The most relevant rare diseases associated to RFUO encompass systemic autoinflammatory diseases (SAIDs), for which genetic tests are usually required (including mutations in the following genes: MEFV, TNFRSF1A, MVK, NLRP3, NOD2, etc.), and lysosomal storage disorders (LSDs) (including FD, Gaucher disease, Pompe disease, mucopolysaccharidoses, etc.), for which specific enzyme assays and genetic tests are required. Here, NOD2 is linked to mucopolysaccharidosis.