Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-κB activity predict the Blau syndrome/EOS clinical phenotype.
Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-κB activity, which was defined as the ratio of NF-κB activity without a NOD2 ligand, muramyldipeptide, to NF-κB activity with muramyldipeptide.
All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-κB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-κB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment.
NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.
Sarcoidosis is a systemic inflammatory disease with unknown etiology, but it can be clinically characterized by swelling of the bilateral hilar lymph nodes and histologically defined by the presence of noncaseating epithelioid cell granulomas. A special subtype called early-onset sarcoidosis (EOS; MIM no. 609464) occurs in children younger than 4 years of age and is characterized by a distinct triad of skin, joint, and eye disorders without apparent pulmonary involvement (1). An autosomal-dominant disease with clinical manifestations similar to those of EOS has been recognized as Blau syndrome (MIM no. 186580) (2, 3). The gene responsible for Blau syndrome has been mapped close to the inflammatory bowel disease 1 (IBD1) locus by linkage analysis (4), and later the nucleotide-binding oligomerization domain 2 gene (NOD2) was identified by Miceli-Richard et al to be responsible for Blau syndrome (5). In the study by Miceli-Richard et al, 2 European patients with EOS had no mutation in NOD2; therefore, it remained controversial whether Blau syndrome and EOS have the same etiology.
In 2004, we encountered a 27-year-old Japanese man with multiple lichenoid papules. He was almost blind, exhibited camptodactyly, and had a continuous low-grade fever. This case of sporadic systemic granulomatosis with clinical features of EOS showed the same NOD2 mutation, the arginine-to-tryptophan substitution at amino acid 334 (R334W), as that detected in Blau syndrome (6). Therefore, we expanded this report (6) and retrospectively examined cases of EOS in Japan and observed that 9 of 10 patients with EOS had NOD2 mutations (7). Until recently, other investigators have also confirmed that Blau syndrome and EOS are clinically and genetically identical across various ethnic groups (8–10).
NOD2 activates NF-κB after recognizing a signal from a bacterial cell wall component, muramyldipeptide, in the cytoplasm of monocytes, and thus can work as an intracellular sensor of bacteria (11, 12). NOD2 has a tripartite domain structure consisting of 2 amino-terminal domains (termed caspase activation and recruitment domains) that are composed of protein–protein interaction cassettes, 1 centrally located NOD, and carboxy-terminal leucine-rich repeats (LRRs) (13). Using assays of NF-κB activity, an impaired ligand-dependent response was demonstrated for 3 Crohn's disease–associated mutations located in NOD2 LRRs (14, 15), whereas enhanced ligand-independent NF-κB activity was demonstrated for NOD2 alleles associated with Blau syndrome and EOS (5, 7, 16). However, it remains unknown how increased basal NF-κB activity derived from gain-of-function mutations in NOD2 affects the pathogenesis of Blau syndrome/EOS and whether a genotype–phenotype correlation exists between the clinical manifestations or onset of Blau syndrome/EOS and NOD2 mutations.
Because Blau syndrome/EOS is so rare, very few reports are in the literature. Therefore, it was worthwhile to conduct a nationwide survey limited to patients with a specific ethnic background, such as Japanese patients. In this study, we precisely documented the clinical manifestations in a cohort of Japanese patients with Blau syndrome/EOS and NOD2 mutations, including 9 previously reported cases (7), and explored the genotype–phenotype correlation to the basal NF-κB activity associated with each mutation, especially focusing on the correlation of visual impairment with the most frequent mutations, R334W and R334Q.
PATIENTS AND METHODS
Patients and clinical information.
Among patients with clinically diagnosed Blau syndrome/EOS, the 20 patients with NOD2 mutations were included in this study (7, 17–20). None of these mutations were identical to the reported single-nucleotide polymorphisms (SNPs) of NOD2, nor were they detected in 100 Japanese healthy volunteers. Clinical information and patient histories were collected from medical records and by direct interviews of the patients and their attending physicians. The presence of each symptom was established as follows: a) persistent or repeated transient skin lesions without definite cause were determined, b) persistent or repeated transient arthritis without definite cause was determined, c) uveitis was diagnosed by an ophthalmologist, and d) remittent or intermittent fever without definite cause was determined under close examination at the time of hospital admission. The age at disease onset was defined as the age of the patient when any of the above-mentioned symptoms appeared.
