Cryopyrin-associated periodic syndromes are autoinflammatory disorders that form a clinical continuum ranging from a mild to a severe phenotype. These entities include NOMID, MWS, and FCAS. FCAS is mild with a good prognosis, whereas NOMID is the most severe phenotype with the worst prognosis. Although patients with FCAS have normal life spans, approximately 20% of NOMID patients die before reaching adulthood.14–16
The pathogenesis of CAPS involves either dominantly inherited or de novo
gain of function mutations in the CIAS1
gene located on chromosome 1q44.3,4,7CIAS1
encodes cryopyrin, also known as NALP3 (NACHT, leucine-rich repeat and pyrin domain containing protein 3) or NLRP3. Most of the identified mutations occur in the region encoding the NACHT
domain in exon 3. Cryopyrin is involved in the assembly of a macromolecular complex called the inflammasome that is involved in innate immunity. It leads to the activation of the caspase-1 enzyme, which in turn cleaves pro-IL-1beta and pro-IL-18 into their active proinflammatory forms, IL-1 and IL-18.1,3,6,7
The binding of IL-1beta to IL-1 receptor (IL-1R) initiates a cascade of signals resulting in early inflammatory responses. The balance between IL-1 and IL-1R is essential in distinguishing proinflammatory and anti-inflammatory responses in the body.17
The overproduction of activated ILbeta can result in excessive IL-1-mediated inflammation causing autoinflammatory disorders such as CAPS.
It is important to recognize the clinical features of patients with CAPS. Although multiple organ systems can be involved, a migratory maculopapular skin rash () resembling urticaria is usually the first notable manifestation in CAPS. The rash is nonpruritic, and when the skin is biopsied, it demonstrates perivascular infiltration with polymorphonuclear leukocytes and lymphocytes.4
As demonstrated in , rash was one of the most common presenting symptom in our subjects across groups. More severe presenting symptoms such as aseptic meningitis were common in the NOMID and NOMID/MWS groups. Findings suggestive of ongoing inflammatory processes in the head and neck region including cervical lymphadenopathy can also be present. In their literature review, Torbiak et al18
reported lymphadenopathy in all 32 patients with NOMID. Cervical lymphadenopathy was present in 45% to 56% of patients in our study groups. Additional phenotypic features observed in our cohort included high arched palate and MEE.
Figure 5 Typical maculopapular rash on the flank of a patient with CAPS. Printed with permission from Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581-592. (more ...)
Hearing loss in CAPS has been reported in the literature. Prieur et al19
reported perceptive “deafness” of various degrees in 75% of patients with NOMID. Bilateral SNHL has been described in up to 85% of patients with MWS.20
However, given the rarity of CAPS, a comprehensive description of audiometric characteristics is lacking.
For those patients in our cohort for whom sufficient pure-tone threshold data were available, 62% of ears had hearing loss, and it was most prevalent in those with NOMID and NOMID/MWS. SNHL was the most common type, and the degree ranged from normal to profound (). Two FCAS patients had high-frequency SNHL; only 1 of these patients is suspected of having CAPS-related SNHL. Hearing loss is characteristically worse in the higher frequencies ( and ) and appears to progressively worsen with age in all groups except FCAS, the mildest form of CAPS ().
Young age and cognitive delay were prohibitive factors for sufficient pure-tone data collection in 30% of ears in our CAPS patients. In these patients, comprehensive sedated auditory steady-state responses were used to estimate peripheral hearing sensitivity and determine appropriate clinical intervention. These data were not included in our analysis because of the variability associated with these predictions of behavioral thresholds.21
Clinicians should be aware that sedated evoked potential assessment of hearing may be required in this population.
Cochlear enhancement on FLAIR-MRI sequences was observed most often in those with NOMID and NOMID/MWS, the subgroups with a higher prevalence of HL. Cochlear enhancement appears to be an accurate predictor of cochlear HL (), and this relationship may provide insight into the mechanism of SNHL in CAPS.
