Trisomy 19 ependymoma, a newly recognized genetico-histological association, including clear cell ependymoma

Ependymal tumors constitute a clinicopathologically heterogeneous group of brain tumors. They vary in regard to their age at first symptom, localization, morphology and prognosis. Genetic data also suggests heterogeneity. We define a newly recognized subset of ependymal tumors, the trisomy 19 ependymoma. Histologically, they are compact lesions characterized by a rich branched capillary network amongst which tumoral cells are regularly distributed. When containing clear cells they are called clear cell ependymoma. Most trisomy 19 ependymomas are supratentorial WHO grade III tumors of the young. Genetically, they are associated with trisomy 19, and frequently with a deletion of 13q21.31-31.2, three copies of 11q13.3-13.4, and/or deletions on chromosome 9. These altered chromosomal regions are indicative of genes and pathways involved in trisomy 19 ependymoma tumorigenesis. Recognition of this genetico-histological entity allows better understanding and dissection of ependymal tumors

Pathognomonic oral profile of Enamel Renal Syndrome (ERS) caused by recessive FAM20A mutations

Amelogenesis imperfecta (AI) is a genetically and clinically heterogeneous group of inherited dental enamel defects. Commonly described as an isolated trait, it may be observed concomitantly with other orodental and/or systemic features such as nephrocalcinosis in Enamel Renal Syndrome (ERS, MIM#204690), or gingival hyperplasia in Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome (AIGFS, MIM#614253). Patients affected by ERS/AIGFS present a distinctive orodental phenotype consisting of generalized hypoplastic AI affecting both the primary and permanent dentition, delayed tooth eruption, pulp stones, hyperplastic dental follicles, and gingival hyperplasia with variable severity and calcified nodules. Renal exam reveals a nephrocalcinosis which is asymptomatic in children affected by ERS. FAM20A recessive mutations are responsible for both syndromes. We suggest that AIGFS and ERS are in fact descriptions of the same syndrome, but that the kidney phenotype has not always been investigated fully in AIGFS. The aim of this review is to highlight the distinctive and specific orodental features of patients with recessive mutations in FAM20A. We propose ERS to be the preferred term for all the phenotypes arising from recessive FAM20A mutations. A differential diagnosis has to be made with other forms of AI, isolated or syndromic, where only a subset of the clinical signs may be shared. When ERS is suspected, the patient should be assessed by a dentist, nephrologist and clinical geneticist. Confirmed cases require long-term follow-up. Management of the orodental aspects can be extremely challenging and requires the input of multi-disciplinary specialized dental team, especially when there are multiple unerupted teeth

Lymphatic Malformations Genetics, Mechanisms and Therapeutic Strategies

Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.Peer reviewe

GLMN (glomulin)

Review on GLMN (glomulin), with data on DNA, on the protein encoded, and where the gene is implicated

Glomuvenous malformation (GVM)

Review on Glomuvenous malformation (GVM), with data on clinics, and the genes involved

Clinical phenotype of adolescent and adult patients with extracranial vascular malformation.