Clinical evaluation was performed primarily when individual symptoms first appeared that were hardly affected by treatment or disease duration. The severity of visual impairment was assessed in accordance with the World Health Organization definition (21). Briefly, moderate visual impairment was defined as visual acuity between 6/18 and 3/60, and severe visual impairment was defined as acuity of 3/60 or less in the better eye with best correction, as previously described (9). Written informed consent was obtained from the patients and their families, and the study protocol was in accordance with the guidelines of the Institutional Review Board of Kyoto University Hospital.
Genomic DNA was extracted from the peripheral blood of the patients, and sequencing of all exons and exon–intron junctions of NOD2 was performed as previously described (7).
Generation of NOD2 mutants and NF-κB luciferase assay.
Expression plasmids of NOD2 and its mutants were subcloned into the p3xFLAG-CMV vector, as previously described (7). Blau syndrome/EOS–associated mutants were generated using the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA), as described previously (7). The ability of each construct to induce NF-κB activity was assessed by dual luciferase reporter assay in HEK 293 human embryonic kidney cells, as previously described (7).
We determined the age at the time of this survey, the age at onset of each symptom, and the NOD2 genotype for all patients as well as the distribution of age at disease onset. Next, we analyzed the relationship between age at disease/symptom onset and basal NF-κB activity due to mutated NOD2. Basal NF-κB activity was defined as the ratio of NF-κB reporter activity without muramyldipeptide to NF-κB reporter activity with muramyldipeptide, as determined using the in vitro NF-κB luciferase assay described above. The activity was arbitrarily categorized as low (<0.3), moderate (0.3–0.5), and high (>0.5). Finally, we analyzed the relationship between visual impairment (normal, moderate, severe) and basal NF-κB activity (low, moderate, high) due to individual mutated NOD2 genes, particularly the 2 most frequent mutations, R334W and R334Q. We did not perform statistical analysis because of the limited number of patients.
Genotype and basal NF-κB activity.
The study population comprised 9 male patients and 11 female patients, with a median age of 17 years (range 7–48 years) and a median disease duration of 15 years (range 5–43 years). Fourteen of these 20 cases were sporadic (EOS), and 6 were familial (Blau syndrome). The familial cases were in 3 unrelated families; 2 families (patients 14 and 15 and patients 16 and 17, respectively) had Blau syndrome/EOS symptoms in 2 generations, and 1 family (patients 1 and 2) had Blau syndrome/EOS symptoms in 3 generations. The most frequent heterozygous mutation of NOD2 was R334W (1000C>T), which was recognized in 2 familial and 5 sporadic cases (total of 9 cases), followed by R334Q (1001G>A) in 3 sporadic cases, and E383G (1148A>G, a novel amino acid substitution) in 2 familial cases (in 1 family). H496L (1487A>T), T605P (1813A>C), D382E (1146C>G), M513T (1538T>C), N670K (2010C>A), and C495Y (1484G>A) were detected in 1 sporadic case each (Table 1).
Table 1. Demographic and clinical characteristics of the patients with Blau syndrome/early-onset sarcoidosis*
Age at onset
Age at onset
Age at onset
Age at onset
Patient 5 also had left ventricular dysfunction and pulmonary hemorrhage due to bronchial granuloma. Patient 10 also had interstitial pneumonia. Patient 11 also had hepatosplenomegaly and parotid swelling. Patient 18 also had renal calcification. OD = right eye; OS = left eye; yr = years; mo = months; Int = intermittent; LP = multiple lichenoid papules; SE = scaly erythematous plaques; EN = erythema nodosum–like lesion; Poly = polyarticular; A = anterior; P = posterior; Per = persistent; HM = hand motion; Oligo = oligoarticular.
Nine mutations were identified in the centrally located NOD region (Figure 1a) and were associated with increased basal NF-κB activity in the absence of muramyldipeptide (Figure 1b), which is consistent with the finding of a previous study on Blau syndrome/EOS–associated NOD2 mutations (16). We also confirmed that 100 healthy control subjects and their genotyped asymptomatic relatives did not have these amino acid substitutions. Therefore, we concluded that these NOD2 mutations (amino acid substitutions) detected in patients with Blau syndrome/EOS were not SNPs but rather were disease-causing mutations.
