Chapter 4 76 Although multiple urine samples over a period of time would result in a more representative result of a patient’s typical albumin excretion, the absence of proteinuria, especially in the MO patient group, strongly suggests that indeed, no clinically significant pathology is present. In this study, 6 out of 19 patients had a confirmed EXT1 or EXT2 mutation status. As stated in the introduction, the clinical diagnosis of the autosomal dominant disease of MO is often made without genetic testing, as in previous studies, a germline mutation in the EXT1 or EXT2 gene was found in almost 90% of cases.(59, 62) All MO patients in this study were included through the Dutch Multiple Hereditary Exostoses/Multiple Osteochondromas Association. In this study, outcome parameters were similar in subjects with and without a confirmed genetically confirmed diagnosis. Most patients from the historic PALGA cohort did not have a confirmed EXT1 or EXT2 mutation. At least four patients from this cohort can be classified as having MO based on clinical criteria. The only clinical data we had available on these patients, were the pathology reports. So this is most likely an underestimation of the total amount of MO patients within this cohort. We deduce that if a specific morphological phenotype with pathophysiological consequences would exist due to these mutations, our method results in an adequate appreciation of this topic. Besides the single patient described, the fact that no changes were found implies that EXT1 or EXT2 mutations do not necessarily cause changes to glomerular morphology. However, these results could be misinterpreted due to a lack of power. In conclusion, this study shows that in humans, mono-allelic germline EXT1 and EXT2 mutations do not result in proteinuria or significant changes to the endothelial glycocalyx. Loss of heterozygosity could be an explanation for the very rare case of MO glomerulopathy described previously.(56) Based on the current study, MO patients do not appear to be at an increased risk for clinically significant pathology of the glycocalyx or glomerular filtration barrier. Future studies might further elucidate the loss of heterozygosity theory and potentially identify other factors that might lead to the rare specific renal phenotype seen in only a very small subset of MO patients. This could assist in understanding not only the MO phenotype, but the pathophysiology of the glomerular filtration barrier and endothelial glycocalyx.
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