NOD2 Genes Mutation in a Blau Syndrome Accompany with Congenital Hyperuricemia: A Case Report

Rationale: Blau syndrome (BS) is a chronic auto-inflammatory granulomatous disorder associated with the nucleotide-binding oligomerization domain-containing 2 (NOD2) gene mutations. Gene mutation is one cause of congenital hyperuricemia, However, the relationship between NOD2 and hyperuricemia was unknown. Patient concerns: A 3.5-year-old girl was admitted to hospital because of pain in the left calf and red eyes, otherwise, she suffered from skin rash, and skin cysts in the wrist and ankle joints before.Diagnoses: The girl was diagnosed with sporadic BS (SBS) accompanied with congenital hyperuricemia according to her clinical presentation and gene mutation.Interventions: The patient received prednisolone combined with adalimumab and methotrexate for controlling SBS. Oral febuxostat to alleviate uric acid levels. Outcomes: Her serum uric acid decreased to normal levels after 2 weeks with oral febuxostat tablet. Four months following the treatment, the number of cysts was decreased and ocular damage was not progressed. Lessions: Blau syndrome is a relatively new entity that clinical spectrum continues to expand. This patient provides some information, which would be assist the diagnosis.

Bilateral Optic Disc Swelling as a Plausible Common Ocular Sign of Autoinflammatory Diseases: Report of Three Patients with Blau Syndrome or Cryopyrin-Associated Periodic Syndrome

The aim of this study is to describe bilateral optic disc swelling in three consecutive patients with Blau syndrome or cryopyrin-associated periodic syndrome at a single institution. Case 1 was a 30-year-old woman receiving 25 mg etanercept twice weekly who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 5 months old and genetically diagnosed with Blau syndrome with CARD15/NOD2 mutation (N670K) at 13 years old. At 10 years old, she began to have uveitis with optic disc swelling in both eyes, resulting in macular degeneration and optic disc atrophy at 17 years old only when etanercept was introduced. Case 2 was a 21-year-old man receiving adalimumab every 2 weeks who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 1.5 years old and genetically diagnosed as Blau syndrome with CARD15/NOD2 mutation (C495Y) at 5 years old. At 8 years old, around the time of adalimumab introduction, he began to show bilateral optic disc swelling which continued until the age of 16 years when the dose of adalimumab was increased. Case 3 was a 20-year-old woman receiving canakinumab every 8 weeks for systemic symptoms such as fever, headache, vomiting, and abdominal pain and later for sensorineural hearing disturbance on both sides. She had been diagnosed genetically with cryopyrin-associated periodic syndrome with NLRP3 mutation (Y859C) at 7 years old. At 5 years old, she was found to have bilateral optic disc swelling, which continued until the age of 10 years when she began receiving canakinumab (IL-1β inhibitor). Bilateral optic disc swelling might be tentatively designated as a plausible common ocular feature, if it occurred, in autoinflammatory diseases to pay more attention to ophthalmic complications in rare diseases.

Tofacitinib effectiveness in Blau syndrome: a case series of Chinese paediatric patients

Objective Blau syndrome (BS), a rare, autosomal-dominant autoinflammatory syndrome, is characterized by a clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis and associated with mutations of the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Aim of this study was to assess the efficacy of tofacitinib in Chinese paediatric patients with BS. Methods Tofacitinib was regularly administered to three BS patients (Patient 1, Patient 2, and Patient 3) at different dosages: 1.7 mg/day (0.11 mg/kg), 2.5 mg/day (0.12 mg/kg), and 2.5 mg/day (0.33 mg/kg). The clinical manifestations of the patients, magnetic resonance imaging results, serological diagnoses, therapeutic measures and outcomes of treatments are described in this report. Results The clinical characteristics and serological diagnoses of all BS patients were greatly improved after the administration of tofacitinib treatment. All patients reached clinical remission of polyarthritis and improvements in the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and inflammatory cytokines. Conclusion Tofacitinib, a Janus kinase (JAK) inhibitor, is a promising agent for BS patients who have unsatisfactory responses to corticosteroids, traditional disease-modifying antirheumatic drugs, and biological agents.

Late-onset panuveitis in a Chinese girl with sporadic Blau syndrome: a case report

The onset of ocular symptoms at age 18 is relatively rare in BS and the eye lesions are usually serious.We reported a case of a 18 year-old Chinese girl with late-onset mild panuveitis with sporadic Blau syndrome .

