Chapter 4 68 osteochondromas (MO, OMIM no. 133700 and 133701), previously also known as hereditary multiple exostoses (HME) and multiple hereditary multiple exostoses (MHE) (58). MO is defined as a disease ‘characterized by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones.’ (59, 60). More than 85% of MO patients have a germline mutation in the EXT1 or EXT2 gene.(59) The EXT1 and EXT2 gene products form a co-polymerase that initiates chain elongation in heparan sulfate glycosaminoglycan synthesis.(9) Existence of another exostosin gene, EXT3, has been suggested but not proven.(61) However, as stated above, the diagnosis is often based on radiological and clinical assessment. Therefore, in many patients, genetic testing is regarded as optional in establishing the diagnosis.(62) In MO patients, a decrease in HS levels has been described in the circulatory system and in exostosis growth plates (63, 64). However, the effect of heterozygous EXT1 and EXT2 mutations on the endothelial glycocalyx have not yet been described. Moreover, it is currently unknown whether a loss of HS as a result of perturbed HS assembly results in an increase in glomerular permeability in humans. HS is also a major structural component of the glycocalyx, a coat of sugars, proteins, and lipids, lining the luminal side of the endothelium (65). Endothelial dysfunction is an important process in both cardiovascular and renal disease (66, 67). Recent technological advances have now made it possible to assess the red blood cell (RBC) count accessibility to the endothelial surface glycocalyx, in which a healthy glycocalyx is reflected by a low perfused boundary region (PBR) and a glycocalyx at risk is reflected by a high PBR (5, 68). Methods Ethics Ethical approval for this study was obtained through the LUMC Medical Ethical Committee under registration number P15.106. Anonymized patient material from the PALGA search was handled in accordance with institutional guidelines, Good Research Practice, and the Code of conduct for responsible use. MO patient study population Patients were approached through the Dutch HME-MO Association (www.hme-mo.nl). Controls were obtained from the general population and matched for age and gender. All participants were required to be capacitated and over 18 years of age. After obtaining informed consent, participants were handed a digital questionnaire. Data on mutation status, use of medication, smoking, hypertension, and relevant medical history was
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