A Case Report of Blau Syndrome / 罕见病研究

Blau syndrome is a rare genetic disorder characterized by the a mix of granulomatous arthritis, uveitis, and dermatitis. Patients typically manifest multisystem involvement, including ocular, skin, and skeletal abnormalities. Blau syndrome is extremely rare, with a global incidence of less than one in a million among children. In this multidisciplinary consultation, we present a case of a 21-year-old young female patient having multisystemic involvement since early childhood. She was presented with multiple joint swelling, skin lesions, increased eye discharge, and accompanied by hypertension and arterial abnormalities, and received a diagnosis of uveitis. The patient had been receiving steroid treatment since the age of 6 and has tried various medications, with some improvement in joint swelling and ocular symptoms. Through this rare disease multidisciplinary consultation, we aim to provide guidance in the molecular diagnosis of the patient, multisystem assessment, and the selection and formulation of treatment plans. Additionally, we hope that by reporting this case, clinical physicians can gain a better understanding of the diagnosis and comprehensive treatment strategies for Blau syndrome, thereby improving the management and treatment of rare diseases.

Analysis of 8 Cases of Blau Syndrome/Early-onset Sarcoidosis——Clinical Manifestations, Histopathology Features and Gene Mutation Diversity / 罕见病研究

  Objective  To summarize the clinical manifestations, pathological features and gene mutation diversity of Blau syndrome/early-onset sarcoidosis.  Methods  We collected general data, clinical manifestations, and auxiliary examination results from 8 patients who were diagnosed of Blau syndrome/early-onset sarcoidosis and treated in our hospital from January 2011 to December 2022, and then summarized and analyzed their characteristics and diversity.  Results  Among the 8 patients, 4 were males and 4 were females. The onset age was 3 to 8 months old. Rash was the first symptom in 7 patients(87.5%). 6 patients(75.0%) had papules and erythema.3 cases(37.5%) had arthritis. 2 cases(25.0%) had uveitis and other eye inflammation. 4 cases (50.0%) also showed intermittent fever. 3 cases (37.5%) showed symptoms in nerve and respiratory system, and hypertension respectively. The skin histopathology of 8 patients showed non-caseous granuloma formation. In laboratory detection, CRP and TNF-α were significantly increased before treatment, while IL-6, IL-8, TNF-α and IL-2 receptor(IL-2R) were significantly decreased in 5 patients after glucocorticoid therapy. The results of genetic testing showed that 4 of the 7 patients had p.R334W(c.1000C > T) mutation, 1 had p.H313R(c.938A > G) and p.R471C(c.1411C > T)double mutation, and 1 had p.476_477del (c.1427_1429delcct).  Conclusions  Blau syndrome/early-onset sarcoidosis has significant features in clinical manifestations, histopathology and gene mutation, but it also has diversity.

Establishment of animal model of Blau syndrome / 中国药理学通报

Aim To establish stable and reliable animal models of Blau syndrome (BS) in vivo. Methods C57BL/6J mice were intraperitoneally injected with muramyl dipeptide (MDP) or L18-MDP to induce systemic inflammatory model of BS. Meanwhile, positive drug etanercept (ETN) was set to investigate the response of the model to evaluate effectiveness. SD rats were intravitrealiy injected with MDP to establish BS-associated uveitis model. Serum levels of TNF-a, IL-6 and IL-8 were detected by enzyme linked immunosorbent assay (ELISA). Histopathologic al changes of rat eyeballs were detected by HE staining and the expressions of p65, p-ERK, p-p38, p-JNK, TNF-a, IL-6 and IL-8 in vitreous were determined by immunohistochem-istry (IHC) staining. Results The serum level of TNF-a in mice increased after intraperitoneal injection of MDP (P < 0.05), and increased significantly after L18-MDP injection (P < 0.01). Meanwhile, the levels of IL-6 and IL-8 were also markedly induced by L18-MDP (P < 0. 01, P < 0. 01). ETN treatment evidently inhibited the increased levels of these above cytokines induced by L18-MDP (P < 0. 05, P < 0. 01). After the intravitreous injection of MDP in SD rats, there were numerous inflammatory cells infiltrated in retina and vitreous, and the retina was seriously damaged. The staining levels of p65, p-ERK, p-p38, p-JNK, TNF-a, IL-6 and IL-8 in eyeball tissues were significantly enhanced. Conclusions The systemic animal model of BS can be successfully established by intraperitoneal injection of L18-MDP in C57BL/6J mice, and the good BS-relat-ed uveitis can be induced by intravitreous injection of MDP in SD rats, which provides the simple, convenient, repeatable and i-deal animal models for exploring the pathogenesis of BS and e-valuating the efficacy of drugs.

