Infantile myofibromatosis and capillary malformation of the skin due to PDGFRB mosaicism.

This report describes the case of a 25-year-old female patient with multicentric infantile myofibromatosis since early infancy, superficial capillary malformations and congenital hypoplasia of the third and fourth finger of her right hand. All known lesions were located in the upper extremities, the chest and the upper back. A pathogenic, gain-of-function platelet-derived growth factor receptor-beta (PDGFRB) variant (p.

Angiopoietin-TIE2 feedforward circuit promotes PIK3CA-driven venous malformations.

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 Pik3ca-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.

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients.

Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations.

Background: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification.

Methods And Results: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies.

[The Duplicity of Incidents: Cervical Lymphatic Malformation in two Newborns].

We report on two neonates born the same day, both with an isolated cervical lymphatic malformation. Cervical masses were detected by ultrasound late in the third trimester. Following interdisciplinary case conferences, a caesarean section in the presence of a neonatal team was the chosen delivery mode in both cases.

C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.

C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments.

Targeting the microenvironment in the treatment of arteriovenous malformations.

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology.

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

Unlabelled: To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations.

Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies.

Complex Lymphatic Anomalies: Report on a Patient Registry Using the Latest Diagnostic Guidelines.

Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA.

Comprehensive Analyses of Coagulation Parameters in Patients with Vascular Anomalies.

Background: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding.

Rhabdomyosarcoma xenotransplants in zebrafish embryos.

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of antitumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families.

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management.

Efficacy of Sirolimus in Patients Requiring Tracheostomy for Life-Threatening Lymphatic Malformation of the Head and Neck: A Report From the European Reference Network.

Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known.

Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.

Vascular malformations are most often caused by somatic mutations of the PI3K/mTOR and the RAS signaling pathways, which can be identified in the affected tissue. Venous malformations (VMs) commonly harbor PIK3CA and TEK mutations, whereas arteriovenous malformations (AVMs) are usually caused by BRAF, RAS or MAP2K1 mutations. Correct identification of the underlying mutation is of increasing importance, since targeted treatments are becoming more and more relevant, especially in patients with extensive vascular malformations.

Additive value of transarterial embolization to systemic sirolimus treatment in kaposiform hemangioendothelioma.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor in children, which can be accompanied by life-threatening thrombocytopenia, referred to as Kasabach-Merritt phenomenon (KMP). The mTOR inhibitor sirolimus is emerging as targeted therapy in KHE. As the sirolimus effect on KHE occurs only after several weeks, we aimed to evaluate whether additional transarterial embolization is of benefit for children with KHE and KMP.

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS.

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern.

A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways.

The H2.0-like homeobox transcription factor (HLX) regulates hematopoietic differentiation and is overexpressed in Acute Myeloid Leukemia (AML), but the mechanisms underlying these functions remain unclear. We demonstrate here that HLX overexpression leads to a myeloid differentiation block both in zebrafish and human hematopoietic stem and progenitor cells (HSPCs).

Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche.

Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment, the haematopoietic niche, which regulates HSPC behaviour. The location of this niche varies across species, but the evolutionary pressures that drive HSPCs to different microenvironments remain unknown. The niche is located in the bone marrow in adult mammals, whereas it is found in other locations in non-mammalian vertebrates, for example, in the kidney marrow in teleost fish.

Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells.

The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively.

Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa).

Introduction: Kratom (Mitragyna speciosa) is a common medical plant in Thailand and is known to contain mitragynine as the main alkaloid. According to an increase in published reports and calls at German poison control centers, it has been used more frequently as a drug of abuse in the western hemisphere during the last couple of years. Despite this increase, reports of severe toxicity are rare within the literature.