Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model. / ç ´éª¨ç»†èƒžä¸­ä¿¡å·ç´ 3Aè¡¨è¾¾çš„å‡å°‘å¯¼è‡´å°é¼ GSDæ¨¡åž‹ä¸­æ·‹å·´ç®¡æ‰©å¼ .

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.

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

BACKGROUND: Gorham-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 PRESENTATION: This 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. CONCLUSION: It 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.

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.

Epidural Hematoma related to lower limb pain and massive liver bleeding in Gorham-Stout disease: A case report.

RATIONALE: Gorham-Stout disease (GSD) is a rare disease that causes massive osteolysis and proliferation of abnormal lymphangiomatous tissues. Patients with GSD often experience pain associated with bone fractures and chylothorax. However, bleeding caused by abnormal lymphangiomatous tissue or hematological dysfunction rarely occurs. PATIENT CONCERNS: A 22-year-old female patient with GSD presented with severe left hip and lower limb pain. The GSD had disappeared her right pelvic bone and femur, but no abnormalities were found in the bones at the site of the pain. DIAGNOSES: The patient presented with a chylothorax and cerebrospinal fluid leakage. She was treated with sirolimus and an epidural blood patch, and her symptoms resolved. Computed tomography and magnetic resonance imaging revealed an epidural hematoma extending from L3 to the caudal region, and blood results revealed a consumption coagulopathy. INTERVENTIONS: We presumed that the hematoma caused pain and prescribed pregabalin and morphine. The pain gradually subsided. OUTCOMES: An unexpected liver subcapsular hemorrhage occurred 4 months later, and the patient went into hemorrhagic shock. Transcatheter arterial embolization was promptly performed, and the patient recovered. LESSONS: GSD infrequently causes bleeding related to abnormal lymphangiomatous tissues and coagulopathy, yet it can lead to serious events if it occurs.

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.

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

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.

Gorham-Stout disease affecting the spine with cerebrospinal fluid leakage and Chiari-like tonsillar herniation: a rare case report and review of literature.

BACKGROUND: Gorham-Stout disease (GSD) is a very rare disorder characterized by massive osteolysis of poorly understood aetiology. The association between GSD involving the skull base and cerebrospinal fluid (CSF) leakage has been reported in the literature. However, few cases of CSF leakage and Chiari-like tonsillar herniation in GSD involving the spine have been reported. CASE PRESENTATION: We present the case of a 20-year-old man with GSD involving the thoracic and lumbar spine, which caused CSF leakage and Chiari-like tonsillar herniation. The patient underwent four spinal surgeries for osteolytic lesions of the spine over a 10-year period. Here, we discuss the possible aetiology of the development of CSF leakage. Epidural blood patch (EBP) was performed at the T11-T12 level to repair the CSF leakage. After EBP treatment, rebound intracranial hypertension (RIH) developed, and tonsillar herniation disappeared 2 months later. CONCLUSIONS: GSD involving the spine with CSF leakage and Chiari-like tonsillar herniation is relatively rare. For patients who have undergone multiple spinal surgeries, minimally invasive treatment is an alternative treatment for CSF leakage. EBP can repair CSF leakage secondary to GSD and improve chronic brain sagging, with reversibility of Chiari-like malformations.

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.

A case of restitution ad integrum in Gorham-Stout disease.

Gorham-Stout disease (or "vanishing bone" disease) is a rare mono or polyostotic disease of unknown etiology, characterized by intraosseous angiomatous proliferation leading to bone resorption. We report the case of a 17-year-old woman presenting with symptomatic osteolytic lesions of the frontal vault. Imaging was suggestive of Gorham-Stout disease without argument for other diagnoses. An unusual evolution of the "vanishing bone" lesions was observed on the scan after one year, with a full recovery of the lytic lesions. This report shows for the first time a spontaneous restitutio ad integrum of bone matrix in Gorham-Stout disease.

Gorham-Stout syndrome: A chylothorax disease with bony destruction: A case report.

