State of the art paper Genetics Genetic syndromes with vascular malformations – update on molecular background and diagnostics Adam Ustaszewski1,2, Joanna Janowska-Głowacka2, Katarzyna Wołyńska2, Anna Pietrzak3, Magdalena Badura-Stronka2 1Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland Corresponding author: 2Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Adam Ustaszewski Poland Institute of Human Genetics 3Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland Polish Academy of Sciences 32 Strzeszynska St Submitted: 19 April 2018; Accepted: 9 September 2018 60-479 Poznan, Poland Online publication: 25 February 2020 Phone: +48 61 65 79 223 E-mail: adam.ustaszewski@ Arch Med Sci 2021; 17 (4): 965–991 igcz.poznan.pl DOI: https://doi.org/10.5114/aoms.2020.93260 Copyright © 2020 Termedia & Banach Abstract Vascular malformations are present in a great variety of congenital syn- dromes, either as the predominant or additional feature. They pose a major challenge to the clinician: due to significant phenotype overlap, a precise diagnosis is often difficult to obtain, some of the malformations carry a risk of life threatening complications and, for many entities, treatment is not well established. To facilitate their recognition and aid in differentiation, we present a selection of notable congenital disorders of vascular system development, distinguishing between the heritable germinal and sporadic somatic mutations as their causes. Clinical features, genetic background and comprehensible description of molecular mechanisms is provided for each entity. Key words: arteriovenous malformation, vascular malformation, capillary malformation, venous malformation, arterial malformation, lymphatic malformation. Introduction Congenital vascular malformations (VMs) are disorders of vascular architecture development. They may involve any vessel type and are accordingly classified as capillary, venous, arterial, lymphatic and arte- riovenous, any of which can occur alone or in combinations. Congen- ital VMs are not only a cosmetic issue, as they can lead to serious or even life-threatening complications including congestive heart failure, ischemia, brain and spinal cord stroke and glaucoma. Vascular malfor- mations are a feature of numerous genetic syndromes. Due to the over- lapping symptoms, the differential diagnosis of genetic syndromes with VMs may be troublesome [1, 2]. Moreover, the effect of a particular gene mutation is often pleiotropic, giving rise to multiple phenotypes. While most well-known VM syndromes are caused by a constitutional muta- tion, some are revealed to result from somatic mutations, present in only a fraction of cells in the body. Creative Commons licenses: This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY -NC -SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/). Adam Ustaszewski, Joanna Janowska-Głowacka, Katarzyna Wołyńska, Anna Pietrzak, Magdalena Badura-Stronka Capillary malformation-arteriovenous AVMs and AVFs; what is more, these alterations malformation syndrome have been also observed sporadically in PWS [1, 9, 10]. This constellation of VMs related to RASA1 Capillary malformations (CMs, port-wine stains) mutations was named capillary malformation – are the most common VMs, occurring in 0.3% of arteriovenous malformation syndrome (CM-AVM) newborns [1]. Capillary malformations present as [1]. Subsequently, a number of studies reported on lightly colored, reddish to pink, flat, slow-flow cu- atypical CMs caused by RASA1 mutations [2, 3, 5, taneous lesions in the form of irregularly shaped 6, 11–23]. It was demonstrated that alterations of macules. They may be confused with other macu- RASA1 might also act as an additional factor in lar skin lesions such as naevus flammeus neona- other vascular development disorders, including torum, commonly known as angel’s kiss or salm- vein of Galen malformations (VOGMs) and HHT on patch. Unlike hemangiomas, however, capillary [24–26]. RASA1 encodes RAS p21 protein activa- malformations do not diminish with age but tend tor 1 (p120-RasGAP) consisting of five domains. to darken and thicken. Capillary malformations It is a negative regulator of the Ras/MAPK and usually are sporadic lesions, although recently, fa- MAPK/ERK pathway, converting the Ras protein miliar occurrence and genetic syndromes present- into its inactive GDP-coupled form [6, 27]. The ac- ing with CMs have been reported [3]. tive GTP Ras form interacts with the Raf protein The recently described capillary malformation- that is responsible for phosphorylation of proteins arteriovenous malformation (CM-AVM) syndrome involved in cell growth, proliferation and differ- is an underdiagnosed