation of lymphatic endothelial cells (LECs), in which the expression of Sema3A is low compared to that in OCPs. In the presence of recombinant Sema3A, the growth, migration, and tube formation of LECs were inhibited, further confirming the inhibitory effect of Sema3A on LECs in vitro. Using an LEC-induced GSD mouse model, the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo. We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss, whereas the injection of lentivirus expressing Sema3A short hairpin RNA (shRNA) into the tibiae caused GSD-like phenotypes. Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment, compared with the control. Based on the above results, we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

Recurrent Intracranial Hypotension and Cerebellar Tonsillar Herniation in Gorham–Stout Disease: 11-year Follow-up

Recurrent Intracranial Hypotension and Cerebellar Tonsillar Herniation in Gorham–Stout Disease: 11-year Follow-up

A Case of Vanishing Mandible: Diagnosis and Treatment Considerations for Gorham-Stout Disease of the Mandible

A Case of Vanishing Mandible: Diagnosis and Treatment Considerations for Gorham-Stout Disease of the Mandible

Gorham-Stout syndrome with cervical involvement treated with radiotherapy: a case report

Gorham-Stout disease (GSD), vanishing bone or phantom bone disease, is an uncommon disease whose etiology is uncertain and its pathophysiology poorly understood. This syndrome is characterized by the spontaneous destruction of the bone matrix associated with massive osteolysis and proliferation of lymphatic vascular structures in the affected areas. In the present article we present a case of GSD in a 10-year-old male patient with osteolytic lesions affecting the skull base, including the occipital bone, the petrous portion of the temporalis and clivus, as well as the vertebral bodies from C1 to C5. This syndrome should be suspected when there is bone pain that does not subside with analgesic treatment. An initial study with an x-ray will help us infer the disease in search of a bone deformity. The treatment depends on the characteristics of the lesion, the best being surgery with radiotherapy.

Trametinib inhibits lymphatic vessel invasion of bone in a mouse model of Gorham-Stout disease.

Gorham-Stout disease (GSD) is a rare lymphatic anomaly that can be caused by somatic activating mutations in KRAS. This discovery has led investigators to suggest that MEK inhibitors could be a novel treatment for GSD. However, the effect of MEK inhibitors on bone disease in animal models of GSD has not been investigated. We recently reported that Osx-tTA;TetO-Vegfc mice exhibit a phenotype that resembles GSD. Osx-tTA;TetO-Vegfc mice overexpress VEGF-C in bone, which stimulates the development of lymphatic vessels in bone and the gradual loss of cortical bone. The objective of this study was to characterize the effect of trametinib, an FDA-approved MEK1/2 inhibitor, on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. Immunoblotting was performed to assess the effect of trametinib on VEGF-C-induced phosphorylation of ERK1/2, AKT, and S6 in primary human lymphatic endothelial cells (LECs). Prevention and intervention experiments were performed to determine the effect of trametinib on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. We found that trametinib blocked VEGF-C-induced phosphorylation of ERK1/2 in primary human LECs. We also found that trametinib prevented VEGF-C-induced lymphatic invasion of bone and cortical bone loss in Osx-tTA;TetO-Vegfc mice. Additionally, trametinib slowed the progression of disease in Osx-tTA;TetO-Vegfc mice with established disease. However, it did not reverse disease in Osx-tTA;TetO-Vegfc mice. Our results show trametinib impacts bone disease in Osx-tTA;TetO-Vegfc mice. These findings further support the testing of MEK inhibitors in patients with GSD and other RAS pathway-driven complex lymphatic anomalies with bone involvement.

Gorham-Stout disease

Gorham-Stout disease (GSD), also called vanishing bone disease, is an extremely rare skeletal disorder characterized by destruction of osseous matrix due to a massive process of osteolysis and proliferation of blood and lymph vessels, followed by a lack of deposition of new bone matrix. GSD can occur either at the level of a single bone or affect several bones, although the bones of the upper part of the skeletal system, especially at maxillofacial level, seem to be preferentially involved. To date, the diagnosis of GSD, mainly based on radiographic and histological analyses, is often made by excluding the presence of other diseases. Unfortunately, despite the several studies on GSD that have been carried out since its discovery, the pathogenesis of this disease is still unknown. Consequently, the therapies currently used are mainly aimed at keeping the disease under control, trying to avoid its progression, but they are not decisive, and this is in fact due to the lack of knowledge of its pathogenetic and pathophysiological bases. This concise review aims to provide a brief overview of the state of the art of current research regarding the etiopathogenesis of GSD and the discovery and development of new and different diagnostic and therapeutic methods. KEY WORDS: GSD, lymph vessel, blood vessel, bone cells

Gorham-Stout Disease; A Differential Diagnostic Dilemma.

