Case Report: Muckle–Wells Syndrome Mimicking Juvenile Idiopathic Arthritis

Muckle–Wells syndrome (MWS) is one of three clinical forms of cryopyrin-associated periodic syndrome (CAPS), a rare hereditary intermittent fever syndrome due to genetic mutations in the NOD-like receptor 3 (NLRP3) gene [1]. CAPS-associated NLRP3 mutations gain function, leading to a hyperactive cryopyrin inflammasome, increased myeloid cell-derived pro-inflammatory cytokine release, and systemic and tissue inflammation, leading to disease symptoms [2]. Hence, early and correct diagnosis of MWS, a monogenic autoinflammatory disease, is sometimes difficult. Juvenile idiopathic arthritis (JIA) refers to a clinically heterogeneous group of patients with arthritis of unknown cause, with more than six weeks duration that starts before age 16 years old [3]. Juvenile psoriatic arthritis (JPA), enteritis-related arthritis (ERA), oligoarthritis, rheumatoid factor (RF)–negative polyarthritis, RF–positive polyarthritis, and undifferentiated arthritis are the seven types recognized under the current classification of JIA [4]. The diagnosis of JIA requires the exclusion of other diseases and long-term observation, so it is also challenging to diagnose correctly. This article reports a case of MWS mimicking JIA. A 10-year-old boy presented with arthralgia for seven months and rashes for 20 days before his first hospital admission. The patient experienced needle-pricked pain on the inner side of the right knee joint seven months before admission, which lasted for one day and self-relieved. Subsequently, there was pain on the right foot's inner side, swelling, and difficulty walking. Later, intermittent pain in the right knee and foot could be relieved by administering Votalin (diclofenac sodium enteric-coated tablets, a type of NSAIDs). Twenty days before admission, there was no apparent cause for the appearance of red patches and papules, which gradually spread from the waist and abdomen to the whole body. After 2–3 days of topical medication, they disappeared. Once the drug was stopped, the rash reappeared. The skin was slightly protruding, without itching, accompanied by local pain, and the rash recurred. Upon further investigation of the patient's history, the patient experienced recurrent fever starting one year after birth, with fever intervals ranging from 1 to 3 months, presenting as a moderate fever. Parents reported that the patient developed a fever after catching a cold and could self-heal. Intermittent conjunctival congestion was also diagnosed as allergic conjunctivitis. In the past three years, there have been intermittent abdominal pain and diarrhea. The symptoms are not severe, and they resolve spontaneously. There is no correlation between abdominal pain and fever. The abnormal items in the examination results after admission are shown in Figure 1. Other organ functions and routine examinations not mentioned above showed no significant abnormalities. The discharge diagnosis was arthritis, and no special treatment was given. No abnormalities were found in ophthalmic examinations related to immune system diseases, and no abnormalities were found in neurological examinations. After six months of discharge, the patient was readmitted due to abdominal pain, diarrhea, and fever for eight days. Due to an abdominal ultrasound showing thickening of the intestinal wall (about 5 mm), gastroscopy and gene sequencing (whole exome sequencing) were performed after hospitalization. The gastroscopy results are shown in Figure 2. When the patient was readmitted, they were 140 cm tall (p10-p25) and 34.5 kg (p25-p50) in weight, with a height lower than that of their peers—1SD. The bone age is slightly delayed by one year. Based on recurrent joint pain, rash, and abdominal pain, as well as HLA-B27 positivity and persistently high levels of inflammatory markers, we considered juvenile idiopathic arthritis or inflammatory bowel disease–related arthritis. However, the child's colonoscopy did not show any obvious signs of inflammatory bowel disease, and the diagnosis is questionable. After six weeks, the results of whole exome sequencing in the patient overturned our diagnosis. Gene sequencing showed a heterozygous mutation c.2582A>G: p.Y861C in the NLRP3 gene Exon7, with transcript number NM:004895.5. Further testing showed that neither the father nor the mother had the mutation, indicating that the patient's heterozygous mutation is wild type. It can be inferred that the patient's onset is genetically related, but the mutation does not exist in the existing database, and future protein-level experiments are still needed for verification. The patient reported no hearing loss and was recommended to seek medical attention at an otolaryngology department. A comprehensive examination indicated moderate hearing loss, high-frequency decline type, and a diagnosis of sensorineural hearing losswas made. Blood interleukin-1β was 118 pg/mL (reference value ≤ 5 pg/mL). Reviewing the medical history, MWS can explain every symptom of the patient, such as intermittent fever, joint pain, arthritis, rash, conjunctivitis, growth retardation, and hearing impairment. Finally, we corrected the diagnosis to MWS. Because the interleukin-1 antagonist is not listed in mainland China, the child is currently receiving thalidomide and tranilast capsules treatment; the patient is currently 13 years old and has no secondary sexual characteristics. After completing relevant examinations, such as growth hormone stimulation tests, supplementary treatment such as growth hormone supplementation may be considered. In addition, studies have shown that neutrophils may be a new therapeutic target for CAPS. Although complete depletion of neutrophils may expose CAPS patients to a high risk of infection, blocking neutrophil aggregation may be an effective strategy to reduce skin inflammation in CAPS patients [5]. Autosomal