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Stimulation of Treg Cells to Inhibit Osteoclastogenesis in Gorham-Stout Disease

ABSTRACT: Gorham-Stout disease (GSD) is a very rare syndrome displaying excessive bone erosion and vascular lesion. Due to the rarity of the disease and to the limited studies, its etiopathogenesis is not entirely known. The involvement of immune system in the progressive osteolysis was recently suggested. Indeed, extensive reciprocal interactions between the immune and skeletal systems have been demonstrated. This study aimed to evaluate alterations of immune cells in GSD. An increase of CD8+ cells and reduction of CD4+ and CD4+CD25+CD127low cells was revealed in patients. Interestingly, patients’ regulatory T cells maintain the ability to respond to extracellular stimuli and to regulate osteoclastogenesis; GSD cells proliferate under aCD3/CD28 signal reaching similar levels to those observed in control culture and exert their immunomodulatory activity on effector T cells. GSD Treg cells preserved their inhibitory effects on the osteoclastogenesis. These results suggest that stimulation of Treg cells could open the way for the identification and testing of new therapeutic approaches for patients affected by GSD.

SUBMITTER: Rossi M

PROVIDER: S-EPMC8430039 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A report of two children with Gorham-Stout disease.

Project description:BackgroundGorham-Stout disease is a rare condition characterized by unifocal and massive type IV osteolysis (variant of idiopathic nonhereditary osteolytic disease) with a slow progression, which is self-limiting for some years. It is characterized by recurrent vascular tumors with disruption of the anatomical architecture and intraosseous proliferation of vascular channels that leads to the destruction and resorption of the bone matrix. The aim of this study is to present the clinical features of this disease, as well as the importance of prompt diagnosis and treatment, with a review of the reported cases.Case reportsWe describe two cases of Gorham-Stout disease between 2013 and 2017 with surgical interventions, follow-up and results. Case one involves an 11-year-old male with involvement of the left iliac bone, with adequate evolution after a surgical procedure with a lyophilized cadaveric tricortical bone allograft. Case two involves a 6-year-old male with cervical spine C1-C3 repercussion; in the protocol for surgical treatment, he presented with signs of spinal cord compression and died.ConclusionDiagnosis of Gorham-Stout disease is made by exclusion, and its clinical presentation varies widely, from spontaneous remission to a fatal outcome.

| S-EPMC6591827 | biostudies-literature

Gorham-Stout disease of spine accompanying chylothorax: a case description.

Project description: Not available

| S-EPMC10585519 | biostudies-literature

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib.

Project description:Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.

| S-EPMC8410066 | biostudies-literature

Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.

Project description:BackgroundGeneralized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies.ProcedureDisease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed.ResultsEighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment.ConclusionsSirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.

| S-EPMC6428616 | biostudies-literature

Personalized Therapy for Generalized Lymphatic Anomaly/Gorham-Stout Disease With a Combination of Sunitinib and Taxol.

Project description:The recently revised ISSVA classification approved in Melbourne in April 2014 recognizes generalized lymphatic anomaly and lymphatic malformation in Gorham-Stout disease. The 2 entities can overlap in presentation, as both are characterized by destructive lymphatic vessel invasion of the axial skeleton and surrounding soft tissues. At least at present, no standard therapeutic options exist, and due to the rarity of the disease, no clinical trials are available. We present 2 patients, 1 with generalized lymphatic anomaly and 1 with lymphatic malformation in Gorham-Stout disease, with severe exacerbation during puberty. The first child presented in florid pulmonary failure and pleural effusion, the other with severe pain due to bone destruction of the pelvis and inability to walk. Both were treated using individualized protocols. The manuscript describes the rationale for choosing sunitinib in combination with low-dose (metronomic) taxol. Both patients experienced clinical and radiologic response without major toxicities, suggesting that patients with rare conditions may benefit from individualized, molecularly based therapies.

