9 Disorders of the Venous System Pascal Brouillard,1 Nisha Limaye,1 Laurence M. Boon,1,2 Miikka Vikkula1,3 1Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium, 2Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium, 3Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium 9.1 INTRODUCTION hemangioma) and more slow-growing vascular malfor- mations. The latter are subcategorized according to the The vasculature is the first organ system to develop during type(s) of vessel(s) altered [5–7] into capillary, venous, embryogenesis, delivering nutrients, growth factors, and arteriovenous, lymphatic, and combined malformations. oxygen to tissues and removing wastes. It is made up of four major types of vessels: arteries, capillaries, veins, and lymphatic vessels, all of which have a single layer of endo- 9.2 THE VENOUS SYSTEM thelial cells (ECs) forming the innermost layer. In blood Veins collect CO2-rich blood from the capillary net- vessels, the endothelial tubes are supported by a layer of work and contain about 75%–80% of the total volume of vascular smooth muscle cells (vSMCs) and/or pericytes blood in the body. They have larger lumens than arteries, (together called mural cells) of variable thickness. A base- with thinner, less muscular walls. Venous flow is passive, ment membrane separates the endothelial and vSMC essentially mediated by physical movements of the body layers, with an extracellular matrix (ECM) of fibrous and and the aspirating effect exerted by the heart. The pres- elastic proteins and carbohydrate polymers forming the ence of valves ensures correct orientation of blood flow. outermost sheath. Lymphatic vessels lack the outer ECM Some veins, especially in the legs, are exposed to high sheath, and continuous vSMC and basement membrane pressure due to gravitational forces and subject to fre- layers are only present in certain large vessels. quent distortions (i.e., varicose veins). The mechanisms that give rise to the mature vascular During vascular development, a primary capillary network are complex. These developmental processes, plexus is formed early on by in situ differentiation of termed vasculogenesis, angiogenesis, and lymphangio- hemangioblasts, originating from the mesoderm, into genesis, involve a plethora of signaling molecules and their ECs that assemble to form endothelial tubes (vascu- receptors, acting at different time points: the angiopoietins logenesis). In response to the hemodynamic forces of (ANGPTs), ephrins, fibroblast growth factors, platelet-de- local blood flow, this plexus is progressively remodeled rived growth factors (PDGFs), transforming growth factors during angiogenesis to form the three types of blood (TGFs), bone morphogenetic proteins (BMPs), vascular vessels. At the cellular level, the “venous” phenotype of endothelial growth factors (VEGFs), and many others. the ECs is determined very early, even before the ves- Vascular anomalies are localized defects that occur sel is committed to being a vein [8]. In the trunk of the during vascular development [1–5]. They are subdi- embryo, the venous system is first present as symmet- vided into proliferative vascular tumors (mainly infantile rical bilateral vessels. The veins on the left then regress Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00009-4 Copyright © 2020 Elsevier Inc. All rights reserved. 251 252 SECTION 1 Cardiovascular Disorders progressively while those on the right evolve into the superior and inferior vena cava. Defective remodeling may lead to retention of embryonic veins, such as per- sistence of superior vena cava [9,10], the right umbilical GVM VMCM vein [11], or saphenous vein [12]. 9.3 DISORDERS OF THE VENOUS SYSTEM VM Venous malformations (VMs) are the most frequent mal- HCCVM MAFFUCCI SDR formations seen in interdisciplinary vascular anomaly centers. Several inherited or sporadically occurring sub- types exist. They are discussed here. Varicose veins and varicosities are discussed with the disorders affecting lym- phatic vessels (Chapter 8). Malformations with a capillary BRBN KTS or arteriovenous component are described in Chapter 10. Diagnostics and management of acute and chronic venous Figure 9.1 Venous anomalies: GVM on leg; cutaneous and diseases have been extensively reviewed elsewhere [13]. mucosal venous malformations (VMCMs) on lips; sporadic VM on foot; HCCVM on arm; multiple spindle cell hemangioendo- 9.3.1 Glomuvenous Malformation theliomas and enchondromas on hand of patient with Maffucci syndrome; intestinal and cutaneous VMs of patient with BRBN The most frequently inherited VM, glomuvenous malfor- syndrome; CLVM on legs of patient with