dominant mutations in the nucleotide-binding cause CAPS and leucine-rich repeat receptor family pyrin domain containing 3 (NLRP3) gene that encodes cryopyrin, the protein responsible for assembly of the inflammasome and regulation of the proinflammatory cytokine interleukin-1 beta (IL-1β) [6]. Defective cryopyrin leads to spontaneous and increased production of IL-1β, resulting in clinical symptoms such as urticarial rash, fever, and arthralgia without exogenous stimuli [7]. According to clinical symptoms, CAPS can be divided into three different subtypes: FCAS-CAPS1, Muckle–Wells syndrome (MWS-CAPS2), and chronic infant neurological cutaneous and joint syndrome (CINCA-CAPS3)/multiple neonate inflammation disease (NOMID) [8]. MWS is an intermediate type of CAPS in terms of severity. Patients described as having MWS present with intermittent fever, widespread urticarial papules, and plaques lasting 1–2 days with associated abdominal pain, myalgias, arthralgias, conjunctivitis, episcleritis, and sensorineural hearing loss [9, 10]. However, their disease is typically not triggered by exposure to cold [10]. Hearing loss and the development of amyloidosis are also reported in many MWS patients [10]. There are also case reports that indicate CAPS should be considered when dermatologists encounter an untypical recalcitrant urticaria-like rash because the correct diagnosis and timely treatment can dramatically improve the quality of life of these patients [11, 12]. Literature reports indicate that CAPS can overlay tumor necrosis factor type 1A receptor-associated periodic syndrome (TRAPS) [13]. Therefore, the diagnosis of this disease is challenging. In combination with the case we reported, our patient has almost all the typical symptoms of MWS except for renal amyloidosis, which had not yet occurred. The results of genetic testing can also provide sufficient evidence for diagnosis. But why did we misdiagnose the case as a JIA? It is a question worth pondering and exploring. Firstly, HLA-B27 positivity is also interference, and it is rare to see HLA-B27 described in the case reports of MWS. Secondly, representative symptoms seen in patients with MWS, such as rash, fever, arthralgias, and conjunctivitis, can also be seen in patients with JIA. Inflammatory markers remain high throughout the condition, and the predominantly neutrophilic blood profile can all indicate a disease diagnosis. An article suggests that neutrophils are major IL-1β producers in CAPS and thus might play a key role in CAPS pathology [5]. It is inconsistent with the characteristics of JIA that only intermittent administration of small doses of NSAIDs can provide effective relief, which leads us to consider autoinflammatory diseases. After adalimumab, the patient developed symptoms of fever accompanied by systemic pain, which could be resolved by itself after 1–2 days, and the treatment did not reduce the patient's periodic fever, joint pain, and high inflammation, so it was not used for subsequent treatment. The most important thing is to perform whole-exome gene sequencing actively when clinical indicators with suggestive significance appear and fever occurs, instead of controlling symptoms after administering biological agents, as gene testing is crucial for accurately diagnosing CAPS. As we all know, JIA is an exclusionary diagnosis. All arthritis of unknown origin starting at less than 16 years old and lasting six weeks can be diagnosed as JIA after excluding other diseases. Because, in children, as in adults, several different diseases exist that all cause chronic arthritis, the terms juvenile idiopathic arthritis and juvenile idiopathic arthritis onset forms will probably become outdated as more is learned about each disease [14]. JIA is a synonym for a group of diseases. JIA can easily be misdiagnosed when any condition with similar symptoms is difficult to diagnose. The finding is that anti-interleukin-1treatment can also be effective for JIA; some JIA patients have a pronounced, complete response to interleukin-1 blockade (much the same as in cryopyrin-associated autoinflammatory syndromes) [14]. In short, clinical doctors, especially pediatricians, should understand inflammatory diseases sufficiently to diagnose them early, avoid misdiagnosis, and improve patients' quality of life. The clinical manifestations of MWS in this case are relatively mild, but it is unknown whether neuropathic deafness and kidney damage will affect the child with age. Whether current treatment can improve the prognosis also requires long-term observation. For children with suspected autoimmune or autoinflammatory diseases whose diagnosis is unclear, whose onset age is young, in whom multiple target organ damage occurs, and whose treatment is not smooth, it is necessary to improve whole-exome gene testing actively. The child did not show any neurological symptoms, but we should pay attention to this during follow-up. Literature reports indicate that half of CAPS patients will experience neurological symptoms [16]. Increased awareness of this rare but treatable autoinflammatory syndrome among clinicians would probably decrease morbidity and mortality. Z.B.Y. and Z.B.Z. organized the materials and wrote this manuscript. H.L. and B.Z. searched the literature and reviewed the manuscript. J.H. provided ideas for the diagnosis and treatment of this patient's illness. L.L. provided ideas and revised the manuscript. All authors read and approved the final manuscript. We thank all participants and staff of this paper, and also thank the physicians at the Tianjin Children's Hospital affiliated with Tianjin University. This is to certify that the content of this paper meets the requirements of medical ethics after review by the ethics committee. The authors have nothing to report. The authors declare no conflicts of interest. All data generated or analyzed during this study are included in this article.