Treatment for Gorham-Stout syndrome with a combination of teriparatide and denosumab.

Gorham-Stout syndrome is an aggressive, non-hereditary, and rare disease affecting bone metabolism. Its etiology and pathogenesis remain elusive. The syndrome manifests with diverse clinical symptoms, often leading to frequent misdiagnoses and presenting challenges in treatment. In this study, we report a case of cranial and maxillary osteolysis in a 47-year-old female patient with somatic mutations in the VEGF-A, VEGF-B, and VEGF-C genes and the EPHB4 gene. After treatment with bisphosphonates, this patient still had persistent resorption of the mandible, but switching to a teriparatide and denosumab combination yielded substantial improvement. This study is the first report to show that teriparatide combined with denosumab can be used to treat Gorham-Stout syndrome.

Clinical and radiological improvement in Gorham-Stout disease after sirolimus treatment.

BACKGROUND: Gorham-Stout disease (GSD) is a rare syndrome characterized by lymphatic malformations, mainly in bone structures, causing progressive osteolysis. Lymphatic endothelial cell proliferation depends on several growth factors that use the phosphoinositide-3 kinase (PI3K)/Akt pathway and converge on the mammalian target molecule of the rapamycin (mTOR) pathway. These findings have allowed treating GSD with mTOR pathway inhibitors such as sirolimus or everolimus. CASE REPORT: We present the case of a one-year-old female patient referred to our institution after a right femur fracture and progressive limb volume increase, disproportionately to the trauma. After several episodes of soft tissue infections, imaging studies showed pseudarthrosis, lytic lesions, and progressive loss of the right femur that ended in total absence. A femur biopsy showed lymphatic structures positive with D2-40 staining, diagnosing GSD. After six months of non-response to traditional treatments, the limb was disarticulated at the hip level, and oral sirolimus treatment was initiated, showing clinical and radiological improvement with minor lytic lesions and evidence of ossification after 20 months of treatment. CONCLUSIONS: Oral sirolimus treatment for GSD inhibits angiogenesis and osteoclastic activity, stimulating bone anabolism and leading to arrested osteolysis progression and improved ossification, quality of life, and patient prognosis. Therefore, sirolimus should be considered a therapeutic option for this rare disease.

INTRODUCCIÓN: La enfermedad de Gorham-Stout es un trastorno poco frecuente caracterizado por malformaciones linfáticas localizadas sobre estructuras óseas que causan osteólisis progresiva. La proliferación de células endoteliales linfáticas depende de factores de crecimiento que utilizan la vía de la fosfoinositida-3 cinasa (PI3K)/Akt y convergen en la vía de la molécula diana de rapamicina de los mamíferos (mTOR). Este conocimiento ha permitido el tratamiento de esta enfermedad con inhibidores de esta vía como sirolimus o everolimus. CASO CLÍNICO: Se presenta el caso de una paciente de sexo femenino de un año referida a nuestra institución tras presentar fractura de fémur derecho y aumento de volumen de dicha extremidad posterior a un traumatismo. Después de diversos episodios de infecciones de tejidos blandos se realizaron estudios de imagen que mostraron pseudoartrosis, lesiones líticas y ausencia total del fémur derecho, así como una biopsia de fémur que mostró estructuras vasculares positivas con tinción D2-40, diagnosticándose enfermedad de Gorham-Stout. Durante su abordaje, se realizó la desarticulación de la extremidad a nivel de la cadera y se inició tratamiento con sirolimus oral, presentando una mejoría clínica y radiológica con menores lesiones líticas y evidencia de osificación posterior a 20 meses de tratamiento. CONCLUSIONES: El tratamiento con sirolimus oral para la enfermedad de Gorham-Stout inhibe la actividad osteoclástica y la angiogénesis, estimulando el anabolismo óseo que resulta en la detención de la progresión de la osteólisis y una mejoría en la osificación, la calidad de vida y el pronóstico del paciente. Por tal motivo, el sirolimus debe considerarse como una opción terapéutica para esta enfermedad.

The molecular mechanism of Gorham syndrome: an update.