RATIONALE: Gorham-Stout syndrome is a sporadic condition characterized by a tumor-like lesion with extensive osteolysis, severe symptoms, and a poor prognosis. Poor prognostic indicators include osteolytic lesions of the spine and pleura effusion. PATIENT CONCERNS: A 67-year-old Chinese man with five months history of chest tightness presented to our institution with aggravated shortness of breath. Ultrasonography demonstrated hydrothorax on the right side. The patient's imaging studies (computerized tomography [CT] scan, magnetic resonance imaging, and positron emission tomography [PET]/CT) revealed osteolytic lesions (the skull, several spines, several ribs, both shoulder blades, and the pelvis). DIAGNOSES: Gorham-Stout syndrome. (4) Interventions: We advised the patient to follow a low-fat diet. On the patient, we performed a superior vena cava angiography. The injection of zoledronic acid was used to prevent bone loss. OUTCOMES: We found resolution of chylothorax after a low-fat diet, superior vena cava angiography and injection of zoledronic acid. LESSONS: The possibility of Gorham -Stout syndrome should be ruled out in patients with clinical chylothorax. The relief of chylothorax requires comprehensive treatment.

Thoracic Gorham-Stout disease masquerading as an ovarian malignancy: a differential diagnosis in non-malignant causes of raised Ca-125 and overview of this rare pathology.

Gorham-Stout disease (GSD) is thought to be due to uncontrolled proliferation of vascular and lymphatic structures within bone tissue causing destruction and osteolysis of bone. We present a patient in her mid-40s who reported chronic shoulder pain, a pleural effusion and irregular periods. Investigations showed osteolysis of her ribs, pleural effusions, an ovarian mass and a raised carbohydrate antigen 125 (Ca-125). She was subsequently diagnosed with GSD, and referred to gynaecology-oncology in consideration of potential ovarian malignancy. GSD is a diagnosis of exclusion that requires a high degree of clinical suspicion, as well as multiple investigations to achieve diagnosis. Clinicians rely on a small number of case reports to provide guidance for this. Therefore, this report provides an overview of a rare pathology, considers the differentials of a raised Ca-125 and describes how a pleural effusion, which links them both, alarmed us regarding an incidental finding of an ovarian cyst.

[Complicated lymphatic anomaly: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features, clinical manifestations and different diagnosis of patients with complicated lymphatic anomaly. Methods: The clinical and pathologic data of four patients with complicated lymphatic anomaly diagnosed and treated in Peking Union Medical College Hospital from January 2000 to December 2021 were collected and analyzed. Results: One Gorham-Stout disease case and three generalized lymphatic anomaly cases were included in this cohort. Patients' ages ranged from 7 to 32 years. There were three males and one female. The positions of biopsy included three bone biopsy and one bronchus biopsy. Microscopically, all cases showed diffuse enlarged lymphatic channels. At the same time, osteogenesis was obvious in Gorham-Stout disease case. Radiologically, cortical loss was seen in Gorham-Stout disease, and lytic bone confined to the medullary cavity presented in generalized lymphatic anomaly. The three generalized lymphatic anomaly cases also had coagulopathy, and two had effusion. Conclusions: The histologic feature of complicated lymphatic anomaly was diffuse lymphatic malformation, and the diagnosis depends on clinical and pathologic information. The treatment and prognosis of these diseases are different, and therefore it is necessary to understand their clinical and pathologic features and make the correct diagnosis.

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.

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

BACKGROUND: Gorham-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 PRESENTATION: We 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. CONCLUSIONS: The 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.

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.

Gorham-Stout disease of skull base leading to cranial settling and rhinorrhea: a case-based review.

PURPOSE: Gorham-Stout disease (GSD) is a rare progressive osteolytic disorder, theoretically caused by lymphovascular endothelial proliferation. Spinal involvement carries a dismal prognosis because of neurological consequences. Lesions of the skull base are extremely rare and entail even more devastating prognosis due to cervical instability and cerebrospinal fluid (CSF) leakage. Due to scarcity of this condition, the aim of this study was to give an overview of skull base GSD and review the cases with such condition reported in the literature. METHODS: In this case-based review, different aspects of skull base GSD are discussed, and a sample clinical case of GSD leading to cranial settling and rhinorrhea is presented. The characteristics, symptoms, and managements of all English-language PubMed-reported cases were reviewed, and different features of presentation and methods of treatments were analyzed. RESULTS: Based on the literature review, most of the cases encountered serious problems in the course of the disease. Meningitis/CSF leakage was detected in 12 of 26 collected cases, followed by hearing loss/tinnitus/otitis media in 10 cases, headache in 8, and neck pain/stiffness in 8 patients. Despite a variety of treatments, improvement was only observed in 8 of 26 collected cases. The reminders showed either stable condition or worsening and death. CONCLUSION: All cases of GSD of the skull base should be evaluated for rhinorrhea/otorrhea and cranial settling, both of them being among the most life-threatening conditions. Since definite treatment, in order to stop disease progression, is sometimes impossible, symptomatic and supportive treatment should be started as possible.