In the early 21st century, it has become evident that the underlying mechanism of CAPS is the gain-of-function variants in NLRP3, which belongs to nucleotide-binding oligomerization domain-like receptor family. These variants lead to excessive release of interleukin-1β (IL-1β), a strikingly proinflammatory cytokine [7]. In the nucleus, the NLRP3 gene is actively transcribed by NF-κB, which is stimulated by pathogen-associated molecular pattern molecules (PAMPs) derived from bacteria, viruses and lipopolysaccharides (LPS), as well as damage-associated molecular pattern molecules (DAMPs) derived from ATP, uric acid and calcium pyrophosphate. As a consequence, NLRP3 protein forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and other components, which activates pro-caspase 1 to caspase 1 and stimulates IL-1β. In patients with CAPS, this pathway is repeatedly activated due to gain-of-function variants of NLRP3, resulting in recurrent inflammation and various symptoms, including periodic fever, nonpruritic urticaria-like rash, sensorineural hearing loss, headaches and fatigue.

According to Infevers, a website providing a genetic database for autoinflammatory diseases (https://infevers.umai-montpellier.fr/web/), there are currently over 300 sequence variants identified in NLRP3 gene. The p.Ile257Met variant identified in our family is a novel one corresponding to “Uncertain Significance” (PM2 and PP4) in ACMG guidelines [8], while we have not confirmed the gain-of-function phenotype in the variant. To confirm a gain-of-function phenotype for the p.Ile257Met variant, further testing is necessary.

GI symptoms are generally not the predominant manifestations of CAPS. However, Kuemmerle-Deschner et al. [5] reported that the GI symptoms such as abdominal pain, diarrhea, constipation, nausea, vomiting occur more frequently in CAPS patients with low penetrance NLRP3 variants, which result in less inflammasome activation, less caspase activation and less IL-1β production. On the basis of the clinical features of our family pedigree, the p.Ile257Met variant appears to be a low penetrance variant associated with GI symptoms in Japanese patients with CAPS.

There seems to be four possible mechanisms underlying the abdominal symptoms in patients with CAPS. They are (1) serositis, (2) irritable bowel syndrome (IBS), (3) IBD and (4) secondary amyloidosis [9,10,11,12,13,14,15,16,17]. Among those mechanisms, serositis associated with NLRP3 inflammasome activation through elevated IL-1β production seems to be the most likely, because serositis has been shown to occur in patients with FMF, which is another IL-1β-mediated autoinflammatory disease, even in the absence of abnormalities on CT [18,19,20]. However, IBS should be considered as a possible contributing factor to her abdominal symptoms.

In our case, the history of sensorineural hearing loss triggered the diagnosis of CAPS. It has been reported that 62% of CAPS patients experience sensorineural hearing loss, and cochlear enhancement on FLAIR-MRI sequences was observed in 87% of CAPS patients with sensorineural hearing loss [21]. This enhancement, indicating the breakdown of the labyrinth-blood barrier of the cochlea, is presumably caused by leakage of inflamed microvessels, leading to cochlear tissue damage [22] and ultimately irreversible sensorineural hearing loss, if left untreated [23, 24]. In this case, the patient’s sensorineural hearing loss persists, presumably due to the prolonged interval of approximately 15 years between its onset and the initiation of treatment.

Wengrower et al. [25] reported that 38% of IBD patients exhibit hearing loss as an extra-intestinal manifestation (EIM). Furthermore, it has been reported that the average hearing thresholds are higher in IBD patients, particularly in those with ulcerative colitis, when compared to healthy people [26, 27]. In monogenic IBD, certain variants are known to cause high-frequency sensorineural hearing loss, such as STXBP3 variants [28]. Because hearing loss in IBD often progresses slowly and may be asymptomatic in its early stages [27], active audiological assessment should be considered in patients with suspected CAPS or active IBD.

In conclusion, our experience suggests that CAPS should be considered in the differential diagnosis of IBD-like conditions in adolescents. Thus, it seems to be necessary to understand extra-gastrointestinal complications of CAPS. Also, there may be a need to regard the disease as a differential diagnosis of monogenic IBD.