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

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

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

Parkes Weber Syndrome: Contribution of the Genotype to the Diagnosis

Objectives: Parkes Weber syndrome (PWS) is a rare disorder that combines overgrowth, capillary malformations, and arteriovenous malformations (AVM)/arteriovenous fistulas, for which underlying activating mutations in the ras/mitogen-activated protein kinase/extracellular-signal-regulated kinase signaling pathway have been described. The clinical overlap with Klippel-Trenauny syndrome, associated with mutations in PIK3CA, is significant. This case series aimed to elaborate on the phenotypic description of PWS, to underline its clinical overlap with Klippel-Trenauny syndrome and nonsyndromic AVM, and to evaluate the contribution of genotypic characterization to the diagnosis. Methods: All patients diagnosed with PWS upon enrollment in the Bernese VAScular COngenital Malformations (VASCOM) cohort were included. The diagnostic criteria of PWS were retrospectively reviewed. A next-generation sequencing (NGS) gene panel (TSO500, Illumina) was used on tissue biopsy samples. Results: Overall, 10/559 patients of the VAScular COngenital Malformations cohort were initially diagnosed with PWS. Three patients were reclassified as nonsyndromic AVM (Kristen Rat Sarcoma Viral oncogene homolog [KRAS], KRAS+tumor protein p53, and protein tyrosine phosphatase non-receptor type 11). Finally, 7 patients fulfilled all clinical diagnostic criteria of PWS. Genetic testing was available in 5 PWS patients. Only 1 patient had the classic RASA1 mutation; another patient had mutations in G protein subunit alpha q (GNAQ) and phosphatase and tensin homolog. In a third case, a PIK3CA mutation was detected. In 2 patients, no mutations were identified. Conclusion: Overgrowth syndromes with vascular malformations are rare and their clinical overlap hampers the classification of individual phenotypes under specific syndrome labels, sometimes even despite genetic testing. To provide optimal patient care, an accurate phenotypic description combined with the identification of molecular targets for precision medicine may be more meaningful than the syndrome classification itself

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

Two Cases of Cardiac Arteriovenous Malformation Complicated by a Local Angioproliferative Process

Vascular malformations of the heart are extremely rare with only a few cases of the arteriovenous type of vascular malformation (AVM) reported. We investigated the pathology of two additional cases, which were complicated by the occurrence of a local vasoproliferative response of immature but benign vessels. We suppose that the mass forming effect of this vasoproliferative response, which has also been reported recently as a complication of congenital AVM elsewhere in the body, has significantly contributed to the onset of symptoms and ultimate death of both patients

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 dis-eases. 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. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus state -ments on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-facePeer reviewe