GS is a rare LSD which presents with a wide range of clinical features. The musculoskeletal system is one of the organ systems typically affected, resulting in varying degrees of musculoskeletal deformities (1). A few studies also report patients with articular complaints (5-8), yet knowledge on GS-related joint pathology is limited. Our patient exhibits a remarkable frequency and severity of osteoarticular abnormalities and in addition presented with severe relapsing inflammatory arthritis in both knees, which has never been described before. The differential diagnosis for arthritis in the pediatric population is broad and therefore it can be challenging to obtain a correct diagnosis (9, 10). In the present case, owing to comprehensive examinations (i.e. physical examination, laboratory tests, radiologic imaging and microscopic examination) multiple possible causes for the recurrent inflammatory joint pathology could be rejected (in particular there were no signs of infectious arthritis, reactive arthritis, osteoarthritis, arthritis secondary to a malignancy or crystal induced arthritis). However, the clinical results were not conclusive and therefore the primary cause for the recurrent arthritis remains elusive.
A diagnosis which could explain the clinical picture is the JIA subtype: ANA negative oligo-articular JIA. JIA is the most common acquired chronic musculoskeletal pediatric disease and defined by joint inflammation, of unknown origin, that persist for more than 6 weeks and starts before the age of 16 years (10). JIA is a diagnosis per exclusionem (10), and therefore should be considered as a possible diagnosis in this case. However, microscopic examination in our patient showed numerous foamy macrophages with extensive vacuolization in the synovial tissue of the inflamed joint, which is not associated with JIA. Given the evidence of storage products within the macrophages of the inflamed synovial tissue and no conclusive diagnosis, GS itself should be considered as the primary cause for the recurrent arthritis. We hypothesize that the prolonged articular build-up of storage material has induced arthritic cascades, resulting in the development of the inflammatory joint pathology as observed in our patient.
According to the sparse literature on joint complaints in GS, to date, GS cannot be linked directly to joint inflammation. Nevertheless, disease-related arthritis has been described in several other LSDs, such as: Fabry disease (MIM #301500) (11), Farber lipogranulomatosis (MIM #228000) (12-16), Gaucher disease (MIM #230800) (16-19), a-Mannosidosis (MIM #248500) (20), Fucosidosis (MIM #230000) (21), Aspartylglucosaminuria (MIM #208400) (22), Cystinosis (MIM #219800) (23) and in a number of subtypes of Mucopolysaccharidoses (MPSs) (24-26). Although, some arthritic mechanisms seem to be LSD specific (e.g. vascular occlusion secondary to bone marrow infiltration with storage cells in Fabry disease (27) and Gaucher disease (28), and crystal induced arthritis in Cystinosis (29)), systemic as well as local inflammatory processes possibly related to the effects of prolonged articular build-up of storage material in general have been reported. For instance, the abundance of unmetabolized substrates in LSDs might induce aberrant immune responses with subsequent expansion of immune cells of the innate immunity as well as adaptive immunity (26, 30-34). Moreover, it is thought that storage products in MPSs possibly could act as self-antigens and subsequently might provoke the necessary signals to activate autoimmunity processes (35). Another potential key player in LSD related joint inflammation could be the increased activation of Toll Like Receptor 4 (TLR4), as described in MPSs (26, 36). TLR4 activation is related to the upregulation of numerous pro-inflammatory proteins, such as chemokines, cytokines (e.g. tumor necrosis factor [TNF] and interleukin-1 [IL1]), nitro oxide products, metalloproteinases, prostanoids and growth factors (26, 36). Since the cause for storage product deposition in LSDs cannot be eliminated, the trigger for the above described inflammatory cascades is continuously present and therefore eventually might lead to persistent inflammatory activity known as metabolic inflammation (26). Activation of TLR4 does not only have systemic effects, but also induces local mechanisms which show several similarities to arthritic processes observed in rheumatoid arthritis. For example, the increased levels of TNF and IL1 could result in hyperproliferation of immature synoviocytes and subsequent synovial hyperplasia (26, 36). Despite all the aforementioned inflammatory processes, extensive joint inflammation in LSDs, similar to the arthritic joint pathology as observed in our patient, is rare and, to our knowledge, has only been described in 3 children diagnosed with MPS-IX (25). According to the fact that the vast majority of patients suffering from LSDs do not exhibit inflammatory arthritis, presence of genetic susceptibility for development of autoimmune responses to storage material should be considered in our case.
In this study, we report, for the first time, the case of a boy affected by GS presenting with relapsing inflammatory arthritis in both knees. Given the evidence of storage material in the inflamed synovial tissue and absence of clues typical for other potential diagnoses, GS itself is considered as the primary cause for the origination of the inflammatory arthritis. Based on literature about joint inflammation complicating LSDs, we hypothesize that the chronic articular accumulation of GS storage products triggered local as well as systemic arthritic responses, resulting in the recurrent episodes of inflammatory joint pathology in our patient. Nevertheless, future identification of other patients with GS is required to corroborate the existence of an arthritic clinical phenotype of GS and to assess the underlying pathophysiology.