Autoinflammatory diseases (AIDs) were initially defined as seemingly unprovoked episodes of inflammation, without high titer autoantibodies or antigen specific T cells 1. It is recently proposed that the AIDs are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition 2. AIDs represent a wide disease spectrum, ranging from Mendalian disorders such as Blau's syndrome (BS) to a more complex (polygenic) mode of inheritance such as Crohn's disease 2. In clinical practice, particularly in tertiary referral centers, physicians may encounter various autoinflammatory phenotypes which could cause highly costly and unnecessary repetitive workups. We hypothesized these phenotypes could be associated with unidentified gene mutations. Herein, we report an adult case series with similar clinical phenotypes to support a novel AID entity associated with positive nucleotide oligomerization domain (NOD2) gene mutations.

A total of seven patients were included in the study. All were Caucasians, with four being men (57.1%). The mean age at disease onset was 40.7 years (range 21 to 60 years) and disease duration was 3.2 years (range 1 to 8 years). No family history of any AIDs was reported.

AIDs are characterized by seemingly unprovoked episodes of inflammation, without high titer autoantibodies or antigen specific T cells, and derive from genetic variants of the innate immune system, including Mendalian and genetically complex disorders 1. The disease entity we describe in the present paper consists of periodic fevers, skin disease, inflammatory arthritis, serositis, sicca-like symptoms and elevated acute phase reactants but the hallmarks of autoimmunity are lacking, therefore it is congruent with an AID. This constellation of clinical phenotypes together with the NOD2 gene mutation may constitute a variant of the AIDs. To our knowledge, this disease entity does not fit any known AIDs. Given its strong association with the gene mutation, we presently categorize and designate this disease as a new AID. We believe that this condition may be underdiagnosed due to a lack of awareness of this clinical entity. This disease entity could represent a polygenic disease because it did not appear rare. This disorder seems similar to pediatric BS in phenotypes and genotypes to some extent, thus we will focus the following discussion on a Blau's-like syndrome as well as Crohn's disease.

BS (MIM186580) is an autosomal dominant AID, which was originally characterized by a triad of granulomatous dermatitis, arthritis and uveitis 3. Currently, BS and early onset sarcoid arthritis are accepted as the same disease 4. There have been over 154 cases of pediatric BS reported, involving 41 families 5. Other manifestations include fevers, abnormal liver function tests, large vessel arteritis, cranial neuropathy, pneumonitis, lymphadenitis, sialadenitis, erythema nodosum 56 and sinus of valsalva aneurysm 7. To the best of our knowledge, there have been no reports of adult onset cases of BS. Our case series study demonstrates that the clinical manifestations of this new adult disease entity are partially within the reported clinical spectrum of pediatric BS; however, the disease entity also differs from pediatric BS in that the former may not present with the classic triad of the pediatric form and has some distinct clinical features as discussed below.

First, we found that periodic fevers, dermatitis and polyarthralgias/inflammatory polyarthritis are common in our case series but without deformity, Camptodactyly (flexion contracture of the fingers and toes), that was originally reported in the members of a single family by Blau 3. Second, while pediatric BS can present with a variety of skin manifestations 5, our adult patients showed predominantly non-granulomatous dermatitis with occasional granulomas. Third, uveitis has been reported in 61% (46/76) of the pediatric BS patients 8; however, none of our patients had uveitis.

Among the seven patients, there were three cases of GI symptoms which prompted an exhaustive search for Crohn's disease. One patient carried a history of questionable Crohn's disease, but symptoms of periodic fevers and skin disease with minimal evidence of active Crohn's disease would argue against the likelihood of Crohn's disease in this patient. Although granulomas are known to occur in both Crohn's disease and BS 9, non-granulomatous dermatitis as in our series is extremely rare in Crohn's disease 10. Nevertheless, these patients did not have cogent evidence of Crohn's disease. Therefore, an intermediate subset of the new AID with Crohn's disease-like presentation ought to be entertained in these patients and Crohn's disease should be listed as a differential diagnosis.

The NOD2 gene mutations (chromosome 16q12-21) have been principally linked to both Crohn's disease and BS 11121314. To date, there are 105 NOD2 gene mutation sequence variants reported 15. NOD2 IVS8⁺¹⁵⁸ gene mutation was initially reported to confer higher risk for Crohn's disease in Ashkenazi Jews 16. Subsequently, two available studies failed to replicate the association between the gene mutation and Crohn's disease in the Ashkenazi Jews 17 and Jewish Israeli population 18. None of our patients were Jewish. It is worth noting that this gene mutation was not studied and reported in pediatric BS until it was recently reported to associate with the disease in a single case report where Borzutzky A, et al. 19 described a nine-month-old Caucasian boy who developed fever, migratory rash consistent with cutaneous tuberculoid granulomas and inflammatory arthritis. In conjunction with granulomatous panuveitis, the patient was diagnosed with early onset sarcoidosis/Blau's syndrome, and the NOD2 gene mutation IVS8⁺¹⁵⁸ was found. In our series, the IVS8⁺¹⁵⁸ NOD2 gene mutation was detected in all patients. Interestingly, four patients with positive IVS8⁺¹⁵⁸ also carried the R702W gene mutation. These findings suggest that the combined IVS8⁺¹⁵⁸ and R702W gene mutations may confer a higher risk for the currently described new AID. Of note, there were cases of similar clinical presentations with negative NOD2 gene mutations in our study. For example, one adult case of Sjögren's syndrome and one case of adult onset sarcoidosis without pulmonary involvement had negative NOD2 gene mutations. To the best of our knowledge, there have been no reports on the involvement of IVS8⁺¹⁵⁸ in other diseases apart from Crohn's disease in Ashkenazi Jews and BS to date. We presently propose that the gene mutation IVS8⁺¹⁵⁸ may be entertained as a diagnostic marker for the new entity. However, the clinical relevance of such gene mutations to these diseases remains to be determined given the limited studies. We anticipate more investigations, such as analysis of haplotype frequency, DNA sequencing of the entire gene and the genotype-phenotype correlation in the new AID using genome wide association study.

Our adult case study suggests that the currently described disease entity constitutes a new category of AIDs, which phenotypically resembles the pediatric BS cases and can mimic Crohn's disease. Genotypically, the IVS8⁺¹⁵⁸ NOD2 mutation appears associated with the disease, particularly in conjunction with R702W. This new disease entity may be genetically complex rather than Mendalian.

AIDs: autoinflammatory diseases; BS: Blau's syndrome; CT: computerized tomography; FMF: familial Mediterranean fever; GI: gastrointestinal; NOD2: nucleotide oligomerization domain; NSAIDs: nonsteroidal anti-inflammatory drugs; TRAPS: tumor necrosis factor receptor associated periodic fever syndrome.

The authors declare that they have no competing interests.

YQ contributed to the conception and design of the study. YQ, ZL, CP, BN, PM, JB and SL participated in data collection. YQ, ZL, PM and SB participated in data analysis and interpretation, and drafting and reviewing of the manuscript. All authors have read and approved the manuscript for publication. Written consent to publish was obtained from the patients.