The defining characteristic of EOS is its onset in children younger than age 4 years (1). In the present study, despite the median age at disease onset of 14 months, the first clinical symptoms developed at age 5 years or older in 2 patients (patients 2 and 17, who were members of different Blau syndrome families) with the E383G mutation and the R334W mutation, respectively (Table 2). In patient 2, skin rash developed at age 5 years; in patient 17, arthritis developed at age 8 years (Table 1).
Table 2. Age of the patients at the onset of disease and symptoms*
Disease onset (n = 20)
Fever (n = 11)
Rash (n = 19)
Arthritis (n = 19)
Uveitis (n = 18)
Values are the number (%). The median age at disease onset was 1 year 2 months; the median age at onset of fever and rash was 2 years; the median age at onset of arthritis was 2 years 9 months; the median age at onset of uveitis was 4 years 6 months.
The earliest presenting symptom was skin rash in 13 patients (65%), arthritis in 8 patients (40%), and ocular symptoms in 1 patient (patient 15, who had familial Blau syndrome with the R334W mutation) (Table 1). Approximately 95%, 95%, and 90% of patients, respectively, had skin, joint, and ocular symptoms. Consistent with the previous report (1), a triad of skin, joint, and ocular symptoms developed (in this order) in many patients with Blau syndrome/EOS. The median age at onset of rash, arthritis, and uveitis was 24 months, 33 months, and 4.5 years, respectively (Table 2).
The triad of symptoms.
All except 1 patient (patient 6 [with the R334Q mutation]) had skin manifestations. Consistent with a previous report (22), the most frequent skin symptom was scaly erythematous plaques with multiple lichenoid papules. Several patients (patients 1 and 2 with the E383G mutation, patient 5 with the R334Q mutation, patient 9 with the R334W mutation, and patient 19 with the N670K mutation) had erythema nodosum–like lesions on their lower limbs in addition to solid lichenoid eruptions. Notably, 3 patients (patients 16 and 17 with the R334W mutation and patient 18 with the M513T mutation) showed only scaly erythematous plaques without lichenoid papules (Table 1).
All except 1 patient (patient 12 with the R334W mutation) had joint lesions (polyarticular arthritis in 17 patients and oligoarticular arthritis in 2 [patients 16 and 17]) (Table 1). Both patients with oligoarticular arthritis, who had familial Blau syndrome with the R334W mutation, had camptodactyly without obvious synovial cysts. Camptodactyly with synovial cysts is frequently described as a typical joint sign in patients with Blau syndrome/EOS (10). A consequence of arthritis was the use of a wheelchair for daily mobility in 2 patients (patient 5 with the R334Q mutation and patient 10 with the R334W mutation).
All except 2 patients (patient 6 with the R334Q mutation who also lacked skin eruptions and patient 20 with the C495Y mutation) had ocular lesions. The lesions were bilateral, although visual acuity was asymmetric, as in previous studies (22, 23). Moreover, 17 (89%) of all 18 patients with ocular lesions had panuveitis, while only 1 patient (patient 18 with mutation M513T) had anterior uveitis, which demonstrated the predominance of panuveitis over anterior uveitis. Ocular symptoms were the last of the triad to develop in 15 of the 18 patients and the first to develop in only 1 patient (patient 15 with mutation R334W).
Clinical features other than the triad of symptoms.
It is noteworthy that 11 patients (55%) experienced fever at a median age of 24 months, almost simultaneously with skin and/or joint symptoms (Table 1). Five patients had persistent fever reaching 38–40°C, and 6 patients had intermittent fever. In particular, in 1 patient (patient 9 with mutation R334W) the disease developed with intermittent fever (which then became persistent fever over the next 6 months) and finger joint swelling. In only 1 previous report (10), fever is mentioned as a clinical symptom of Blau syndrome/EOS, although there are some case reports in which fever was present at disease onset (24).
Four patients had involvement of organs other than the skin, joints, and eyes (Table 1). Two patients had pulmonary lesions (interstitial pneumonitis in patient 10 with the R334W mutation and bronchial granuloma in patient 5 with the R334Q mutation). Bilateral hilar lymph nodes, which are identified by chest radiography and/or computed tomographic scanning, were not observed in any patient. Patient 11 with the R334W mutation exhibited hepatosplenomegaly and parotid swelling (19), and patient 18 with the M513T mutation exhibited renal calcification. No cases of large-vessel vasculitis were observed in this cohort, even though vasculitis has been reported in patients with EOS (25–27).