Gorham syndrome, also known as "vanishing osteopathy" and "invasive hemangiomatosis," is a rare clinical syndrome whose etiology is unknown and can invade the whole-body skeleton. At present, more than 300 cases have been reported at home and abroad, usually manifesting as spontaneous chronic osteolysis with no periosteal reaction at the lysis site and occult onset, often with fractures, scoliosis, chylothorax, etc. When waiting for medical treatment, the condition is serious, and the prognosis is poor. At present, there is no effective treatment. The main pathological manifestations of Gorham syndrome are the non-neoplastic abnormal proliferation of lymphatic vessels or blood vessels and osteolysis caused by osteoclast proliferation or increased activity. At present, there is no unified conclusion regarding Gorham syndrome's pathogenesis. This paper starts with the two most studied osteolysis methods at present, osteoclast osteolysis and osteolysis caused by vascular and lymphatic proliferation and summarizes the corresponding most possible molecular mechanisms in recent years to provide more ideas for Gorham syndrome treatment.

Complex Lymphatic Anomalies: Report on a Patient Registry Using the Latest Diagnostic Guidelines.

Background: Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA. Methods: Thirty-six consecutive patients were recruited for the "GLA/GSD Registry" of the University Hospital of Freiburg, Germany (2015-2021). Clinical data were prospectively collected provided that a signed informed consent form was obtained. The latest proposed diagnostic guidelines were retrospectively applied. Results: Thirty-two patients (38% males) were included in the study; 15 GLA, 10 GSD, 3 KLA, and 4 CCLA patients were identified. Eighty-four percent already had symptoms by the age of 15 years. Osteolysis and periosseous soft-tissue infiltration were associated with GSD (p < 0.001 and p = 0.011, respectively), ascites and protein-losing enteropathy with CCLA (p = 0.007 and p = 0.004, respectively), and consumption coagulopathy with KLA (p = 0.006). No statistically significant differences were found in organ involvement, distribution of osteolytic lesions, number of affected bones and fractures. Twenty-five patients had complications; one patient with GLA died despite multimodal treatment. Spontaneous regression was seen in one patient with untreated KLA. Conclusions: CLA are rare, and their overlapping clinical presentations make differential diagnosis difficult. The characterization of our case series contributes to the phenotypic description and differentiation of these four clinical entities. A further understanding of their pathogenesis is crucial for evaluating targeted therapies and optimizing medical care.

Difficult Therapeutic Decisions in Gorham-Stout Disease-Case Report and Review of the Literature.

Gorham-Stout disease (GSD) is a very rare, life-threatening condition characterized by the proliferation of lymphatic vessels and osteolysis. Unfortunately, no standard treatment has been determined for management of GSD. The available therapies are not equally effective and carry substantial side-effects. We report a 42-year-old female with GSD manifested in multifocal osteolysis and chronic chylothorax and ascites. The combined treatment with sirolimus and zoledronic acid due to its synergism of action was introduced. To our knowledge, this is the first Polish case report of adult patients with Gorham-Stout disease.

Refractory serositis in Gorham-Stout syndrome.

BACKGROUND: Gorham-Stout syndrome (GSS) is a rare disorder with various presentations and unpredictable prognoses. Previous understandings of GSS mainly focused on progressive bone destruction, while we identified a group of GSS patients with serous effusion as the first symptom. This study aimed to investigate the clinical characteristics of patients with GSS having serous effusion as the first symptom. METHODS: Patients diagnosed with GSS were identified through the Peking Union Medical College Hospital Medical Record System. The demographic, clinical, laboratory, and imaging data were collected. Patients who first presented with serous effusion were recruited into the serous group, while those with bone destruction were recruited into the bone group. RESULTS: Of the 23 patients with GSS enrolled, 13 were in the bone group and 10 in the serous group. The median disease duration was shorter and exercise tolerance was lower in the serous group. Despite less frequent bone pain in the serous group, the frequency of bone involvement was similar to that in the bone group. Patients in the serous group had higher rates of bilateral pleural effusion and multiple serous effusion. However, serous effusion also developed with disease progression in the bone group. Of the 17 patients treated with bisphosphonates, 14 reached bone-stable state. However, 5 out of 10 patients with serous effusion still had refractory effusions after bisphosphonates treatment. Three patients received sirolimus treatment, with an improvement in serous effusion. Seventeen patients were followed up; three patients died, two in the bone group and one in the serous group. CONCLUSIONS: This study discovered that GSS could first be presented with serous effusion. We believe that this may be a new phenotype of the disease. Sirolimus might help in controlling serous effusion and improving prognosis.

How we approach the diagnosis and management of complex lymphatic anomalies.

Complex lymphatic anomalies (CLA) are congenital diseases of the lymphatic circulation system that are associated with significant morbidity and early mortality. While guidelines for the comprehensive evaluation of the CLA were recently published, the diagnostic approach and medical management are not standardized. This article presents the clinical features of four CLA: Gorham-Stout disease, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and central collecting lymphatic anomaly. We also offer three cases from the authors' practice and our views on diagnostic testing and disease management including supportive care, medical therapies, and other interventions.

