An Adult Patient With a Novel Mutation in NLRP3 Gene Associated With Cryopyrin-Associated Periodic Syndrome Mimicking Adult-Onset Still Disease
Cryopyrin-associated periodic syndromes (CAPSs) represent a group of autoinflammatory monogenic diseases characterized by caspase 1 and interleukin 1β activation associated with autosomal or de novo mutations of the NLRP3 gene.1–3
We describe a 26-year-old male patient with no relevant antecedents who was referred to our center following 2 years of episodic fever (>39°C), with no specific pattern, which was associated with periumbilical abdominal pain, cervical adenopathies, polyarthralgias, and erythematous macules in his face, thorax, and arms, which were exacerbated by exposure to cold. The attacks had duration of 48 to 72 hours, and the patient had approximately presented 20 attacks in the last year. Physical examination showed superior macular, erythematosus rash without pruritus, with irregular borders, well defined, with scaly surface, some confluent-forming plaques, plus left cervical adenopathy, widespread abdominal pain, and polyarthritis (wrists, ankles, and knees). Fundoscopy and audiogram were normal.
Initial laboratory tests revealed mild neutrophilic leukocytosis. Ferritin and C-reactive protein levels were normal at first consultation and high during clinical course and symptoms flares (up to 1600 ng/mL [reference range, 24–336 ng/mL] and up to 9.4 mg/dL [reference, 0.5 mg/dL], respectively). Bone marrow biopsy revealed hypoplasia with no evidence of malignancy. Biopsies of cervical adenopathies and skin showed reactive follicular hyperplasia and necrotic keratinocytes with lymphocytic inflammatory infiltrate in perivascular areas of the dermis. No amyloid infiltrate was found. Infectious, endocrine, and malignant causes were dismissed. A rheumatic etiology was considered; however, the antibodies panel was negative (anti-SSA, anti-SSB, anti-La, anti-Sm, antinuclear autoantibodies, antineutrophil cytoplasmic antibodies, and rheumatoid factor).
A diagnosis of adult-onset Still disease (AOSD)4,5 was established after verification of the fulfillment of Yamaguchi and Fautrel criteria. First-line nonsteroidal anti-inflammatory drug (naproxen 250 mg every 8 hours) and steroid (prednisolone 30 mg once daily) treatment was started. The patient showed a lack of response to this regimen, and methotrexate 15 mg weekly for 18 months, tocilizumab 8 mg/kg monthly for 5 doses, and intravenous immunoglobulin 400 mg once daily for 5 days were added. The refractoriness to these treatments challenges the diagnosis of AOSD.6,7 Clinically, the patient showed an exacerbation of febrile episodes and adverse effects to the steroids (hypertension, diabetes, osteoporosis, and avascular necrosis of the femoral head).
Considering an autoinflammatory disease, exome sequencing was performed using a library from Ion AmpliSeq Exome technology (Life Technologies, Carlsbad, CA). This found a novel missense mutation in exon 5 of the NLRP3 gene E607V (c.1820A>T) (NM_001079821.2), predicting a deleterious effect on different programs (PROVEAN, SIFT, PolyPhe2, MutationTaster, MutationAssesor, and FATHMM). This finding, added to the classification criteria published by Kuemmerle-Deschner et al,8 allowed us to diagnose CAPS: raised inflammatory markers (elevated C-reactive protein) plus at least 2 of 6 CAPS-typical symptoms (cold-triggered episodes and musculoskeletal symptoms). We did not investigate the presence of autoreactive T lymphocytes. It was decided to treat with canakinumab 150 mg monthly for 3 doses; the patient had a good clinical response to this regimen because of a decrease in C-reactive protein, a significant improvement in joint and cutaneous involvement, absence of fever, and absence of attacks triggered by cold. Since the first consultation until the final diagnosis, 2 years passed.
Autoinflammatory diseases are a rare cause of fever of unknown origin in adults in this epidemiological setting, and in this case, an atypical response to AOSD treatment allowed the diagnosis of CAPS because of the episodic symptoms with no autoantibody titers or antigen-specific T cells and the NLRP3 mutation present in the patient and his asymptomatic father.