KTS (left side more mation (GVM, OMIM 138000) accounts for roughly 5% of affected). BRBN, blue rubber bleb nevus; CLVM, capillaro–lym- VMs [14] and is often improperly called “glomangioma” or phatico–venous malformation; GVM, glomuvenous malfor- “(multiple) glomus tumor” although it is not a tumor and mation; HCCVM, hyperkeratotic cutaneous capillary–venous malformation; KTS, Klippel–Trenaunay syndrome; VM, venous never becomes malignant. GVM is characterized by the malformation. presence of a variable number of “glomus cells” around dis- tended venous channels [15,16]. Similar rounded cells are present in paraganglioma (OMIM 115310, 168000, 601650 familial history of the disease [20]. Yet, a series of clini- and 605373) and (subungual) solitary glomus tumor. All cal criteria and a few biomarkers have been defined[21] . are sometimes referred to as “glomus tumor.” However, GVM is usually raised, nodular, present at birth, and paraganglioma are tumors of the parasympathetic ganglia, slowly expands during childhood (Fig. 9.1). It is often most commonly located in the head and neck area, caused multifocal and hyperkeratotic. Its color varies from pink by mutations in subunits of the succinate dehydrogenase to purplish dark blue [20]. Sometimes, it is flat and pur- enzyme complex [17]. Solitary glomus tumors are usually ple in color, especially in the newborn. This plaque-like subungual painful lesions histologically characterized by GVM usually darkens with time [22]. GVMs are mainly the presence of glomus cells, but without important vascu- located on the extremities, involve skin and subcutis, and lar component [18]. are often painful on palpation. It cannot be completely GVM segregates as an autosomal dominant disease, emptied by compression. Contrary to VM, GVM is rarely with incomplete penetrance and variable expressiv- encountered in mucosae [20]. Patients with GVM have ity [19]. Frequently, a single individual in a family is normal mental and physical development, normal blood more severely affected and is brought to the medical cell counts, coagulation, liver and renal function, electro- attention, whereas most of the other affected individu- lytes, plasma proteins, and urinalysis. They do not have als have small lesions and never consider treatment. As intestinal hemorrhage either, what distinguishes them penetrance is below 100% and many individuals have from patients suffering from blue rubber bleb nevus tiny asymptomatic lesions, it is likely that the inherited (BRBN) syndrome (MIM 112200) [23]. D-dimer level is nature of patient’s lesions is overlooked. normal in GVM [24]. In two patients, thoracic plaque- Clinical distinction of GVM from VMs and muco- type GVM was associated with pleural effusion [25]. cutaneous venous malformations (VMCMs) can be The alterations in the mutated gene seem to cause specif- difficult in patients with few small lesions and without ically abnormal cutaneous vascular development. Currently, CHAPTER 9 Disorders of the Venous System 253 the best therapy is surgical resection of the entire GVM, control both TGF beta (TGFβ) and hepatocyte growth which is curative, and is facilitated by the noninfiltration of factor (HGF) pathways (Fig. 9.2), which are crucial for GVM in underlying tissues [20]. Alternatively, sclerother- vSMC differentiation [32,33]. In vitro, GLMN interacts apy can be used for a GVM that is soft on palpation. with FKBP12 and might impede its binding and inhibi- GVMs are caused by loss-of-function mutations in tion of TGFβ receptor signaling [34,35]. FKBP12 also a gene named glomulin (GLMN), the exact function of inhibits downstream signaling of mTOR [36,37]. Com- which is still unknown [26]. It encodes a protein of 594 plete loss of GLMN in GVMs could thus result in inhibi- amino acids. Forty distinct mutations have been reported tion of TGFβ and mTOR signaling. in 162 families [19,26,27]. Sixteen of these mutations were GLMN also interacts with the intracellular part of detected in several families, accounting for 85% of the ped- the HGF receptor c-Met. Upon HGF binding, GLMN igrees with a GLMN mutation. The most frequent mutation is tyrosine phosphorylated, released, and induces phos- is c.157_161del (aka 157delAAGAA), present in 72 kin- phorylation of p70S6-kinase [35], thereby controlling dreds (44.4%). Screening first for these shared mutations protein synthesis [36,37]. As HGF triggers downstream is therefore recommended to accelerate genetic diagnosis. signaling mediating vascular SMC migration [33], lack There is no correlation between the position of a muta- of GLMN in GVMs likely alters this signaling. tion in the GLMN gene