BACKGROUND In recent years, genotypic characterization of congenital vascular malformations (CVM) has gained attention; however, the spectrum of clinical phenotype remains difficult to attribute to a genetic cause and is rarely described in the adult population. AIM The aim of this study is to describe a consecutive series of adolescent and adult patients in a tertiary center, where a multimodal phenotypic approach was used for diagnosis. METHODS We analyzed clinical findings, imaging, and laboratory results at initial presentation, and set a diagnosis according to the International Society for the Study of Vascular Anomalies (ISSVA) classification for all consecutively registered patients older than 14 years of age who were referred to the Center for Vascular Malformations at the University Hospital of Bern between 2008 and 2021. RESULTS 457 patients were included for analysis (mean age 35 years; females 56%). Simple CVMs were the most common (n=361, 79 %), followed by CVM associated with other anomalies (n=70, 15%), and combined CVM (n=26, 6%). Venous malformations (n=238) were the most common CVM overall (52%), and the most common simple CVM (66%). Pain was the most frequently reported symptom in all patients (simple, combined and vascular malformation with other anomalies). Pain intensity was more pronounced in simple venous and arteriovenous malformation. Clinical problems were related to the type of CVM diagnosed, with bleeding and skin ulceration in arteriovenous malformations, localized intravascular coagulopathy in venous malformations and infectious complications in lymphatic malformations. Limb length difference occurred more often in patients with CVM associated with other anomalies as compared to simple or combined CVM (22.9 vs 2.3%, p< 0.001). Soft tissue overgrowth was seen in one quarter of all patients independent of the ISSVA group. CONCLUSIONS In our adult and adolescent population with peripheral vascular malformations, simple venous malformations predominated, with pain as the most common clinical symptom. In a quarter of cases, patients with vascular malformations presented with associated anomalies on tissue growth. The differentiation of clinical presentation with or without accompanying growth abnormalities need to be added to the ISSVA classification. Phenotypic characterization considering vascular and non-vascular features remains the cornerstone of diagnosis in adult-as well as pediatric patients

Angiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations

Funding Information: The computations of scRNA-seq data were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) partially funded by the Swedish Research Council through grant agreement no. 2018-05973, and the National Academic Infrastructure for Supercomputing in Sweden (NAISS), partially funded by the Swedish Research Council through grant agreement no. 2022-06725, under projects NAISS 2023/22-192 and NAISS 2023/23-457. This work was supported by grants from the Knut and Alice Wallenberg Foundation (2018.0218 and 2020.0057; to T.M.), the Swedish Research Council (2020-0269; to T.M.), Göran Gustafsson foundation (to T.M.), the Swedish Cancer Society (19 0220 Pj, 22 2025 Pj; to T.M.), Sigrid Juselius Foundation (240137; to T.M.), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (no. 814316; to M.K., H.S., M. Po, T.M. and M.V.), Fonds de la Recherche Scientifique - FNRS grants T.0240.23 and P.C005.22 (to M.V.), T.00.19.22 and P.C013.20 (to L.M.B.), Fondation Saint Luc (to L.M.B.), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO IP X.1548.24; to M.V.), the European Research Council Consolidator Grant EMERGE (no. 773047; to M. Po), the Deutsche Forschungsgemeinschaft (DFG, project number 456687919 – SFB 1531; to M. Po), the Leducq Foundation (to M. Po and M.V.), European Research Council Starting Grant PREVENT (no. 101078827; to R.H.), the charity cycling tour ‘Tour der Hoffnung’ (to F.K.), EJPRD Joint Transnational Call 2023, NARRATIVE (to L.M.B.); FKZ 01GM2405 (to F.K.). A.-K.D.R., L.M.B., M.V. and F.K. are members of the VASCA Working Group of the European Reference Network for Rare Multisystemic Vascular Diseases (project identification no. 769036). Open access funding provided by Uppsala University. Publisher Copyright: © The Author(s) 2025.Venous malformations (VMs) are vascular anomalies lacking curative treatments, often caused by somatic PIK3CA mutations that hyperactivate the PI3Kα–AKT–mTOR signaling pathway. Here, we identify a venous-specific signaling circuit driving disease progression, where excessive PI3Kα activity amplifies upstream TIE2 receptor signaling through autocrine and paracrine mechanisms. In Pik3caH1047R-driven VM mouse models, single-cell transcriptomics and lineage tracking revealed clonal expansion of mutant endothelial cells with a post-capillary venous phenotype, characterized by suppression of the AKT-inhibited FOXO1 and its target genes, including the TIE2 antagonist ANGPT2. An imbalance in TIE2 ligands, likely exacerbated by aberrant recruitment of smooth muscle cells producing the agonist ANGPT1, increased TIE2 activity in both mouse and human VMs. While mTOR blockade had limited effects on advanced VMs in mice, inhibiting TIE2 or ANGPT effectively suppressed their growth. These findings uncover a PI3K–FOXO1–ANGPT–TIE2 circuit as a core driver of PIK3CA-related VMs and highlight TIE2 as a promising therapeutic target.publishersversionpublishe