Gorham-Stout Disease Resulting in Spinal Deformity Treated by Fusion Surgery Combined With Everolimus Therapy: A Case Report.

CASE: Gorham-Stout disease (GSD) is a rare disorder characterized by progressive localized osteolysis and lymphatic malformation. A 26-year-old woman with GSD presented to our hospital with a Cobb angle of 100° and a kyphosis angle of 88°. Everolimus therapy was initiated to control the disease prior to surgery. After halo-gravity traction for 4 weeks, we performed anterior and posterior spinal fusion. Postoperative computed tomography revealed satisfactory bone union and no significant loss of correction 1 year post-surgery. CONCLUSION: This case suggests that anterior and posterior spinal fusion combined with everolimus therapy can be a therapeutic option for GSD.

Gorham-Stout disease successfully treated with sirolimus (rapamycin): a case report and review of the literature.

BACKGROUND: Gorham-Stout disease (GSD) is a rare disease characterized by bone lesions and osteolysis. Therapy usually involves surgical resection. Sirolimus (Rapamycin) is used in some patients with GSD but the efficacy and safety of Sirolimus remains unclear. We propose that Sirolimus may be a novel therapeutic for GSD and present a case and review of literature that supports this. CASE PRESENTATION: We presented a 1-year-old boy with GSD involving osteolysis of the right humerus with fracture of the left femur complicated by an effusion in the right pleural cavity. X-rays showed osteolysis in the right clavicle. A large pleural effusion was observed on the right-side, and the left lung was significantly compressed. X-rays also showed a fracture of the left femur. A femoral biopsy was performed that showed necrotic tissue in the cortical bone and a large number of irregularly shaped capillaries that proliferated within the necrotic tissue. Dilated lymphatic vessels were seen adjacent to the cortex, with fibrous tissue hyperplasia. We prescribed sirolimus, which is an oral mTOR inhibitor, for two consecutive years. The boy recovered well without other progressive bone lesions and participates in normal daily activities. His growth and development are the same as that of his peers. DISCUSSION AND CONCLUSION: Gorham-Stout disease is a rare and enigmatic disease characterized by the presentation of an intraosseous lymphatic anomaly (LM), which results in progressive bone resorption. Based on this case report and a literature review, we conclude that sirolimus may be an effective alternative medication for GSD.

Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL-stimulated NFATc1 activity.

Osteolytic skeletal disorders are caused by an imbalance in the osteoclast and osteoblast function. Suppressing the differentiation and resorptive function of osteoclast is a key strategy for treating osteolytic diseases. Dracorhodin perchlorate (D.P), an active component from dragon blood resin, has been used for facilitating wound healing and anti-cancer treatments. In this study, we determined the effect of D.P on osteoclast differentiation and function. We have found that D.P inhibited RANKL-induced osteoclast formation and resorbed pits of hydroxyapatite-coated plate in a dose-dependent manner. D.P also disrupted the formation of intact actin-rich podosome structures in mature osteoclasts and inhibited osteoclast-specific gene and protein expressions. Further, D.P was able to suppress RANKL-activated JNK, NF-κB and Ca2+ signalling pathways and reduces the expression level of NFATc1 as well as the nucleus translocation of NFATc1. Overall, these results indicated a potential therapeutic effect of D.P on osteoclast-related conditions.

Gorham-Stout disease: good results of bisphosphonate treatment in 6 of 7 patients.

Background and purpose - Gorham-Stout disease (GSD) is a rare mono- or polyostotic condition characterized by idiopathic intraosseous proliferation of angiomatous structures resulting in progressive destruction and resorption of bone. Little is known about the course of disease and no previous study has evaluated patients' quality of life (QoL).Patients and methods - This is a retrospective analysis of 7 consecutive patients (5 males) with a median age at diagnosis of 14 years and a median follow-up of 7 years who were diagnosed with GSD in our department between 1995 and 2018. Data regarding clinical, radiographic, and histopathological features, and treatment, as well as sequelae and their subsequent therapy, were obtained. QoL was assessed by Musculoskeletal Tumor Society Score (MSTS), Toronto Extremity Salvage Score (TESS), and Reintegration to Normal Living (RNL) Index.Results - 3 patients had a monoostotic and 4 patients a polyostotic disease. Besides a diagnostic biopsy, 4 of the 7 patients had to undergo 8 surgeries to treat evolving sequelae. Using an off-label therapy with bisphosphonates in 6 patients, a stable disease state was achieved in 5 patients after a median of 20 months. The median MSTS, TESS, and RNL Index at last follow-up was between 87% and 79%.Interpretation - Due to its rare occurrence, diagnosis and treatment of GSD remain challenging. Off-label treatment with bisphosphonates appears to lead to a stable disease state in the majority of patients. QoL varies depending on the individual manifestations but good to excellent results can be achieved even in complex polyostotic cases with a history of possibly life-threatening sequelae.

