Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

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.

Clinical and radiological improvement in Gorham-Stout disease after sirolimus treatment / Mejoría clínica y radiológica en la enfermedad de Gorham-Stout después del tratamiento con sirolimus

Abstract 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.

Resumen 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.

Síndrome de Gorham Stout en un paciente pediátrico. Presentación de un caso

Dentro de la clasificación de los síndromes de osteòlisis idiopática, la enfermedad de Gorham-Stout ocupa el cuarto lugar. Es un cuadro clínico caracterizado por la destrucción progresiva de tejido óseo y proliferación vascular, con angiomatosis y linfangiomatosis ósea que produce una osteòlisis progresiva del esqueleto, con pérdida de masa ósea en las áreas afectadas. Este artículo tiene como objetivo presentar un paciente pediátrico con síndrome de Gorham Stout atendido en el Hospital Provincial Pediátrico Universitario José Luis Miranda, de Villa Clara. Es una paciente femenina, de dos años de edad, con cuadro febril de una semana de evolución, aumento de volumen en región dorsal y pérdida de peso. Al examen físico se constataron palidez cutáneo-mucosa y lesión nodular indolora de tres centímetros en la región dorsal. Reapareció la fiebre y se observó marcado aumento de volumen en la región dorso lumbar. Mediante tomografía axial computarizada y resonancia magnética se evidenció osteòlisis de cuerpos vertebrales desde D8 a L2 y aumento de las partes blandas adyacentes. Las manifestaciones clínicas e imagenológicas obligaron a descartar etiologías infecciosas y neoformativas. Se descartaron las primeras y por cumplir con los criterios requeridos se concluyó como enfermedad de Gorham. Esta es una rara y peculiar condición patológica músculo-esquelética en la cual el hueso, virtualmente, se desintegra y es reemplazado por tejido conectivo vascular. Su etiología es especulativa, con una presentación clínica muy variable. Los estudios imagenológicos resultan de gran utilidad. Posee un pronóstico indeterminado a pesar de las opciones terapéuticas empleadas. Por ser un síndrome extremadamente raro se decidió la presentación del caso.

Within the idiopathic osteolysis syndromes classification, Gorham-Stout disease ranks fourth. It is a clinical picture characterized by the progressive destruction of bone tissue and vascular proliferation, with angiomatosis and bone lymphangiomatosis that produces a progressive osteolysis of the skeleton, with loss of bone mass in the affected areas. This article aims to present a pediatric patient with Gorham Stout syndrome treated at the José Luis Miranda University Pediatric Provincial Hospital in Villa Clara. A 2-years-old female patient with a one week fever evolution, increased volume in the dorsal region and weight loss. The physical examination revealed cutaneous-mucosal pallor and a three centimeters painless nodular lesion in the dorsal region. The fever recurred and a marked increase in volume was observed in the dorsal lumbar region. Computed axial tomography and magnetic resonance imaging revealed osteolysis of the vertebral bodies from D8 to L2 and an increase in the adjacent soft tissues. The clinical and imaging manifestations made it necessary to dismiss infectious and neoformative etiologies. The former were dismissed and because they fulfill the required criteria it was concluded as Gorham's disease. This is a rare and peculiar musculoskeletal pathological condition in which bone virtually disintegrates and is replaced by vascular connective tissue. Its etiology is speculative, with a highly variable clinical presentation. Imaging studies are very useful. It has an indeterminate prognosis despite the therapeutic options used. Because it is an extremely rare syndrome, the presentation of the case was decided.

Orthotic management with a customized humeral brace for Gorham-Stout disease of the humerus: A case report

@#Gorham-Stout disease is characterized by massive osteolysis or "vanishing bone" on radiograph. Due to its rarity, no standard Physical Medicine and Rehabilitation (PM&R) management has been published. With this comes the dilemma of managing another case of vanishing right humerus in a 13 year-old male, right handed student, with normal growth and development. To date, this could be the third documented case in the Philippines, but the first with humeral involvement, and the first to manage using a customized humeral brace. The absence of the right humerus affects the bimanual overhead and tabletop activities of the patient, for which a custom-made humeral orthosis was provided to manage the limited activities. There were improvements in activities such as writing, card turning, stacking, and lifting objects of variable weights, as well as with hand dexterity as evidenced by the standardized hand function tests done prior and post brace fitting. Being a rare bone disease with no standard management and unpredictable course, cases are managed symptomatically. For this case of an absent humerus significantly affecting upper extremity function, orthotic management is one aspect that could be recommended to achieve positive functional outcomes.

Chylous Manifestations and Management of Gorham-Stout Syndrome / 대한흉부외과학회지

Gorham-Stout disease (GSD) was first described by Gorham and colleagues in 1954, but its precise mechanism and cause remain to be elucidated. In this condition, voluminous and potentially fatal chylous effusions into the thorax can occur. Herein, we describe a case of GSD in which the patient presented with massive pleural effusions and mottled osteolytic bone lesions. We performed multiple operations, including thoracic duct ligation using video-assisted thoracoscopic surgery and thoracotomic decortication, but these procedures did not succeed in preventing recurrent pleural effusion and chest wall lymphedema. After administering sirolimus (0.8 mg/m2, twice a day) and propranolol (40 mg, twice a day), the process of GSD in this patient has been controlled for more than 2 years.

