Hyaline Fibromatosis Syndrome (HFS) is a rare genetic disorder caused by loss-of-function mutations in the gene CMG2. Patients develop subcutaneous nodules and painful joint contracture. CMG2 is a transmembrane protein of poorly understood physiological function. To understand better the pathogenesis of HFS and the role of CMG2 in this disease, we compared by mass-spectrometry the composition of nodular and matching non-nodular tissues. Two tissue pairs were analyzed, both obtained after surgical resection of nodules from a HFS patient. Our shotgun proteomics analysis showed that nodules were enriched in serum protein, which correlated with previous descriptions of blood vessel leakage in these tissues. Importantly, we also observed a clear accumulation of collagen VI in nodules. Collagen VI accumulation was caused by CMG2 loss-of-function and is the main cause of the nodule formation.