Pediatric cerebrospinal fluid rhinorrhea caused by low flow vascular anomaly of the temporal bone: A case series.

OBJECTIVE: Atraumatic cerebrospinal fluid (CSF) rhinorrhea is uncommon in children and necessitates a multi-disciplinary evaluation for an etiology. Underlying osseous abnormality due to extensive or multifocal low flow vascular anomaly should be considered as a potential cause of spontaneous CSF leak. Treatment of multifocal low flow vascular anomalies may include medical and surgical approaches. In this series, we seek to determine the presenting signs and symptoms and medical and surgical treatment options for multifocal or extensive low flow vascular anomalies. METHODS: A retrospective case series at a quaternary care children's hospital was compiled. All children with CSF rhinorrhea diagnosed and treated for multifocal low flow vascular anomalies at our institution were included. A total of four patients were identified. RESULTS: All four patients had delay in initial diagnosis of underlying cause of meningitis and CSF rhinorrhea. Average age at diagnosis of multifocal low flow vascular anomaly was 7 years. This was on average 4 years after initial presentation for medical attention. Treatment approach was multidisciplinary and included medical management with sirolimus and bisphosphonates as well as surgical approaches to the skull base (lateral and anterior) to prevent CSF egress. CONCLUSION: Consideration of multifocal low flow vascular anomaly should be included in any pediatric patient presenting with CSF rhinorrhea.

Role of Lymphatic Embolization in Chylothorax Associated with Gorham-Stout Disease: A Case Report.

A 45-year-old male patient with spontaneous chylothorax and osteolysis in the right 1st and 2nd ribs was diagnosed with Gorham-Stout disease based on clinical manifestations and bone biopsy. The chylothorax temporarily decreased after a successful selective lymphatic embolization. The patient presented with recurrent chylothorax, mild chest discomfort, and progressive osteolysis (despite administering sirolimus) during the follow-up period of 15 months.

Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease.

PURPOSE: Gorham-Stout disease is a very rare disorder characterized by progressive bone erosion and angiomatous proliferation; its etiopathogenesis is still unknown, and diagnosis is still performed by exclusion criteria. The alteration of bone remodeling activity has been reported in patients; in this study, we characterized circulating osteoclast and osteogenic precursors that could be important to better understand the osteolysis observed in patients. METHODS: Flow cytometry analysis of PBMC (Peripheral Blood Mononuclear Cells) was performed to characterize circulating osteoclast and osteogenic precursors in GSD patients (n = 9) compared to healthy donors (n = 55). Moreover, ELISA assays were assessed to evaluate serum levels of bone markers including RANK-L (Receptor activator of NF-κB ligand), OPG (Osteoprotegerin), BALP (Bone Alkaline Phosphatase) and OCN (Osteocalcin). RESULTS: We found an increase of CD16-/CD14+CD11b+ and CD115+/CD14+CD11b+ osteoclast precursors in GSD patients, with high levels of serum RANK-L that could reflect the increase of bone resorption activity observed in patients. Moreover, no significant alterations were found regarding osteogenic precursors and serum levels of BALP and OCN. CONCLUSION: The analysis of circulating bone cell precursors, as well as of RANK-L, could be relevant as an additional diagnostic tool for these patients and could be exploited for therapeutic purposes.

Differential Diagnosis of Generalized Cystic Lymphangiomatosis: A Literature Review.

BACKGROUND: Generalized cystic lymphangiomatosis (GCL) is a rare disease characterized by the widespread proliferation of lymphatic vessels, often seen in the pediatric patient group. Imaging techniques are instrumental in revealing the extent and morphological features of the disease. OBJECTIVE: The objective of this study is to interpret the radiological findings of GCL and address the differential diagnosis between GCL and other lymphatic malformations in light of the relevant literature data. METHODS: The sample of this retrospective study consisted of six pediatric patients, four males and two females, diagnosed with GCL based on clinical, radiological, and histopathological findings between 2015 and 2022. The age of the patients at the time of diagnosis and their symptoms at admission were obtained from the hospital database. Radiological imaging findings were evaluated in detail based on the involved systems (thorax, abdomen, and musculoskeletal). RESULTS: The median age of the sample, 4/6 were male, was 9 years at admission (min. 3, max. 12). The most common symptom at admission was dyspnea, often accompanied by pleural effusion. Bone involvement was the most common extrathoracic finding. Abdominal involvement was primarily asymptomatic, and the spleen was the most frequently involved organ in the abdomen. CONCLUSION: The diagnosis of GCL is challenging because of its rarity and overlapping diseases. Whole-body magnetic resonance imaging is a valuable tool as it reveals the typical radiological features of GCL and how far it has spread throughout the body.

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.

Introduction: Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs. Methods: This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration. Results: Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable. Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

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.

Abnormalities in C-type lectin-like receptor 2 in a patient with Gorham-Stout disease: the first case report.

Background: Gorham-Stout disease (GSD) is a form of lymphangiomatosis of unknown etiology, characterized by abnormal distribution of lymphatic vessels. Platelets and lymphangiogenesis are closely related via C-type lectin-like receptor 2 (CLEC-2)/podoplanin. Key Clinical Question: Despite similarities between abnormal lymphatic vessels in CLEC-2-deficient mice and patients with GSD, whether CLEC-2 on platelets is involved in GSD pathogenesis is unknown. Clinical Approach: We examined CLEC-2 expression in platelets of a patient with lethal GSD. Most of the patient's platelets expressed aberrant CLEC-2 that was not detectable by certain monoclonal antibodies for human CLEC-2. Further, this population was not activated by a CLEC-2-activating snake venom, rhodocytin. Possible causes of abnormal CLEC-2 including anti-CLEC-2 autoantibodies, podoplanin binding to CLEC-2, and pathogenic CLEC1B gene alteration were excluded. Conclusions: We believe that this is the first report of a patient with structurally and functionally abnormal CLEC-2. CLEC-2 abnormality may be associated with dysregulated lymphangiogenesis in GSD.