condition, often considered entiation [28, 29]. The changes in p120-RasGAP a sporadic collection of infantile hemangiomas concentration levels have an impact on angio- or “port-wine stain”. The skin changes typical genesis [30]. The CM-AVM syndrome follows the for CM-AVM syndrome are acquired macules or pattern of autosomal dominant inheritance with papules that are multifocal (present in more than incomplete penetrance and variable phenotype, one region or location of the body), small (ranging in part due to the localized nature of VMs [31]. from less than 1 cm to 3 cm in diameter), round Interestingly, De Wijn reported 100% penetrance to oval in shape and pink to red in color [2]. They in patients with RASA1 deletion [14] while Carr are often surrounded by a white halo suggesting et al. estimated the penetrance at 20% [32]. Eerola vascular steal and show arterial flow on Doppler et al. suggested a predominant inheritance pattern ultrasound. The CM-AVM is usually associat- (similar to the one in glomuvenous and cerebral ed with high-flow arteriovenous malformations cavernous malformations) that requires a somatic (AVMs) or arteriovenous fistulas (AVFs) in muscle, second hit mutation, resulting in complete loss of skin and other tissues (intracranial, intraspinal function of the p120 RAS-Gap protein [1] (Figure 1) and interosseous AVMs have been described) [4]. [33–38]. Chee et al. reported on patients with skin CMs Arguably, other non-synonymous alterations and nontraumatic cerebral hemorrhage due to in- present in other members of Ras/MAPK pathway tracranial AVM [5]. The authors estimate the fre- may lead to vascular development disorders. In- quency of the CM-AVM syndrome in patients with deed, published data indicate that inactivating cerebral AVMs at between 15% and 50% [5]. Boon mutation of the EPHB4 gene which recruits and et al. suggested that patients with multiple atypi- activates RASA1 may result in CM-AVM syndrome cal CMs should be assessed for high-flow lesions in non-RASA1 patients [39–40]. The transmem- such as AVMs or AVFs [6]. In these patients, neu- brane kinase receptor EPHB4 is required for the roimaging screening should be considered. proper functioning of several processes such The differential diagnosis of CM-AVM syndrome as intervening capillary beds and morphogene- should include Klippel-Trénaunay-Weber syndrome, sis, which are crucial for the development of the Parkes Weber syndrome, hereditary hemorrha- vascular system [39, 41]. However, mutations in gic telangiectasia (HHT; Rendu-Osler-Weber syn- RASA1 are still considered the main factor respon- drome) and hereditary benign telangiectasia sible for the CM-AVM syndrome. Table I contains (HBT), which is a mild variant of the HHT, and a brief summary of molecular screening results in Sturge Weber syndrome. All these syndromes fea- patients with CM-AVM syndrome [42–45]. ture cutaneous VMs. Mutations of the RASA1 gene are responsible for Hereditary hemorrhagic telangiectasia several forms of VMs: CMs, AVMs, AVFs, singularly and in complex combinations, as in the rare Parkes Owing to the similar clinical features, HHT may Weber syndrome (PWS) [7, 8]. In 2002, two loci for be mistaken for other CM-AVM syndromes. It has hereditary CMs were identified on chromosome 5 an autosomal dominant inheritance with high (5q14-21 and 5q13-22). A year later, RASA1 (RAS penetrance but considerable intrafamilial variabil- p21 protein activator 1; OMIM 139150) was iden- ity. The incidence of HHT is estimated at 1/8,000 tified as a candidate gene for atypical CMs with in infants [46]. The hallmark of the syndrome is 966 Arch Med Sci 4, June / 2021 Genetic syndromes with vascular malformations – update on molecular background and diagnostics Figure 1. A simplified model of Ras activation as a part of the MAPK/ERK signaling pathway. Ras proteins play a key role in regulation of numerous subsequent signaling cascades and pathways. Mutations in the RASA1 gene may cause a change in Ras activity, resulting in development of CM-AVM syndrome and PWS. There is some evidence that KTWS might also be caused by abnormal Ras function. The complete genetic background of KTWS remains unknown [33–38] multiple AVMs without intervening capillaries, re- bleeding, which usually occurs after the age of sulting in direct connections between arteries and 50 years [49, 50]. The AVMs localized in internal veins, affecting mucosae, skin and internal organs organs may have life-threatening manifestations. with co-occurrence of telangiectases. The HHT They are commonly found in lungs, liver and brain. presentation is age-dependent. While the first In most cases, brain AVMs are already present symptoms are usually