Gorham-Stout disease (GSD) or "Vanishing/Phantom bone disease” is an extremely rare and poorly understood disorder which consist of lymphatic proliferation and osteolysis. The disease has been described as early as from the 1838. It was not until 1954 when Dr. Gorham and Dr. Stout explained GSD. The aetiology of GSD is not well understood with no concrete evidence of genetic or environmental causes. GSD has also shown no obvious race or age predilection. Unfortunately there is not preventive treatment for GDS patient. Management of GSD are focused on palliative care.

Gorham–Stout syndrome, the challenge in diagnosis and unique in treatment: a case report

BackgroundGorham–Stout disease is a rare condition with fewer than 400 reported cases in the literature. The presentation of Gorham–Stout disease varies on the basis of location, extent, fracture, and accompanying symptoms. It lacks a specific histopathological appearance but is characterized by vascular changes and the absence of cellular atypia.Case presentationThis article presents a case study of a 16-year-old Persian boy with an entire femur with Gorham–Stout disease, highlighting the difficulties in managing this condition. The lack of a clear diagnosis resulted in prolonged procedures, delayed medical treatments, and ultimately required total femoral replacement with an endoprosthesis.ConclusionIt is important to note that raising awareness of this disease and its potential complications can facilitate timely and appropriate treatment for patients presenting in the early stages of the disease.

An Atypical Cause of a Child Limp: A Gorham-Stout Disease with a Vanishing Hip.

Gorham-Stout disease (GSD) is a rare bone disease characterized by an abnormal proliferation of endothelial-lined vessels and destruction of the affected bone. As it affects commonly children and young adults, it is associated with significant morbidity and mortality. To date, there is no established treatment strategy for GSD. We report through this observation a rare case of GSD in a child located in the hip and the iliac crest.

Identification of a Biallelic Missense Variant in Gasdermin D (c.823G > C, p.Asp275His) in a Patient of Atypical Gorham-Stout Disease in a Consanguineous Family.

Gorham-Stout disease (GSD), also called vanishing bone disease, is a rare osteolytic disease, frequently associated with lymphangiomatous tissue proliferation. The causative genetic background has not been noted except for a case with a somatic mutation in KRAS. However, in the present study, we encountered a case of GSD from a consanguineous family member. Whole-exome sequencing (WES) analysis focusing on rare recessive variants with zero homozygotes in population databases identified a homozygous missense variant (c.823G > C, p.Asp275His) in gasdermin D (GSDMD) in the patient and heterozygous in his unaffected brother. Because this variant affects the Asp275 residue that is involved in proteolytic cleavage by caspase-11 (as well as -4 and -5) to generate an activating p30 fragment required for pyroptotic cell death and proinflammation, we confirmed the absence of this cleavage product in peripheral monocytic fractions from the patient. A recent study indicated that a shorter p20 fragment, generated by further cleavage at Asp88, has a cell-autonomous function to suppress the maturation of osteoclasts to resorb bone matrix. Thus, the present study suggests for the first time the existence of hereditary GSD cases or novel GSD-like diseases caused by GSDMD deficiency. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

EML4::ALK fusions in complex lymphatic malformations.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications, including pain and pathologic fractures. As with other vascular anomalies, somatic mosaic mutations in oncogenes are often present, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggests additional targeted therapies could be effective.

Gorham-Stout disease in the rib and spine treated with zoledronic acid, calcium, and vitamin D after vertebral biopsy: a case description with literature analysis.

Gorham-Stout disease in the rib and spine treated with zoledronic acid, calcium, and vitamin D after vertebral biopsy: a case description with literature analysis.