| S-EPMC4617281 | biostudies-literature

The spectrum of imaging manifestations of Gorham–Stout disease: a novel dynamic contrast-enhanced MR lymphangiography

Project description:Background To describe the radiological features of Gorham–Stout disease (GSD) as evaluated using plain radiography and dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) imaging techniques. Methods Clinical and conventional imaging data were retrospectively reviewed for 15 patients with GSD between January 2001 and December 2020. After December 2018, DCMRL examinations were performed for lymphatic vessel evaluation in patients with GSD and reviewed in four patients. Results The median age at diagnosis was 9 years (range: 2 months–53 years). The clinical manifestations were dyspnea in seven patients (46.7%), sepsis in 12 (80.0%), orthopedic problems in seven (46.7%), and bloody chylothorax in seven (46.7%). The common sites of osseous involvement were the spine (73.3%) and pelvic bone (60.0%). Among the non-osseous involvements, peri-osseous infiltrative soft-tissue abnormalities adjacent to the area of bone involvement were the most common (86.7%), followed by splenic cysts (26.7%) and interstitial thickening (26.7%). DCMRL demonstrated weak central conducting lymphatic flow in two patients with abnormal giant tortuous thoracic ducts and no flow in one patient. All patients who underwent DCMRL in this study presented with altered anatomical lymphatics and functional flow with collateralization. Conclusion DCMRL imaging and plain radiography are very useful for determining the extent of GSD. DCMRL is a novel imaging tool for the visualization of abnormal lymphatics in patients with GSD, which helps in further treatment. Therefore, in patients with GSD, it might be necessary to obtain not only plain radiographs but also MR and DCMRL images. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-023-02704-7.

| S-EPMC10131433 | biostudies-literature

Massive Axial and Appendicular Skeletal Deformities in Connection with Gorham-Stout Syndrome.

Project description::Background: Etiological understanding is the corner stone in the management of skeletal deformities. Methods: Multi-centre study of patients with deformities in connection with diverse etiological backgrounds. We aimed to study four patients (one boy and three girls) with variable axial and appendicular deformities in connection with a vanishing bone disorder. Results: Axial deformities such as scoliosis, kyphoscoliosis, compressed fused vertebrae, appendicular fractures, dislocations, and vicious disorganization deformities of the joints were in connection with the vanishing bone disorder, namely Gorham-Stout syndrome. Conclusions: It is mandatory to establish proper clinical and radiological phenotypic characterization in children and adults presented with unusual skeletal deformities. Identifying the reason behind these deformities is the key factor to draw a comprehensive management plan.

| S-EPMC6631250 | biostudies-literature

Current concepts from diagnosis to management in Gorham-Stout disease: a systematic narrative review of about 350 cases.

Project description:Patients with Gorham-Stout disease (GSD) present progressive destruction and resorption of bone. Typical bone-related symptoms include swelling, pain and functional impairment in the region involved. The three aspects of GSD etiopathology are osteoclasts, angiogenesis/lymphangiogenesis and osteoblast function. Multi-targeted pharmacological approach includes innovative options and represent milestones of treatment, sometimes associated with radiotherapy. Surgery is mainly used to treat complications: pathologic/impending fractures, spinal instability or deformities and chylothorax. In this narrative review, we highlight current standards in diagnosis, clinical management and therapeutic strategies.

| S-EPMC8788153 | biostudies-literature

Gorham-Stout case report: a multi-omic analysis reveals recurrent fusions as new potential drivers of the disease.

Project description:BackgroundGorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease.Case presentationWe present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data.ConclusionsThe way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease.

| S-EPMC9169400 | biostudies-literature

Pulmonary and pleural lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized lymphatic anomaly, show a high proliferation rate.

Project description:BackgroundGorham-Stout disease (OMIM 123880) and generalized lymphatic anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach.MethodsLymphatic vessels in lung and pleural tissue from both children and adult patients with generalized lymphatic anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67).ResultsWe found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible.ConclusionsThese malformations of the lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.

| S-EPMC4870727 | biostudies-literature

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