Autoinflammatory disease (AUID) is caused by gene variations that change the protein encoded by them, leading to innate immune dysfunction and subsequent systemic excessive inflammatory response [3]. Most patients with AUID show sudden periodic fever, rash, serositis, lymphadenopathy, and arthritis. Inflammatory indexes generally increase during the attack period. However, during the asymptomatic interval, the growth and development of the patients are normal, as well as the inflammatory indexes. Among them, AUID caused by single gene variations are called monogenic autoinflflammatory diseases. Due to their genetic characteristics, the onset of this disease is early, and it can occur from newborn to adolescence [4]. With the development of gene sequencing technology, more than 50 monogenic autoinflflammatory diseases have been identified [5].
In 1962, Muckle and Wells first described MWS with manifestations of urticaria rash, neurosensory hearing loss, and amyloidosis syndrome [6]. The typical clinical characteristics of MWS include: onset from infancy or early childhood, repeated intermittent fever without specific inducing factors (not closely related to cold exposure), accompanied by urticarial-like rash, joint pain, headache, conjunctivitis, etc., and the elevated systemic inflammatory indexes (leukocyte count, neutrophil count, CRP, SAA, ESR, etc.). The symptoms can last from 1 day to 2 weeks, and the interval between onset varies from a few weeks to several months. Sensorineural deafness can occur during adolescence, and 1/3 of patients will have AA-type amyloidosis, which can cause serious complications such as renal failure [7]. The main manifestations in this case were recurrent fever, urticarial-like rash, and conjunctivitis without obvious inducement, accompanied by elevated neutrophils, CRP, SAA, and ESR. After the administration of thalidomide, the symptoms were well controlled, and the laboratory indexes returned to normal. The MWS-DAS score of this case was less than 10 [8, 9]. Considering that the disease activity was mild, long-term follow-up is needed in the future to pay attention to the occurrence of hearing damage, AA amyloidosis, and kidney damage.
CAPS is caused by dominantly inherited or de novo gain-of- function mutations in the NOD-like receptor 3 (NLRP3) (also known as CIAS1 or NALP3) gene located on chromosome 1q44 [10]. The NLRP3 gene encodes the NLRP3 protein (cryopyrin), which can oligomerize and recruit other intracellular proteins such as ASC (apoptosis related spot like protein containing caspase recruitment domain) and several chaperones to form NLRP3 inflammasomes. The formation of this complex activates the proinflammatory protease called caspase-1, which in turn mediates release of proinflammatory cytokines such as IL-1β [11–14]. IL-1β can cause fever, vasodilation, and systemic inflammation. Therefore, NLRP3 gene variation can lead to continuous activation of inflammasomes and excessive production of IL-1, leading to systemic inflammation [15, 16]. The incidence rate of CAPS in the United States is about 1/1,000,000 [17], and the estimated prevalence in France is 1/360,000 [18]. However, the incidence rate in China is still unknown. In 2012, the expert group developed a set of practice guidelines for hereditary recurrent fever (HRF), which pointed out some specific gene variation sites of CAPS (p.R260W, p.D303N, p.L305P, p.E311K, p.T348M, p.L353P, p.A439V, p.V198M, and p.Q703K) [19]. Infevers database (https://infevers.umai-montpellier.fr/web/) listed more than 240 sequence variants of NLRP3 gene as of November 2020, and more than 100 are known to be pathogenic/possible pathogenic, and most of which are located in exon 3 [20]. In recent years, with deepened understanding of the diseases and widespread application of second-generation sequencing technology, many cases of CAPS have been reported in China [21–24]. The R260W (also known as R262W) variation of NLRP3 gene was first reported in 2002 and its involvement in MWS and FCU was confirmed, but some clinical symptoms, such as deafness, AA-type amyloidosis, and cold sensitivity, do not always exist, indicating that NLRP3 gene variation is not an independent pathogenic factor, and there may be epigenetic and other factors involved in the pathogenesis. Unknown gene modification may affect its phenotype [25]. Our sequencing results showed that there was a heterozygous variation in the NLRP3 gene, which led to the R > W missense variation at amino acid 262. Considering his pathogenesis, clinical and laboratory manifestations, he was diagnosed with MWS. Previous studies have found that MWS is common in the Nordic population. Our findings have expanded the ethnic scope and clinical manifestation spectrum of the disease. The variation site of R260W was reported for the first time in China.
The objective of the treatment of CAPS is to inhibit systemic inflammation, prevent organ injury, and improve the quality of life of patients. Due to the central role of IL-1 in the pathogenesis of CAPS, biologically targeted therapy against IL-1 is recommended for CAPS [26]. At present, three IL-1 blockers consisting of anakina, canakinumab, and rilonacept are approved for CAPS. Anakinra is a short acting recombinant IL-1 receptor antagonist, which has been approved by the European Drug Administration (EMA) and the U.S. Food and Drug Administration (FDA). Canakinumab is an EMA and FDA approved fully humanized monoclonal antibody against IL-1, which can selectively bind soluble IL-1. Rilonacept is a soluble recombinant IL-1 receptor antagonist, which has only been approved by FDA. In addition, some non-steroidal anti-inflammatory drugs and immune modulators also play a role in improving symptoms. Taking China's national conditions and economic benefit factors into account, as well as the disease activity status, thalidomide was used for empirical treatment. After medication, the disease was well controlled and the laboratory indicators were normal, but in the later stage, close follow-up is still needed to regularly monitor the disease activity and evaluate organ damage.
As we all know, fever is the most common clinical manifestation in children, and the causes are also diverse. Therefore, the diagnosis and differential diagnosis of fever in children is very challenging. Thus, clinically, children with recurrent fever, rash, musculoskeletal symptoms, and elevated inflammatory indicators, especially those with a positive family history, should be alert to the possibility of CAPS. If CAPS is suspected, the NLRP3 gene should be detected using molecular genetics for the presence of variations. If diagnosis is confirmed, the patients should be treated individually and closely followed up to prevent further organ damage and maximize the quality of life.