Sirolimus on Gorham-Stout disease. Case report / Sirolimus en la enfermedad de Gorham-Stout. Caso clínico

Abstract Background: Gorham-Stout disease (GSD) is a rare disease of unknown etiology characterized by vascular proliferation that produces destruction of bone matrix. Case description: This case is about 43 year old woman who begins with pain in sternum, dyspnea, abdominal mass and, serous-hematic pleural effusion. Imaging tests were performed showing lesions on 6th and 10th left ribs archs. Later, a thoracotomy was performed observed absence of the end of the 6th and lung, pleural and costal biopsy was token. The histologic features described lymphatic vascular proliferation in bone tissue of chest wall. Other pathologies were excluded and in view of the findings, GSD diagnosis was made. Treatment and outcome: treatment was initiated with sirolimus achieving remission of the disease after the first month; however, because the presence of metrorrhagia the treatment was discontinued, reappearing symptoms afterwards. For that reason the treatment was restarted getting disappearance of the symptoms again, 4 weeks later. Clinical relevance: we present the first clinical cases of EGS with pleural effusion with response to sirolimus treatment that could be an alternative to the current therapy.

Resumen Antecedentes: La enfermedad de Gorham-Stout (EGS), es una enfermedad poco común, de etiología desconocida, caracterizada por la proliferación vascular que produce destrucción de la matriz ósea. Caso clínico: Se presenta el caso de mujer de 43 años que comienza con dolor en el esternón, disnea y tumoración abdominal junto con derrame pleural izquierdo de características serohemáticas como forma de presentación de una EGS. En pruebas de imagen que mostraron lesiones líticas en el 6º y 10º arcos costales izquierdos. Posteriormente se realizó toracotomía con biopsia pulmonar, pleural y costal observándose ausencia del extremo de la 6ª costilla. En el estudio histopatológico se describe proliferación vascular linfática en tejido óseo de pared costal. Se excluyeron otras patologías y se diagnosticó EGS. Tratamiento y resultado: Se inició tratamiento con sirolimus consiguiendo remisión completa desde el primer mes. Sin embargo, tras la suspensión del tratamiento por metrorragias, presentó reaparición de los síntomas. Se decide entonces reiniciar el tratamiento, consiguiendo nuevamente desaparición de los síntomas, tras 4 semanas de tratamiento. Relevancia clínica: Se presenta el primer caso clínico de EGS en edad adulta con derrame pleural asociado y con respuesta clínica a sirolimus, fármaco que podría ser una alternativa a la terapéutica actual.

A Case of Gorham-Stout Disease with Progressive Cutaneous Involvement / 대한피부과학회지

Gorham-Stout disease is a rare bone disorder that is characterized by angiomatous proliferation and results in destruction and resorption of the osseous matrix. It has variable presentations and a number of different sites may be affected, including the dermis, soft tissue, and viscera. The involved cutaneous and soft tissue lesions typically present with sponge-like, soft, brown or purple lesions. The clinical course is generally prolonged, with eventual stabilization of the affected bone; however, it is rarely fatal. There is no standard treatment defined for this disease, and variable therapies such as medical, surgical, and radiation therapy have been used. We report a case of 24-year-old man with Gorham disease who presented with progressive cutaneous lesions and severe lymphedema adjacent to the diseased bone.

Presentación atípica del síndrome de Gorham-Stout: Caso clínico / Atypical presentation of Gorham-Stout syndrome: Case report

El síndrome de Gorham-Stout es una patología ósea extremadamente rara de etiología desconocida, caracterizada histopatológicamente por proliferación de los canales vasculares, que origina destrucción y resorción de la matriz ósea. Se presenta el caso de un paciente varón de nueve años de edad con un cuadro agudo caracterizado por fiebre, dolor torácico, dificultad respiratoria y disnea ante pequeños esfuerzos. Se realizaron estudios de imágenes y patología, en los que se encontraron lesiones liticas múltiples y presencia de un linfangioma mediastínico. Se diagnosticó síndrome de Gorham-Stout. Esta es una presentación atípica debido a la localización de la linfangiomatosis y al tamaño de la masa.

Gorham-Stout syndrome is an extremely rare pathology, of unknown etiology. It is characterized by proliferation of vascular channels that causes destruction and reabsorption of the bone matrix. We present a nine year-old male patient with an acute episode characterized by fever, chest pain, respiratory distress and dyspnea. The patient was submitted to computed tomography scan and a biopsy. The findings in the biopsy were multiple lytic lesions, osteolysis, and a mediastinal lymphangioma (lymphangiomatosis). The diagnosis was Gorham-Stout syndrome with atypical presentation.

Gorham-Stout Disease of the Mandible: A Case Report