BLAU SYNDROME OR MONOGENOUS SARCOIDOSIS WITH EARLY ONSET: RUSSIAN COHORT OF PATIENTS

Blau syndrome (BS) is a rare monogenic granulomatous autoinflammatory disease (a variant of genetically determined sarcoidosis) caused by a mutation of the NOD2/CARD15 gene, transmitted in an autosomal dominant manner and manifested by a triad of signs: dermatitis, granulomatous arthritis with pronounced exudative component and involvement of periarticular tissues, uveitis. Objective of the study: to present the variants of the clinical picture and the type of pathogenic variants (mutations) in patients with a rare monogenic granulomatous autoinflammatory disease – BS – in the Russian Federation, the clinical picture of which can mimic juvenile idiopathic arthritis. Materials and methods of research: the observational study included patients with BS who were observed in the children's department of the V.A. Nasonova Research Institute of Rheumatology from 2014 to 2021, the diagnosis of which was confirmed by the detection of a pathogenic mutation in the NOD2/CARD15 gene. Results: the study included 8 children: 6 boys and 2 girls. Ethnic Russians were 5 patients, 1 Jew, 1 of mixed origin (peoples of Dagestan/Russians), 1 Tatar female. The age of onset of the disease is from the first days of life to 2,5 years. Skin lesions were observed in 6 (75%) patients. Atypical arthritis (boggy arthritis) was observed in all patients, in all cases the wrist, ankle and knee joints were involved in the pathological process. Uveitis developed after all other manifestations and was detected in 6 (75%) patients. At the onset, 5 patients had anterior uveitis, 2 of them with subsequent involvement of the posterior segment; in 1 child, the first ophthalmic manifestation was posterior uveitis. In 5 patients, there was no increase in acute phase markers (ESR, C-reactive protein). 5 (62,5%) patients had variant p.R334Q (c.1001G>A), 2 (25%) had variant p.R334W (c.1001G>A), 1 patient had variant p.M513T (c.1538T>C) of the NOD2/CARD15 gene. Conclusions: BS can be encountered in the practice of a pediatric rheumatologist in Russia and requires differentiation from polyarticular juvenile idiopathic arthritis. Identification of the pathogenic variant of the NOD2/CARD15 gene plays a decisive role in the diagnosis.

NOD2-associated granulomatous autoinflammatory syndromes – a short update for clinicians

NOD2 (nucleotide-binding oligomerization domain-2), a pattern recognition receptor, is involved in innate immune defense against pathogens, intestinal mucosal barrier integrity, gut microbiota composition, autophagy, immune homeostasis and inflammation. NOD2 mutations have been associated primarily with childhood diseases (Blau syndrome and sarcoidosis with early-onset, monogenic Crohn’s disease), but also with adult diseases (NOD2-associated autoinflammatory syndrome – NAID, also called Yao syndrome etc.). Intermediate forms between Blau syndrome and NAID have also been described. Blau’s disease and early-onset sarcoidosis are the familial and the sporadic forms respectively of a dominantly inherited rare monogenic autoinflammatory disease. Blau’s syndrome starts in early childhood, evolving with non-caseating granulomatous arthritis with prominent tenosynovitis, dermatitis with a “bronzed”, maculo-papular or scaly skin rash, and intermittent fever. Periodic fever, generalized lymphadenopathy, and granulomatous visceral involvement may be present. Therapy consists in systemic steroids, immunosuppressants and biologic drugs. In adults the NAID or Yao’s syndrome evolves with bouts of systemic inflammation with lower limbs swelling, tenosynovitis and non-erosive arthritis, fever and dermatitis. We discuss the differential diagnosis with other granulomatous diseases. Increased awareness is necessary regarding these rare diseases which may alter the quality of life or lead to disability, in order to improve their prognosis.

Blau syndrome: a case report from Palestine

Background This case study documents the first familial case of Blau syndrome (BS) in Palestine characterized with mutation in CARD15/NOD2. Case presentation Eighteen years old female was initially misdiagnosed with Juvenile idiopathic arthritis (JIA). The patient had been on steroids and methotrexate treatment for the last 16 years, but did not respond well to treatment. Initial examination at Saint John of Jerusalem Eye Hospital Group clinic showed bilateral intermediate uveitis with camptodactyly. The patient’s sister (aged 19 years) had bilateral intermediate uveitis and camptodactyly. Both eyes of their father had signs of old posterior uveitis. Father’s left eye showed 360 degrees posterior synechia, mature cataract with old Keratic precipitates (KPs). He also had camptodactyly. The patient was referred to pediatric rheumatologist to rule out sarcoidosis. Lung CT scan showed bronchiectasis, genetic consultation followed. Complete eye examination, full history, refraction, and Optical coherence tomography (oct) were done. Systemic and topical steroid therapy could not control the ocular inflammation. The family then was referred to a geneticist. Genetic analyses showed that the proband and all three family members had an R334q mutation in the CARD15/Nod2 gene. Conclusions BS should be considered in the differential diagnosis of childhood uveitis, especially in low and middle income countries where it is misdiagnosed in many cases, which delay appropriate diagnosis and thus control. Genetic analysis of the CARD15/Nod2 gene is helpful in the diagnosis. Steroids alone are not enough to control the disease, other immunosuppressants and biologics are needed.