The cochlear modiolus is highly porous and can potentially serve as a conduit between perilymph and cerebrospinal fluid.22
However, the cochlear–brain barrier maintains the composition of the inner ear fluids and protects the inner ear by limiting entry of nonnative substances such as IL-1. In an animal model, it has been shown that bacterial meningitis activates proinflammatory cytokines such as IL-1, IL-6, and TNF-α and initiates a cascade of events, resulting in alteration of the blood–brain barrier diffusion, polymorphonuclear leukocytes and serum protein infiltrations, meningeal inflammation, increased intracranial pressure, and decreased cerebral vascular perfusion.23
In CAPS, cryopyrin-mediated inflammasome and caspase-1 activation might cause inappropriate sustained secretion of inflammatory cytokines including IL-1, leading to chronic aseptic meningitis and subsequent increased permeability of cytokines between perilymph and CSF space via the modiolus. These cytokines can then stimulate the spiral ligament fibrocytes to produce downstream mediators that might induce an unchecked chronic inflammation responsible for cochlear dysfunction and HL.24
This mechanism of HL has been supported by several reports of successful treatment of CAPS patients with anakinra, a type of IL-1 inhibitor.6,25,26
Hearing loss was observed in 2 FCAS patients without detectable aseptic meningitis, yet 1 had CE on FLAIR-MRI. This suggests that CIAS1
mutation might result in uncontrolled local activation of IL-1 within the cochlea. Fujioka et al27
demonstrated the production of proinflammatory cytokines in the spiral ligament, stria vascularis, and spiral ganglion neuron after acoustic trauma to the cochlea. In CAPS, the CIAS1
mutation within the inner ear may lead to unregulated local production of cytokines, such as IL-1beta, and chronic inflammatory responses resulting in cochlear damage, SNHL, and MRI changes. Further pathologic study of temporal bone histology would be helpful to elucidate the mechanism of HL in CAPS.
At this time we do not know whether the mechanism of HL observed in CAPS might also be responsible for inner ear injury in a subset of autoimmune-mediated ear disease (AIED). The pathogenesis of AIED is often considered to be immune-mediated; however, no autoantibodies or antigen-specific T cells to the inner ear have been identified. Assessing patients with suspected AIED by studying the role of IL-1 inflammatory pathway and its blocking agents may help to identify responsive subsets within this group of AIEDs and elucidate their pathogenesis.
Mucosal thickening of the sinuses was detected in the majority of patients with CAPS, and MEE was more prevalent in NOMID patients than expected. Proinflammatory cytokines such as IL-1 and TNF-α are known to be stimulated after viral and bacterial infections and regulate the expression of mucin and other genes involved in the pathogenesis of sinusitis and otitis media.28
In NOMID, the most severe type of CAPS, excessive IL-1 secretion in respiratory mucosa of the middle ear and paranasal sinuses may lead to more frequent otitis media and chronic sinusitis.
There was a high incidence of maxillary hypoplasia (67%) in patients with NOMID. Maxillary sinus hypoplasia is normally observed in up to 10% of computed tomography studies of the head and face.29
The pathophysiology of maxillary hypoplasia is controversial, but it is suggested that negative pressure within the sinus resulting from ostial obstruction can prevent normal pneumatization leading to hypoplasia. In NOMID, chronic sinusitis from uncontrolled inflammation at a very early age might result in ostial obstruction and consequently underdevelopment of maxillary sinuses. The presence of high arched palate and maxillary hypoplasia in patients with CAPS has been reported in other genetic disorders like Apert's syndrome.30
We present the baseline otolaryngologic and audiologic characteristics of patients with CAPS. Hearing loss, especially sensorineural, is one of the most common phenotypic features in CAPS, and it can be progressive. Because of the severe phenotype associated with NOMID, diagnosis is less likely to be delayed and complications such as hearing loss can be readily identified. However, cases involving less severe forms of CAPS may be misdiagnosed or underreported, especially if genetic testing for CIAS1
mutations is not available. CAPS should be included in the differential diagnosis for patients with what appears to be idiopathic or autoimmune HL and any other symptoms of periodic fever syndrome. Furthermore, routine audiological monitoring is recommended in all patients with NOMID, NOMID/MWS, or MWS. Hearing loss should be ruled out in patients with FCAS. Early diagnosis and management of hearing loss are important for appropriate speech–language, cognitive, and social development. Treatment of CAPS with IL-1 antagonists such as anakinra has been promising, and further studies are needed to determine the effectiveness of IL-1 antagonists in preventing, stabilizing, or even reversing cochlear damage and HL.6,25,26