Mere coincidence or an association? Case of juvenile idiopathic arthritis in a patient with Klinefelter syndrome

Dear Editors,

We present an exceptionally rare case of a seven-year-old male with Klinefelter Syndrome (KS) and Juvenile Idiopathic Arthritis (JIA), only the second reported case in the literature to our knowledge [1].

Our patient with KS (47, XXY) and history of left middle “trigger finger” presented with arthritis and tenosynovitis in bilateral wrists without enthesitis, nail changes, uveitis, alopecia, oral ulcers, gastrointestinal symptoms or rash. He had positive antinuclear antibody 1:2560, rheumatoid factor and anti-cyclic citrullinated peptide antibody, and negative HLA-B27 gene and lupus serologies. JIA was diagnosed with a 10-joint clinical juvenile arthritis disease activity score (cJADAS10) of 16 (Fig. 1). Treatment included weekly subcutaneous methotrexate 1 mg/kg and daily prednisolone 1 mg/kg for rapid resolution of arthritis in the wrists. Prednisolone was subsequently tapered off with improvement of cJADAS10 score while methotrexate was continued to maintain remission (Fig. 1).

Fig. 1

Juvenile Idiopathic Arthritis Disease Activity Over Time in Response to Treatment. Patient started treatment with subcutaneous (SC) methotrexate (MTX) and prednisolone at time 0 months. Disease activity at point-of-care was assessed via the 10-joint clinical Juvenile Arthritis Disease Activity Score (cJADAS-10) (range 0–30, 30 represents most severe arthritis) and followed post-diagnosis in response to treatment. Changes in treatment regimen over time are annotated in graph

Individuals with KS demonstrate a greater incidence of certain rheumatologic disorders when compared to euploid individuals. The X chromosome and sex hormones are hypothesized to play a role. Estrogen causes dysregulation of the innate and adaptive immune systems by altering cellular responses in lymphocytes. It also impedes immune tolerance through downregulation of the autoimmune regulator gene and produces various inflammatory cytokines [2]. Studies of rheumatoid arthritis (RA) and lupus in male patients with KS also suggest low testosterone level or a disproportionately higher estradiol/testosterone ratio as contributing factors [3]. Variation in the local action of gonadal hormones and in the genetic makeup of androgen receptor genes are also considered plausible mechanisms [3]. Recent emerging studies attribute the X-inactive specific transcript (Xist) ribonucleic acid as a leading cause of sex bias in autoimmunity. The X chromosome harbors several immunogenic genes which escape inactivation during embryogenesis to promote autoimmunity by a gene-dose effect [4].

Our case raises several questions regarding JIA in patients with KS. Our knowledge is largely based on studies on autoimmune disorders in adults with KS. While RA is known to be associated with KS, there is limited literature on the concurrence of JIA and KS to reliably infer any association or causal relationship. We have yet to decipher how the biological environment of KS might contribute to the pathogenesis and prognosis of JIA. Testosterone treatment for KS has demonstrated improved outcome in acute RA flares [5]. The effect of hormone replacement therapy remains to be explored in our patient. Given the rarity of its concurrence, additional studies are required to understand any association between KS and JIA.