Blau syndrome with incidental multiple enchondromatosis

Blau syndrome (BS) is a rare autosomal dominant disorder that occurs early in childhood. It is caused by mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase activation and recruitment domain 15 (CARD15). NOD2 mutations result in the activation of nuclear factor-kappa B and induction inflammation.1 Some patients develop the disease in a familial manner, but sporadic cases can occur. The main clinical manifestations of BS are the triad of rash, arthritis, and iridocyclitis, while multiple aortitis, deafness, heart disease, liver, spleen, and central nervous system are also involved.2 The disease was first described by Dr. Blau in 1985.3 We report a case of BS complicated with multiple enchondromas. The child presented with fever, rash, swelling and pain in multiple joints, and uveitis in both eyes. The joint biopsy showed granulomatous synovitis, and gene sequencing showed a mutation of NOD2, both consistent with BS. Multiple endophytic chondromas were found on radiographs and magnetic resonance imaging (MRI) of both hands. The 5-year-old male patient was the first boy from healthy nonbiological parents (only one child in the family). Eight months after birth, fever and rash occurred in the child, with no apparent cause, and his temperature fluctuated around 38.5°C, with a hot peak one to two times daily. The rash was characterized as a red clastic rash on the abdomen, lower limbs, and back of feet, without itching. There was no cough, wheezing, vomiting, or diarrhea, and no urgency or pain associated with urination. Convulsion, oral ulcer, photosensitivity, joint swelling and pain, and other discomfort were also absent. Anti-infection treatment was ineffective. At the age of 3 years, the patient developed bilateral ankle joint swelling and pain, with a high surface temperature, but no obvious limitation of movement. Bilateral knee joint and left wrist joint swelling and pain then gradually appeared and slowly worsened. When he was 4 years old, the patient exhibited hypertension, with a maximum of 130−150/90−100 mmHg. The patient had granular material on the right pupil margin and a clouded bilateral cornea. The first, third, and fourth proximal phalanges of the left hand were protuberant without tenderness. The bilateral wrist, ankle, and knee joints were swollen, and several cystic masses could be seen near the joints, which were partially fused. There was no obvious tenderness or limitation of movement. The results of auxiliary examinations are as follows: (1) blood analyses revealed hemoglobin 95 g/L, white blood cell 7.58 × 109/L, platelet 460 × 109/L, erythrocyte sedimentation rate: 81 mm/1 h, and C-reactive protein: 95.4 mg/L. (2) Rheumatoid factor, anti-cyclic citrulline antibody, antinuclear antibody, double-stranded DNA (ds-DNA), human leukocyte antigen B27, and T-cell spot (T-SPOT) were all negative. (3) Carcinoembryonic antigen, alpha-fetoprotein, neuron-specific enolase, 24-h urinary catecholamine, and bone marrow cytology were normal. (4) Anteroposterior and lateral X-rays of ankle joints showed slight swelling of soft tissue around both ankles. X-ray and MRI of both hands showed multiple irregular abnormal signals in the bone marrow cavity and cortex of the right palm and finger, and strip abnormal signals in the bone marrow cavity of the distal ulna of the right hand, which was considered as multiple enchondromas (Figure 1A,B). (5) Synovial pathological examination of the right ankle joint showed granulomatous synovitis. (6) Ophthalmic examination showed bilateral uveitis. (7) Sequencing of the CARD15 gene showed a NOD2 gene mutation 1411C > T(R471C) (Figure 1C). Both parents were carriers, and the patient was homozygous for the mutation (Figure 1D). The patient was treated with oral steroids, methotrexate, and anti-tumor necrosis factor-α (TNF-α) inhibitors, and the rash, joint swelling and pain, and bilateral uveitis were improved. However, multiple enchondromas persisted in both hands during the follow-up, which did not relieve or aggravate the treatment of BS. The patient presented with typical clinical manifestations. Joint pathology showed granulomatous lesions and gene sequencing showed a NOD2 mutation and R471C was previously reported to be related to BS, but it was not located in the helical domain 1 or ATP/Mg2+ patches identified and lacks conservation across different species.4 However, imaging of the patient's hands showed multiple irregular abnormal signals in the bone marrow cavity and cortex, indicating multiple osteochondromas, as previously reported.5 This study also reported that an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis. However, genetic testing was not performed in this case report, possibly because of limited sequencing technology being available at the time. Based on the clear diagnosis of BS in this patient, multiple osteochondromas were found, and these were different from the typical granulomatous lesions of BS. This phenomenon suggested that the bone lesions of BS were not only caseous lesions but also osteochondroma. In addition, this study found that the multiple osteochondromas of the child did not change during long-term follow-up and did not respond to any drugs for the treatment of BS, including oral glucocorticoid, methotrexate, and anti-TNF-α inhibitors. The present study has certain limitations. First, it is only a case report of a single patient and cannot discuss the universality of this phenomenon, which needs to be confirmed by studies with more patients. Second, it is necessary to establish a clearer relationship between the mutation and the coexistence of BS with osteochondromas; further research and genetic investigations are warranted. In conclusion, we report an unusual case of BS presented with osteolytic bone lesions which were irrelevant to noncaseous granulomatous lesions. This finding suggested that the bone lesion in BS was not only caseous but also osteochondroma. Caifeng Li was involved in study conception and design and approval of the final manuscript version. Junmei Zhang and Xiaozhen Zhao were involved in performing most of statistical analysis, writing the draft of the manuscript, data programming and quality monitoring, performance of statistical analyses, critical revisions, and approval of the final manuscript version. The authors thank all the members of the Department of Rheumatology at Beijing Children's Hospital Affiliated with Capital Medical University. This work was supported by grants from the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority, Grand/Award Number: XTCX201819; National Regional Medical Center Opening Project, Grand/Award Number: NRMC0110; BCH Young Investigator Program (BCHYIP), Grant/Award Number: BCHYIP-3-39. The authors declare no conflict of interest. The study was approved by the Ethics Committee of Beijing Children's Hospital (IEC-C-006-V.06). The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's guardians have given their consent for their images and other clinical information to be reported in the article. The patient's guardians understand that their names and initials will not be published and due efforts will be made to conceal the identity of the patient, although anonymity cannot be guaranteed.