BCG vaccination was associated with the onset of disease (i.e., development of multiple papules on the extremities) in 2 patients, although no apparent infection or vaccination was clearly documented in other patients of our cohort. In 1 patient (patient 7 with mutation T605P) who had papules on the extremities, the spread of papules was from the site of BCG vaccination. In the other patient (patient 1 with mutation E383G), Gianotti disease was initially diagnosed, but a close review of her medical history later indicated that her multiple papules were a symptom of Blau syndrome/EOS.
Relationship between the onset of disease/symptoms and basal NF-κB activity due to mutated NOD2.
Because disease duration and treatment varied among patients, we focused on the onset of disease and of each clinical symptom (i.e., fever, rash, arthritis, and uveitis). We evaluated the relationship between age at the onset of disease/symptoms and basal NF-κB activity due to mutated NOD2 (defined as the ratio of NF-κB activity without a NOD2 ligand, muramyldipeptide, to NF-κB activity with muramyldipeptide for each mutated NOD2). The calculated basal NF-κB activity ranged from 0.23 to 0.79 (mean 0.42) for mutated NOD2 and was 0.05 for wild-type NOD2 (Figure 1c).
Because the number of patients with each NOD2 mutation was limited, we arbitrarily categorized basal NF-κB activity as low (<0.3), moderate (0.3–0.5), and high (>0.5). According to these criteria, mutations E383G and H496L were associated with low activity; mutations R334Q, T605P, D382E, R334W, and M513T were associated with moderate activity; and mutations N670K and C495Y were associated with high basal NF-κB activity. Our limited number of patients was insufficient to detect a correlation between the defined basal NF-κB activity and the onset of disease, fever, rash, arthritis, and uveitis (Figure 2). Notably, the age at onset of symptoms varied markedly between patients with the same R334W mutation, even in familial cases (Table 1).
Relationship between visual impairment and basal NF-κB activity due to mutated NOD2.
The most relevant morbidity associated with Blau syndrome/EOS is ocular involvement, which is usually refractory to conventional treatment. Thus, we next explored the relationship between visual impairment and basal NF-κB activity. There was no clear correlation when the analysis included all recruited patients (Table 3). When we focused on the most frequent genotypes R334Q and R334W, between-genotype differences in visual impairment were observed (Table 4). Basal NF-κB activity was higher in patients with the R334W mutation than in those with the R334Q mutation (Figure 1c). None of the 3 patients with the R334Q mutation had visual impairments, while 4 of 9 patients with the R334W mutation had visual impairments. This result suggests that patients with the R334W mutation were more likely to have visual impairments than were those with the R334Q mutation (Table 4).
Table 3. Correlation between visual impairment and basal NF-κB activity*
Disease duration, median (range) years
Except where indicated otherwise, values are the number of patients.
Basal NF-κB activity
Table 4. Correlation between visual impairment and the 2 most frequent genotypes*
Disease duration, median (range) years
Except where indicated otherwise, values are the number of patients.
Previous study (9)
Blau syndrome/EOS is a rare systemic granulomatosis that has been associated with NOD2. In this study, patients with Blau syndrome/EOS and NOD2 mutations were retrospectively recruited nationwide in Japan, to determine whether the NOD2 genotype and its functional abnormality predict the Blau syndrome/EOS clinical phenotype. This study is the first to investigate the correlation between the NOD2 genotype and its functional abnormality and the Blau syndrome/EOS clinical phenotype. Our findings suggest that NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS, although the clinical severity of Blau syndrome/EOS was not clearly associated with basal NF-κB activity due to mutated NOD2 among the limited number of patients we studied.
The classic Blau syndrome/EOS symptom triad is skin rash, arthritis, and uveitis. Corresponding clinical manifestations include widespread erythematous papules, polyarthritis with boggy synovial swellings, and panuveitis (1, 9, 10, 23), which were also identified in the present study. Rose et al described 2 patients who also had 1 episode of erythema nodosum–like lesions during the course of the disease (9). In our cohort, 5 patients had erythema nodosum–like lesions, suggesting that this should be recognized as one of the skin manifestations associated with Blau syndrome/EOS.
