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.

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.

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.

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.

Lymphatic Anomalies in Children: Update on Imaging Diagnosis, Genetics, and Treatment.

Lymphatic anomalies comprise a spectrum of disorders ranging from common localized microcystic and macrocystic lymphatic malformations (LMs) to rare complex lymphatic anomalies, including generalized lymphatic anomaly, Kaposiform lymph-angiomatosis, central conducting lymphatic anomaly, and Gorham-Stout disease. Imaging diagnosis of cystic LMs is generally straightforward, but complex lymphatic anomalies, particularly those with multiorgan involvement or diffuse disease, may be more challenging to diagnose. Complex lymphatic anomalies are rare but associated with high morbidity. Imaging plays an important role in their diagnosis, and radiologists may be the first clinicians to suggest the diagnosis. Furthermore, radiologists are regularly involved in management given the frequent need for image-guided interventions. For these reasons, it is crucial for radiologists to be familiar with the spectrum of entities comprising complex lymphatic anomalies and their typical imaging findings. In this article, we review the imaging findings of lymphatic anomalies, including LMs and complex lymphatic anomalies. We discuss characteristic imaging findings, multimodality imaging techniques used for evaluation, pearls and pitfalls in diagnosis, and potential complications. We also review recently discovered genetic changes underlying lymphatic anomaly development and the advent of new molecularly targeted therapies.

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.

Gorham Stout disease of the temporal bone with cerebrospinal fluid leak.

Gorham Stout disease (GSD) is a rare disease characterized by the proliferation of endothelial lined vessels and replacement of bone by fibrous tissue. The main imaging features are progressive osteolysis and cortical resorption. Temporal bone involvement is rare but presents as a destructive bone lesion that may be misinterpreted as more common lytic processes in the pediatric population, such as infection or Langerhans cell histiocytosis. GSD of the temporal bone is associated with cerebrospinal fluid (CSF) leaks, may present with otorrhea, and can mimic other causes of ear drainage. Here, we report the clinical course, imaging features, and outcomes of a 3-year-old girl with GSD of the temporal bone presenting with CSF leak initially attributed to infection.

Gorham Stout disease: 3 additional cases with 2 very rare polyostotic diseases.

Gorham Stout disease is a very rare monostotic or polyostotic osteolysis and physiopathology of the osteolysis is not yet fully understood. Three new cases are reported with their evolution and treatment. Among these 3 cases, two are very rare cases of polyostotic involvement. One patient finally deceased from respiratory complications despite limb amputation. The two others are alive. Both needed final reconstruction with massive bone allograft for one and with a prosthesis for the other. Monostotic osteolysis is the most frequent presentation of Gorham Stout disease and extensive polyostotic osteolysis is very rare. Treatment methods vary from one clinic to another, from drug treatment to surgical treatment with or without radiotherapy. Sometimes, as a last solution, an amputation of the affected limb is performed. The prognosis depends on the affected region and the reponse to various treatments. Chylothorax seems to be a factor of poor prognosis.

[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.

Gorham Disease Limited to the Left Upper Extremity Without Hand Involvement.

In this case report, we present a young female patient with a history of Gorham disease, who sustained pathologic fractures of the left radius and ulna after a low-impact fall. Massive osteolysis of the left forearm and wrist was noted on plain radiographs. The patient had had 8 previous left upper-extremity fractures without evidence of disease in any other area of the body.

Gorham-Stout disease with parietal bone osteolysis: a case series and review of literature.

BACKGROUND: Gorham-Stout disease (GSD) is a rare and idiopathic bone disorder, characterized by massive osteolysis. To date, there is no established treatment strategy for GSD. We empirically treated two patients, who had presented to us with cranial lesions of GSD. Here, we propose a novel algorithm for the management of Gorham's disease based on our experience and review the literature published to date. METHODS: We reviewed all existing literature on GSD describing the pathophysiology and suggested treatment methods, up to 2018. RESULTS: We found 13 papers with 14 reported cases; an inclusion of our two cases brings the total count up to just 16 recorded cases of GSD involving the skull. Of these, the base of the skull was affected in eight cases, while the remaining eight cases showed cranial involvement. The patients with skull-base involvement were managed conservatively, using medications or radiotherapy. The patients with cranial osteolysis were managed surgically, with an excision of the osteolytic portion, followed by cranioplasty. Of the latter group, the pericranium was not removed in one patient, in whom a very slight progression of the osteolytic process was later observed. CONCLUSIONS: The pathogenesis of GSD remains poorly understood. Further study is required to determine an optimum management strategy. A long-term follow-up will also be necessary to establish the effectiveness of the treatment process. The untreated patients show a progressive resorption of the affected bones of the skull. A painful, vanishing skull deformity is an alarming sign of GSD. Early diagnosis and treatment are necessary to arrest disease progression and to prevent complications.

