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Spontaneous intracranial hypotension is an uncommon etiology of secondary headaches in children. We report a unique case of a girl with kaposiform lymphangiomatosis who developed postural headaches and imaging features of spontaneous intracranial hypotension without a spinal extradural collection. The girl underwent dynamic computed tomography myelography which revealed a cerebrospinal fluid (CSF)-lymphatic fistula related to a lymphatic malformation associated with the right T10 nerve. She underwent surgical ligation of the CSF-lymphatic fistula, resulting in resolution of the headaches. Spinal CSF-lymphatic fistulas are rare and have previously been reported in two patients with Gorham-Stout disease. The current report suggests that patients with systemic lymphatic anomalies who develop postural headaches should undergo evaluation for spontaneous intracranial hypotension and a CSF-lymphatic fistula. If discovered, surgical ligation is a potential treatment.

Somatic mutations in NRAS drive the pathogenesis of melanoma and other cancers but their role in vascular anomalies and specifically human endothelial cells is unclear. The goals of this study were to determine whether the somatic-activating NRASQ61R mutation in human endothelial cells induces abnormal angiogenesis and to develop in vitro and in vivo models to identify disease-causing pathways and test inhibitors. Here, we used mutant NRASQ61R and wild-type NRAS (NRASWT) expressing human endothelial cells in in vitro and in vivo angiogenesis models. These studies demonstrated that expression of NRASQ61R in human endothelial cells caused a shift to an abnormal spindle-shaped morphology, increased proliferation, and migration. NRASQ61R endothelial cells had increased phosphorylation of ERK compared to NRASWT cells indicating hyperactivation of MAPK/ERK pathways. NRASQ61R mutant endothelial cells generated abnormal enlarged vascular channels in a 3D fibrin gel model and in vivo, in xenografts in nude mice. These studies demonstrate that NRASQ61R can drive abnormal angiogenesis in human endothelial cells. Treatment with MAP kinase inhibitor U0126 prevented the change to a spindle-shaped morphology in NRASQ61R endothelial cells, whereas mTOR inhibitor rapamycin did not. [ABSTRACT FROM AUTHOR]

Lymphangioma circumscriptum is a developmental anomaly of lymphatic vessels, which appear as aggregates of clear or hemorrhagic vesicles on the skin or mouth. Glans penis involvement is very uncommon. Because of the sensitivity of the area, possible functional, cosmetic, or psychologic disturbances can result. Lymphangioma circumscriptum is rarely found on this location; hence, vigilance and awareness of this entity is necessary for a swift and proper diagnosis. Two cases are presented on the account of their rarity and unique representation.

Generalized lymphatic anomaly (GLA) and kaposiform lymphangiomatosis (KLA) are rare congenital disorders that arise through anomalous embryogenesis of the lymphatic system. A somatic activating NRAS p.Q61R variant has been recently detected in GLA and KLA tissues, suggesting that the NRAS p.Q61R variant plays an important role in the development of these diseases. To address this role, we studied the effect of the NRAS p.Q61R variant in lymphatic endothelial cells (LECs) on the structure of the lymphatics during embryonic and postnatal lymphangiogenesis applying inducible, LEC-specific NRAS p.Q61R variant in mice. Lox-stop-Lox NrasQ61R mice were crossed with Prox1-CreERT2 mice expressing tamoxifen-inducible Cre recombinase specifically in LECs. Whole-mount immunostaining of embryonic back skin using an antibody against the LEC surface marker VEGFR3 showed considerably greater lymphatic vessel width in LEC-specific NRAS p.Q61R mutant embryos than in littermate controls. These mutant embryos also showed a significant reduction in the number of lymphatic vessel branches. Furthermore, immunofluorescence staining of whole-mount embryonic back skin using an antibody against the LEC-specific nuclear marker Prox1 showed a large increase in the number of LECs in LEC-specific NRAS p.Q61R mutants. In contrast, postnatal induction of the NRAS p.Q61R variant in LECs did not cause abnormal lymphatic vessel morphogenesis. These results suggest that the NRAS p.Q61R variant in LECs plays a role in development of lymphatic anomalies. While this model does not directly reflect the human pathology of GLA and KLA, there are overlapping features, suggesting that further study of this model may help in studying GLA and KLA mechanisms., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Diffuse pulmonary lymphangiomatosis (DPL) is a rare lymphatic disease that can cause diverse respiratory symptoms. A 22-year-old man, whose chest CT had shown an abnormality for years, presented with acute respiratory failure due to the abrupt onset of hemoptysis. The diagnosis of DPL was confirmed by surgical lung biopsy and lymphangiography. Histopathological investigation showed dilated vascular and lymphatic vessels. DPL can cause acute and life-threatening symptoms during its chronic clinical course. A coexisting anomaly in the venous system may be present in DPL patients with hemoptysis.