Gorham-Stout Syndrome of the Shoulder Girdle Successfully Controlled by Antiresorptive Agents: A Report of 2 Cases.

CASE: Gorham-Stout disease (GSD) is a rare disorder characterized by massive bone destruction. Consensus is lacking on the effective treatment strategies for GSD. This report presents 2 cases of GSD, a 47-year-old man and a 72-year-old woman, involving the shoulder girdle which were successfully controlled by antiresorptive agents including bisphosphonates and denosumab, the antireceptor activator of nuclear factor-κB ligand antibody. CONCLUSIONS: These 2 cases suggest that antiresorptive agents targeting osteoclasts can be efficacious therapeutic options for GSD. This is the first case of GSD we are aware of which showed good response to denosumab treatment.

The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies.

BACKGROUND: Lymphatic anomalies (LAs) include several disorders in which abnormal lymphatic tissue invades the neck, chest, and various organs. Progressive cases may result in lethal outcomes and have proven difficult to treat. Sirolimus is showing promising results in the management of vascular anomalies. We examined the efficacy and safety of sirolimus treatment in patients with progressive LAs. METHODS: All patients with LAs treated with sirolimus from May 2015 to September 2018 were included. They received oral sirolimus once a day and the dose was adjusted so that the trough concentration remained within 5-15 ng/mL. We prospectively reviewed the response to drugs (the response rate of radiological volumetric change of the target lesion), severity scores, reported quality of life (QOL), and adverse effects at 6 months after administration. RESULTS: Twenty patients (five with cystic lymphatic malformation (LM), three with kaposiform lymphangiomatosis, three with generalized lymphatic anomaly, six with Gorham-Stout disease, and three with central conducting lymphatic anomaly) were treated with sirolimus at our institution. Fifty percent of patients (10/20) demonstrated a partial response by a radiological examination and a significant improvement in disease severity and QOL scores (P = 0.0020 and P = 0.0117, respectively). Ten patients who had no reduction in lesion size (stable disease group) showed no significant improvement in disease severity and QOL scores. Eighty percent of patients (16/20) had side effects, such as stomatitis, infection, and hyperlipidemia. CONCLUSIONS: Sirolimus impacts the reduction of the lymphatic tissue volume of LMs and could lead to improvement in clinical symptoms and QOL. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000016580 . Registered 19 February 2015.

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.

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

BACKGROUND: Generalized 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. PROCEDURE: Disease 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. RESULTS: Eighteen 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. CONCLUSIONS: Sirolimus 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.

Zoledronic acid : Treatment option for Gorham-Stout disease.

Gorham-Stout disease is a rare bone resorption disease, the etiology and prognosis of which is uncertain but it is thought to be benign. It can involve one or more bones and can cause pain, swelling, deformity and fractures in affected bones. Diagnosis is made with a combination of clinical, radiological and histopathological examinations once other causes of osteolysis have been excluded. Due to its rarity, there is no standard therapeutic approach.

Sirolimus Therapy as Perioperative Treatment of Gorham-Stout Disease in the Thoracic Spine: A Case Report.

CASE: Gorham-Stout disease (GSD) is a rare entity that is marked by progressive osteolysis and bone resorption. A 14-year-old boy who was being followed for scoliosis presented with a marked curve progression and kyphoscoliosis. Imaging revealed osteolysis of the posterior elements and the ribs, suggestive of GSD. The structural compromise threatened spinal cord compression. Preoperative sirolimus therapy was initiated to stabilize the disease prior to corrective instrumentation. A biopsy specimen that was obtained at the time of instrumentation showed lymphatic vascular spaces consistent with GSD. Sirolimus therapy with the addition of bisphosphonate therapy was continued postoperatively. CONCLUSION: To our knowledge, this case report is the first to describe sirolimus therapy combined with surgery for GSD of the spine. The patient did well with consecutive medical optimization and surgical intervention, including postoperative sirolimus and bisphosphonate therapy.