BackgroundSystemic Sclerosis (SSc) is a rare autoimmune disease whose pathogenesis is still poorly understood. The Transforming Growth Factor β superfamily is considered pivotal and a crucial role has been suggested for the type III receptor, Endoglin (ENG). The aim of this systematic review is to investigate and combine the current clinical and molecular available data, to suggest novel hints for further studies.MethodsWe followed PRISMA guidelines; the search was performed on three databases (MEDLINE, Web of Science, Embase) in date November 2nd, 2021. Subsequent to the exclusion of duplicates, we applied as inclusion criteria: 1. focus on the relationship between ENG and SSc; 2. English language. As exclusion criteria: 1. ENG exclusively as a cellular biomarker; 2. no focus on ENG-SSc relationship; 3. review articles and 4. abstracts that did not add novel data. Eligibility was assessed independently by each author to reduce biases. We divided records into clinical and molecular works and subgrouped them by their study features and aim.ResultsWe selected 25 original papers and 10 conference abstracts. Molecular studies included 6 articles and 4 abstracts, whereas clinical studies included 17 articles and 6 abstracts; 2 articles presented both characteristics. Molecular studies were focussed on ENG expression in different cell types, showing an altered ENG expression in SSc-affected cells. Clinical studies mainly suggested that different disease phenotypes can be related to peculiar disregulations in soluble ENG concentrations.DiscussionConcerning the possible limits of our search, boolean operators in our strings might have been uneffective. However, the use of different strings in different databases should have reduced this issue at a minimum. Another bias can be represented by the selection step, in which we excluded many articles based on the role of Endoglin as a histological vascular marker rather than a signaling receptor. We tried to reduce this risk by performing the selection independently by each author and discussing disagreements. Our systematic review pointed out that ENG has a pivotal role in activating different TGFβ-stimulated pathways that can be crucial in SSc pathogenesis and progression.

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease ( ENG , ACVRL1 , SMAD4 , GDF2 ) belong to the TGF‐β/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in‐frame deletion c.289_294del (p.H97_N98). Methods To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non‐carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out. Results We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site. Conclusion We have demonstrated, for the first time, a “founder effect” for a HHT pathogenic variant in Italy.

BackgroundSystemic sclerosis (SSc) is a rare autoimmune disease characterized from peculiar vascular alteration and fibrosis of the skin and internal tissues. SSc pathogenetic mechanisms are still partially unclear but an involvement of the TGFβ pathway, known for being responsible of both angiogenesis and fibrosis, has been proven. Endoglin (ENG) is a TGFβ receptor type III involved in signal regulation, and mutations in ENG gene cause Hereditary Hemorrhagic Telangiectasia type I, a rare disease that shares with SSc the presence of mucocutaneous telangiectasias and disturbed angiogenesis.ObjectivesThe aim of this systematic review is to highlight the role of ENG in the pathogenesis of SSc focusing on a subset of clinical manifestations.MethodsWe performed a systematic review following the PRISMA guidelines, searching the MEDLINE (PubMed), Web of Science and EMBASE databases using as keywords: “Endoglin”, “sENG”, “CD105”, “Systemic sclerosis”, “SSc”, “Scleroderma”, “CREST”. The last search was made on November 2nd 2021. This review includes both conference abstracts (without subsequent publication) and articles that evaluated the relationships between SSc and ENG; we excluded the papers that used CD105 only as a cell marker. We then consulted the references from the papers found in order to search possible articles that escaped our first search.ResultsOf the 656 records identified from the database research, 42 were included in our systematic review (16 abstracts and 26 original papers) (Figure). The majority of these studies (25) measured serum ENG (sENG) looking for correlations with cutaneous, pulmonary and cardiac disease in patients with SSc.Figure. PRISMA flow diagram.High levels of sENG demonstrated an independent association with telangiectasia in 2 studies, with the presence of digital ulcers (DU) in 6 studies but was not related to the occurrence of new DU (2 studies) and it was related to scleroderma pattern late in 2 studies. Between limited and diffuse cutaneous SSc, sENG showed no differences in one study and significantly higher values in lcSSc in another, this latter study also found sENG to be higher in lcSSC compared to systemic lupus erythematous and healthy controls (HC). sENG, moreover, demonstrated a positive correlation with anti-centromere antibodies (two studies). Regarding pulmonary involvement, no correlation between sENG and mean pulmonary arterial pressure was recorded, and two studies found sENG elevated in patients with pulmonary arterial hypertension while no correlation was found from two other papers. High sENG concentrations demonstrated a positive correlation with subclinical atherosclerosis and with high sensitivity troponin, but its concentration did not relate to right heart dysfunction (1 study each). Two different groups evaluated sENG concentration in Localized Scleroderma and found no differences with other connective tissue diseases. One study searched for genetic alterations in the expression of ENG gene and found no difference between SSc patients and HC. Four studies evaluated Eng expression on fibroblast surface: SSc fibroblasts from both systemic circulation and lung showed higher production of Eng than HC. Tissue Eng, moreover, is up regulated in SSc patients where it acts as a regulator of TGFβ signaling and of extracellular matrix production.ConclusionAs suggested by the role of Endoglin in the TGFβ pathway, several authors demonstrated an altered expression of Endoglin in SSc patients. A particular focus of interest is the role of ENG in PAH and DU that occur in SSc. A direct involvement of ENG in PAH is known as mutation in this gene are one of the genetic causes of PAH. However, particularly in pulmonary vascular disease, there are still controversial and insufficient data to draw definitive conclusions. As PAH is a leading cause of mortality in SSc patients this is an area of clinical interest and the study of the TGFβ pathway could lead to useful clinical findings.Disclosure of InterestsNone declared