Gorham-Stout disease involving ipsilateral clavicle and scapula in a child - a case report focusing on imaging and histopathological features of this extremely rare condition.

Gorham-Stout disease (GSD) is a very rare entity of unknown etiology, characterized by excessive intra-osseous proliferation of blood or lymphatic vessels, resulting in progressive resorption of bone matrix and destruction of bone. To date we have found only seven published cases concerning fully confirmed GSD of the shoulder girdle bones in children. Our case concerns an 8-year-old boy with involvement of the left clavicle and scapula. The knowledge of imaging and histopathological features is crucial for establishing the diagnosis of GSD, therefore the exchange of experiences in this field is essential for improving the care of affected patients.

Gorham-Stout Disease with Multiple Bone Involvement-Challenging Diagnosis of a Rare Disease and Literature Review.

Gorham-Stout disease is a rare disorder, which may result in a poor prognosis. This disease, a rare lymphangiomatosis, is defined by progressive bone disappearance due to massive unicentric and multicentric osteolysis. Osteolytic lesions of the spine and pleura effusion are poor prognostic factors. Herein, we will present a case where the onset of disease occurred at the age of 18 with asthenia, myalgia, and major bone pain, followed by incomplete motor deficiency in the lower limbs and, later, in the upper limbs. Imaging studies (CT scan and MRI) of the patient revealed osteolytic lesions (cervical and thoracic vertebrae, rib, and clavicle) and a pathological fracture of the C7 vertebra. Surgical procedures undertaken involved replacing the affected vertebrae with bone grafting and prosthesis. The investigations performed allowed for the exclusion of inflammation, thyroid or parathyroid disease, lymphoma, neoplasia, or autoimmune disorders. A bone marrow biopsy showed osteolysis, the replacement of bone tissues with connective tissue, and chronic non-specific inflammation. The evolution was negative with almost complete osteolysis of the left clavicle, the emergence of new osteolysis areas in the lumbar vertebrae, pelvic bones, and the bilateral proximal femur, splenic nodules, chylothorax, and associated major neurological deficits. Unfortunately, this negative evolution resulted in the patient's death a year after onset.

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.

A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease.

Gorham-Stout disease (GSD), a rare disorder of unknown etiology, is characterized by massive osteolysis that is associated with proliferation and dilation of lymphatic vessels. Variants in cancer-associated genes have been described in complex lymphatic anomalies. To explore the pathogenesis of GSD, we performed the amplicon-based deep sequencing on 50 cancer-related genes to assay affected tissues from the six patients with GSD. In one patient, a somatic activating KRAS c.182A > G variant (p.Q61R) was detected in 1% of the tissue sample. Conversely, the mutant allele was not detected in uninvolved normal skin and blood samples. Histopathology of the patient's tissue sample showed proliferation of abnormal lymphatic and blood vascular endothelial cells, osteoclasts, and activated macrophages. The activating KRAS variant is a known 'hotspot' variant, frequently identified in several types of human cancer. This is the first report of identifying a pathogenic variant in a patient with GSD. This finding may set the stage for elucidation of pathophysiology and the development of novel therapies for GSD.

Abnormal pulmonary lymphatic flow in patients with paediatric pulmonary lymphatic disorders: Diagnosis and treatment.

Pulmonary lymphatic disorders are characterized by the presence of the abnormal lymphatic tissues in the thoracic cavity, presenting clinically as chylothorax, chylopericardium, chyloptysis, interstitial lung disease and plastic bronchitis. These conditions include: neonatal chylothorax, cardiac and non-cardiac plastic bronchitis, non-traumatic chylothorax, post congenital cardiac surgery chylothorax and complex lymphatic malformations. Recently developed lymphatic imaging techniques, such as intranodal lymphangiography and dynamic contrast enhanced magnetic resonance lymphangiography demonstrated abnormal pulmonary lymphatic flow from thoracic duct into pulmonary parenchyma as a pathophysiological mechanism of these diseases. Novel minimally invasive lymphatic interventions, such as thoracic duct embolization, interstitial lymphatic embolization and surgical lympho-venous anastomosis, provide an effective treatment of these conditions.

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.

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.

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.