In the current study, 55% of the patients had fever, which always accompanied at least 1 symptom of the classic triad. Arostegui et al also reported that 50% of their cohort had recurrent or persistent fever (10). These findings suggest that fever is one of the important symptoms of Blau syndrome/EOS and is the reason why Blau syndrome/EOS is misdiagnosed as systemic-onset juvenile idiopathic arthritis (JIA). In fact, patient 11 in our study (who had the R334W mutation) experienced persistent fever reaching 40°C and received aggressive immunosuppressive therapy, because systemic-onset JIA was initially diagnosed. This case alerts us to the possibility that patients with Blau syndrome/EOS can sometimes have fever, and that Blau syndrome/EOS can resemble systemic-onset JIA.
Bilateral hilar lymph nodes, which are often seen in adult sarcoidosis, are not observed in Blau syndrome/EOS, but this does not mean that pulmonary lesions do not occur in patients with Blau syndrome/EOS. In fact, 2 patients (patient 5 [with the R334Q mutation] and patient 10 [with the R334W mutation]) had pulmonary lesions; in particular, patient 10 had the first reported case of sporadic EOS in association with the NOD2 mutation (6). Another case of Blau syndrome/EOS with pulmonary lesions and interstitial pneumonitis, but not bilateral hilar lymph nodes, has also been reported (28). These findings suggest the importance of following up patients with Blau syndrome/EOS to check for not only the classic triad of symptoms but also other abnormalities, including pulmonary lesions.
Blau syndrome/EOS, which usually occurs in children younger than age 4 years, developed at 5 years and 8 years, respectively, in 2 patients in the present study (patient 2 [with the E383G mutation] and patient 17 [with the R334W mutation]). Because both of these patients had a family history of skin rash/arthritis/uveitis, they had been closely monitored by their parents as well as by their physicians. Therefore, it is unlikely that any symptoms that occurred when the patients were younger than 4 years of age were overlooked in these 2 cases. In the literature, there is 1 case of Blau syndrome in which skin rash, persistent fever, and camptodactyly started to develop at age 18 years (10). These findings indicate that the onset of Blau syndrome/EOS can be at age 5 years or older, and that disease onset in a patient younger than 4 years should not be considered requisite for a diagnosis of Blau syndrome/EOS.
In our cohort, the age at disease/symptom onset, organ involvement, and severity of Blau syndrome/EOS varied substantially even within affected families and between individuals with the same NOD2 mutation (e.g., R334W). In other genetic disorders, identical mutations have been associated with phenotypic variation in unrelated individuals, within a family, and even in monozygotic twins (29). Phenotypic variation in Blau syndrome/EOS has been reported in monozygotic twins; therefore, nongenetic factors such as environmental conditions and/or infectious agents might be involved in phenotypic variation (24). Interestingly, in 2 of our cases, BCG vaccination was an obvious triggering factor. In addition, a previous report noted that cutaneous lesions first arose after BCG vaccination in a patient with Blau syndrome/EOS (30). The BCG vaccine contains muramyldipeptide, a ligand for NOD-2 protein (11, 12), which is interesting from a pathophysiologic point of view. However, BCG vaccination did not always cause the onset of disease in patients with Blau syndrome/EOS, because most patients in our cohort were vaccinated with BCG according to the immunization protocol used in areas of Japan where the risk for tuberculosis was high. An unknown endogenous ligand for NOD-2 could influence disease onset and/or progression, similar to uric acid as an endogenous cryopyrin/NLRP3 ligand (31). The potential roles of endogenous ligands, pathogen-associated molecular patterns, and/or danger-associated molecular patterns in disease pathogenesis remain to be elucidated.
Although increased basal NF-κB activity due to mutated NOD2 has been proposed as an etiology of Blau syndrome/EOS, how such activity causes the characteristic symptoms remains unclear. We hypothesized that if increased basal NF-κB activity is the key to the pathophysiology of this disease, it should be related to disease severity or disease progression. Unfortunately, there was no clear correlation between basal NF-κB activity and the onset of disease/symptoms. However, patients with mutated NOD2 and low basal NF-κB activity tended to experience complications, e.g., arthritis and uveitis, at a later age. This finding raises the possibility that basal NF-κB activity may affect disease progression rather than disease onset. Given that NOD-2 protein signals through MAPK/ERK as well as the NF-κB pathway (32), the possibility cannot be excluded that the MAPK/ERK activation potential of each NOD2 genotype might also be correlated with disease severity or progression.