Acquired vulvar lymphangioma (AVL) is not well-characterized. Diagnosis is delayed and the condition is often refractory to therapy., Objective: The objective of this study was to provide a systematic review of AVL including risk factors, disease associations, and management options., Methods: A primary literature search was conducted using 3 databases: PubMed, CINAHL, and OVID, from all years to 2022., Results: In total, 78 publications with 133 patients (48 ± 17 years) were included. Most studies were case reports/series. The most common disease association was prior malignancy (70 patients, 53% of cases) and inflammatory bowel disease (6 patients, 5% of cases). The most common malignancy was cervical cancer (57 patients, 43% of cases). Most patients had prior radiation or surgery, with 36% (n = 48) treated with radiation, 30% (n = 40) with lymph node dissection, and 27% (n = 36) with surgical resection. Common presenting symptoms included discharge/oozing, pain, and pruritus. Most patients underwent surgical treatment for AVL with 39% treated with excision, 12% with laser therapy (the majority used CO 2 ), and 11% with medical therapies. Most patients had failed prior therapies and there was a diagnostic delay., Limitations: Retrospective nature. Most studies were limited to case reports and case series, with interstudy variability and result heterogeneity., Conclusion: AVL is an underrecognized entity and should be considered in patients with a history of malignancy or radiation to the urogenital area. Treatment should include multidisciplinary care and address underlying lymphatic changes, manage any existing inflammatory conditions, and utilize skin-directed therapies and barrier agents while addressing symptoms of pruritus and pain. Prospective studies are needed to further characterize AVL and develop treatment guidelines., Competing Interests: None., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Women’s Dermatologic Society.)

Background: Kaposiform lymphangiomatosis (KLA) is a recently characterized systemic lymphatic anomaly. Activation of RAS/MAPK and PI3K/AKT/mTOR pathways may affect KLA pathogenesis, but the cellular basis of KLA is unclear. Abnormal-spindle endothelial cells that express lymphatic endothelial cell (LEC) markers are characteristic of KLA histopathology. This study evaluated patient-derived KLA cells to establish their morphological and biological characteristics., Procedure: We established cell lines from primary KLA tissues of two patients with KLA and examined their morphological and functional characteristics, messenger RNA and protein expression profiles, gene mutations, and responses to inhibitors of the RAS/MAPK and PI3K/AKT/mTOR pathways., Results: Both KLA cell lines showed spindle-shaped morphology, stained positive for podoplanin (PDPN), and exhibited impaired tube-formation properties. They expressed LEC marker PDPN and mesenchymal stem cell markers (CD90, CD105) in the absence of endothelial cell markers (CD34, CD31, VWF), per real-time polymerase chain reaction. Both mTOR inhibitor rapamycin and MEK inhibitor trametinib inhibited growth of the two cell lines. A NRAS p.Q61R variant was found in one of two independent KLA tissue samples, but not in the KLA cells (per targeted next-generation sequencing); and KLA cells with this variant had elevated AKT phosphorylation levels. ERK phosphorylation levels were undetectable in both KLA cell lines., Conclusions: Inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways may represent potential therapeutic targets in KLA. These patient-derived KLA cell lines will be useful research tools to elucidate KLA etiology, and could pave the way for basic, translational, and preclinical studies of this disease., (© 2021 Wiley Periodicals LLC.)

Diffuse pulmonary lymphangiomatosis (DPL) is a rare lymphatic disease that can cause diverse respiratory symptoms. A 22-year-old man, whose chest CT had shown an abnormality for years, presented with acute respiratory failure due to the abrupt onset of hemoptysis. The diagnosis of DPL was confirmed by surgical lung biopsy and lymphangiography. Histopathological investigation showed dilated vascular and lymphatic vessels. DPL can cause acute and life-threatening symptoms during its chronic clinical course. A coexisting anomaly in the venous system may be present in DPL patients with hemoptysis. [ABSTRACT FROM AUTHOR]

A 29-month-old girl had idiopathic massive pericardial effusion for over 6 months. Lymphangiography was performed for chronic and recurrent pericardial effusion and pulmonary lymphangiectasia, suspected based on CT findings. Magnetic resonance lymphangiography revealed chylolymphatic reflux from a tortuously dilated thoracic duct in the mediastinum to the pericardial space, suggesting primary chylopericardium with lymphangiectasia. Pericardial effusion resolved immediately after thoracic duct embolisation at the lower thoracic level. However, pericardial effusion recurred after 5 months, which resolved after additional embolisation of the abnormal lymphatic collateral vessels from the remnant upper thoracic duct. Here, we report an unusual case with chylous massive pericardial effusion diagnosed by magnetic resonance lymphangiography and treated with percutaneous embolisation.