Elevated expression of c-kit in small venous malformations of blue rubber bleb nevus syndrome

The blue rubber bleb nevus syndrome (BRBNS, syn. bean syndrome) is a rare disease characterized by multiple cutaneous and gastrointestinal venous malformations associated with severe bleeding. However, the underlying molecular mechanisms are unknown and no targeted therapeutic approach exists to date. Here we report the case of a 19-year-old male patient with severe BRBNS in whom we analyzed the expression of tyrosine kinases frequently involved in tumor development by immunohistochemistry (vascular endothelial growth factor receptor-2, stem cell growth factor receptor (c-kit), platelet-derived growth factor receptor-β, and stem cell tyrosine kinase-1). A prominent expression of c-kit was detectable in smaller blood vessels, which also showed a moderate expression of the proliferation marker MIB1. Surprisingly, other growth factor receptors stained negatively. We therefore conclude that pharmacological inhibition of the c-kit signaling pathway in cavernous hemangiomas by selective kinase inhibitors may offer options in the treatment of BRBNS patients

A Clinical Feasibility Study To Image Angiogenesis in Patients With Arteriovenous Malformations Using 68Ga-RGD PET/CT

Objective: Arteriovenous Malformations (AVMs) have an inherent capacity to form new blood vessels resulting in excessive lesion growth and this is further triggered by the release of angiogenic factors. Gallium-68 (68Ga) labeled arginine-glycine-aspartate tripeptide sequence (RGD) positron emission tomography (PET)/computed tomography (CT) imaging (68Ga-RGD PET/CT) may provide insight in the angiogenic status and treatment response of AVMs. This clinical feasibility study demonstrates that 68Ga-RGD PET/CT imaging can be used to quantitatively assess angiogenesis in peripheral AVMs. Methods: Ten patients with a peripheral AVM (mean age 40 years, four men, six women) and scheduled for endovascular embolization treatment, were prospectively included. All patients underwent 68Ga-RGD PET/CT imaging 60 min after injection (mean dose 207±5 MBq). Radiotracer uptake in AVM, blood-pool, and muscle activity were quantified as Standardized Uptake Values (SUVmax, SUVpeak) and descriptive analysis of the PET/CT images was performed. Furthermore, immunohistochemical analysis was performed on surgical biopsy material of peripheral AVMs to investigate the expression pattern of integrin αvβ3.Results: 68Ga-RGD PET/CT imaging showed enhanced radiotracer uptake in all AVM lesions (mean SUVmax 3.0±1.1; mean SUVpeak 2.2±0.9). Lesion/blood and lesion/muscle ratios were 3.5±2.2 and 4.6±2.8, respectively. Radiotracer uptake in AVMs was significantly higher compared to uptake in background tissue (p=0.0006 and p=0.0014) for blood and muscle, respectively. Initial observations include identification of radiotracer uptake in (multifocal) AVM lesions and enhanced radiotracer uptake in intra-osseous components in those AVM cases affecting the bone integrity. Immunohistochemical analysis revealed cytoplasmatic and cell membranous integrin αvβ3 expression in endothelial cells of AVMs. Conclusion: This feasibility study showed increased radiotracer uptake in AVM with angiogenic activity compared to surrounding tissue without angiogenic activity, suggesting that 68Ga-RGD PET/CT imaging can be used as a tool to quantitatively determine angiogenesis in AVM. Further studies will be conducted to explore the potential of 68Ga-RGD PET/CT imaging for guiding current treatment decisions and for assessment of response to anti-angiogenic treatment