From the perspective of quality of life, the ocular manifestations of Blau syndrome/EOS require the closest attention (33). In a previous study, one-third of patients with Blau syndrome/EOS and NOD2 mutations had a poor or extremely poor visual outcome, and the progression of visual field loss was independent of the particular NOD2 mutant and was not associated with disease duration (9). In our cohort, however, patients with the R334W mutation experienced more visual impairment than did patients with the R334Q mutation, although 4 patients with the R334W mutation were from 2 families (patients 14 and 15 and patients 16 and 17, respectively). Therefore, familial genetic and environmental factors could easily influence the phenotype. Thus, in order not to favor our hypothesis, we excluded patients 15 and 17 from the analysis, and the trend was still evident. This observation was consistent with the findings of Rose et al (9), although those investigators did not address this issue. These findings suggest that NOD2 genotyping could help predict the course of eye disease in patients with Blau syndrome/EOS, especially those with the R334Q mutation or the R334W mutation.
The relationship between visual impairment and basal NF-κB activity also remains a matter for discussion. Our data showed that visual impairments were more severe in patients with the R334W mutation than in those with the R334Q mutation, which seems to be consistent with the hypothesis that higher basal NF-κB activity causes more severe disease or more disease progression. However, no ocular symptoms have developed during the 6 years since disease onset in patient 20 (with the C495Y mutation and the highest basal NF-κB activity in our cohort), although ocular symptoms developed in another patient with the same genotype (10). Also, in patient 2, who had the E383G mutation and the lowest basal NF-κB activity, severe visual impairment occurred when she was in her late twenties. These findings contradict our hypothesis that NOD2 genotypes with higher basal NF-κB activity are associated with severe disease. However, Blau syndrome/EOS was promptly diagnosed in patient 20 with the C495Y mutation, who luckily was under the care of the same pediatric rheumatologist who treated patient 19 (who had the N670K mutation) and was treated with systemic steroid therapy. Patient 2 (who had the E383G mutation) subsequently received inappropriate immunosuppressive therapy, because the patient refused steroid treatment. Furthermore, patient 10 (with the R334W mutation), who had no obvious systemic inflammatory findings and did not receive systemic steroid therapy, became blind at 20 years of age. These findings raise the possibility that the extent of visual impairment could be modified by therapy.
Finally, we were not able to prove a link between the clinical severity of Blau syndrome/EOS and basal NF-κB activity in the whole cohort, possibly because of the restricted number of patients and because of the differences in treatment among patients. Therefore, a prospective study involving a sufficient number of patients to allow analysis of each genotype–phenotype correlation would be required to test our hypothesis. Given that there is no standard treatment protocol for Blau syndrome/EOS, some predictors of disease progression, especially progression of visual impairment, would have great benefit for clinicians. We observed a difference in the development of visual impairment only between patients with the R334W mutation and those with the R334Q mutation, which provides a clue that predicts the development of visual impairment in patients with the R334W and R334Q mutations. We also believe that understanding the mechanisms of how NOD2 acts in disease pathogenesis should help in discovering therapeutic targets for the treatment of Blau syndrome/EOS.
Dr. Nishikomori had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Okafuji, Nishikomori, Heike, Miyachi, Nakahata.
Acquisition of data. Okafuji, Fujisawa, Saito, Yoshioka, Kawai, Sakai, Tanizaki.
Analysis and interpretation of data. Okafuji, Nishikomori.
We appreciate the invaluable assistance of the following physicians, who kindly provided materials and allowed us to study their patients: Drs. Sonoko Nagai, Takenosuke Yuasa, Akira Manki, Yoshihiko Sakurai, Mitsuru Nakajima, Hiroko Kobayashi, Ikuma Fujiwara, Hiroyuki Tsutsumi, Shuji Takei, Kumiko Nakao, Yoshikazu Otsubo, Kouichi Ohta, Kazunaga Agematsu, Hiroaki Azukisawa, Hiroyuki Murota, and Kenji Katamura.