A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis.

We describe a single consanguineous family with three affected children exhibiting knee and/or hip pain associated with swelling. Detailed clinical evaluation demonstrated diffuse joint involvement with an unusual proliferative synovitis on MRI. Synovial biopsies were notable for an infiltration of macrophages with abundant cytoplasm filled with faintly basophilic vacuoles. We used homozygosity mapping with a panel of 262,000 single nucleotide polymorphism markers to identify a homozygous stretch of 40.52 Mb on chromosome 3p22.3 - 3p13 that segregated with the arthropathy in the family. Of the 378 genes in the interval, the three hyaluronoglucosaminidase genes were considered good candidates based on the phenotype. Dideoxy sequencing identified a homozygous deletion in HYAL1, c.104delT, resulting in a premature termination codon, p.Val35AlafsX25, found in all three affected children. Enzymatic analysis confirmed total HYAL1 deficiency in the three affected children. This confirms the diagnosis of Mucopolysaccharidosis IX (MPS IX) which has only been described in a single patient to date. In contrast to the previously described MPS IX patient, our three patients display a phenotype limited to the joints, suggesting that this is the primary manifestation of HYAL1 deficiency.