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.

The Lymphatic Endothelial Cell Secretome Inhibits Osteoblast Differentiation and Bone Formation.

Complex lymphatic anomalies (CLAs) are a set of rare diseases with unique osteopathic profiles. Recent efforts have identified how lymphatic-specific somatic activating mutations can induce abnormal lymphatic formations that are capable of invading bone and inducing bone resorption. The abnormal bone resorption in CLA patients has been linked to overactive osteoclasts in areas with lymphatic invasions. Despite these findings, the mechanism associated with progressive bone loss in CLAs remains to be elucidated. In order to determine the role of osteoblasts in CLAs, we sought to assess osteoblast differentiation and bone formation when exposed to the lymphatic endothelial cell secretome. When treated with lymphatic endothelial cell conditioned medium (L-CM), osteoblasts exhibited a significant decrease in proliferation, differentiation, and function. Additionally, L-CM treatment also inhibited bone formation through a neonatal calvaria explant culture. These findings are the first to reveal how osteoblasts may be actively suppressed during bone lymphatic invasion in CLAs.

Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.

Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1 K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.

Case Report and Literature Review: Bisphosphonate, Sirolimus, and Atenolol Treatment in a 4-Year-Old Child Diagnosed with Gorham-Stout Disease.

We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham-Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m2) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.

Diagnostic Dilemma of Vanishing Bone Disease - A Case Report and Review of Literature.

Rationale: Vanishing bone disease (VBD) is a rare bone disorder in which progressive osteolysis may lead to complete disappearance of involved bones. The diagnosis of this disease requires a high degree of clinical suspicion. We present a case of progressive osteolysis of mandible in a patient. Patient Concerns: The patient had been without definitive diagnosis and treatment for over a year. Diagnosis: Diagnosis was made by exclusion of genetic, traumatic, inflammatory, infective, endocrine and neoplastic aetiologies and by carefully correlating clinical, imaging and histopathological findings of the patient. Treatment: Segmental resection of the advancing edge of the lesion was carried out. Outcome: The patient is disease free, with no evidence of further osteolysis, after six months of follow-up. Take-Away Lessons: This article describes the exclusion-based approach adopted to diagnose a case of VBD, aiming to standardise a workup for the diagnosis.

Minimal intervention for neurofibromatosis type I manifestations: A case report.

INTRODUCTION AND IMPORTANCE: Neurofibromatosis type I (NF1, OMIM: 162200) is a benign, autosomal dominant, tumorigenic predisposing syndrome with variable manifestations. Both neurofibromatosis and soft tissue sarcomas are associated with the formation of hematomas. Moreover, skeletal manifestations of NF1 include focal or generalized forms and expansive or infiltrative growth types. CASE PRESENTATION: A 19-year-old NF1 female patient presented with an expanding post-traumatic facial hematoma that resembled a soft-tissue tumor at initial presentation. A congenital neck mass was noted ipsilateral to her craniofacial skeletal deformities. Multiple imaging modalities were used to aid diagnosis, and urgent surgical intervention of the expanding facial lesion was performed. Her neck lesion and skeletal deformities were monitored, and her recovery was uneventful at 1-year follow-up, with no progression. CLINICAL DISCUSSION: A palpable, non-pulsatile soft tissue mass is a common clinical presentation with a diverse differential diagnosis. Despite the low incidence of post-traumatic vascular injuries and lesions in the maxillofacial region, neurofibromatosis-associated vasculopathy remains an underestimated and serious manifestation of NF1. The reported zygomatic arch deformity is believed to be unique. However, the NF1 tumor-associated skeletal malformations are not linearly related. CONCLUSION: NF1 is a multisystem disorder necessitating an early multidisciplinary team approach. Minimal intervention can help convert an emergent operation into an urgent one and preclude the need for major surgery. The case illustrated a rare example of simultaneous affection of soft tissue and jaw bones in NF1 patients.

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.

Gorham-Stout Disease: A Case Report and Review of the Literature.

Gorham-Stout disease causes gradual bone loss (osteolysis) due to an abnormal overgrowth of lymphatic vessels. This rare disease is usually seen in younger people. The etiopathology of Gorham-Stout disease remains unclear. The disease is pathologically characterized by the proliferation of the vascular or lymphatic vessels and, finally, bone matrix destruction. These pathological changes lead to the presence of massive osteolysis on plain radiographs. Thus, plain radiograph findings may lead physicians to consider tumoral conditions, especially metastasis. There are several other conditions on the differential diagnosis list of massive osteolysis, such as metabolic, infectious, malignant, and immunological conditions. After excluding all possible disorders, the disease can be considered in the differential diagnosis. The treatment of the disease is symptom-based, but there is no consensus. Pharmacological methods should be considered first-line treatment. If there is no regression in the course of the disease despite pharmacological treatment, radiotherapy and resection arthroplasty are the treatment of choice in the later stages. In this case report, we present a case of Gorham-Stout disease, which was treated by pharmacological methods. During the one and half year follow-up, the local control of the disease was achieved without any surgical intervention.

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.

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.

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.

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.