Clinical Characteristics and Treatment of Blau Syndrome in Chinese Children-a National Multicenter Study / 罕见病研究

  Objective  To study the demographic and clinical characteristics, correlation of genotype and phenotype and treatment of Blau syndrome to facilitate early diagnosis and timely treatment of Blau syndrome.  Methods  Seventy-two patients with Blau syndrome from 11 centers from May 2006 to April 2022 were retrospectively analyzed, and their general information, clinical data, laboratory examination and treatment medication were collected.  Results  The distribution of patients with Blau syndrome was uniform in geographical north and south of China, and there was no obvious gender bias. The mean age of onset was (14.30±12.81) months, and the age of diagnosis was (55.18±36.22) months. 35% of patients with Blau syndrome happened before 1 year old, and all patients developed before 5 years old. 87.50% (63/72) had granulomatous arthritis, 65.28% (47/72) had rash, 36.11% (26/72) had ocular involvement, 27.78% (20/72) had fever, and 15.28% (11/72) had pulmonary involvement. Arthritic manifestations of Blau syndrome were most at risk, followed by rash, ocular involvement, and fever.The first 25 months of the disease, the risk of developing a rash was the greatest. The risk of developing arthritis was the greatest between 25 months and 84 months. The main mutations were p.R334Q and p.R334W, and patients with p.R334Q mutation had relatively high incidence of fever (35.71%[5/14] vs. 14.29%[1/7], P=0.43) and ocular involvement (42.86%[6/14]vs. 28.57%[2/7], P=0.51). There was a relatively high incidence of rash (85.71%[6/7] vs. 64.29%[9/14], P=0.59) in patients with the p.R334W mutation. Forty-five patients(62.50%)were treated with a combina-tion of glucocorticoid and methotrexate. Twenty-two patients were treated with tumor necrosis factor antagonist in addition to glucocorticoid and methotrexate.  Conclusions  The risk of different clinical manifestations of Blau syndrome from high to low was arthritis, followed by rash, ocular involvement and fever. The main treatment was glucocorticoid combined with methotrexate, to which biological agents could be added.

Familial Blau syndrome:First molecularly confirmed report from India

Blau syndrome (BS) is a rare autoinflammatory disorder characterized by the clinical triad of arthritis, uveitis, and dermatitis due to heterozygous gain-of-function mutations in the NOD2 gene. BS can mimic juvenile idiopathic arthritis (JIA)-associated uveitis, rheumatoid arthritis, and ocular tuberculosis. We report a family comprising a mother and her two children, all presenting with uveitis and arthritis. A NOD2 mutation was confirmed in all the three patients – the first such molecularly proven case report of familial BS from India.

Uveitis in sporadic Blau syndrome: Long-term follow-up of a refractory case treated successfully with adalimumab

The classic entity of autosomal dominant Blau syndrome (BS) consists of arthritis, dermatitis, and uveitis, occurring as a result of mutations in the NOD2 gene pattern recognition receptor. Sporadic cases are those in which no known gene mutation is identifiable. Uveitis in BS can be refractory to conventional therapy. We report a case of sporadic Blau uveitis managed with adalimumab monotherapy after failing to respond to topical steroids, systemic steroids, methotrexate, and infliximab therapy sequentially. Uveitis resolved completely with adalimumab and the patient has had a disease-free period over a 2-year follow-up with bi-monthly injections for arthritis control.

A familial case of Blau syndrome caused by dual NOD2 genetic mutations / 中华实用儿科临床杂志

Objective To provide the diagnostic proof for a suspected Chinese family with BS,and NOD2 gene mutation types and clinical features were analyzed in this study.Methods Nine members (4 males and 5 females) of this family were enrolled.To clarify the genotype,the whole exome sequencing by next-generation sequencing from the proband and his parents was performed,and all members were subjected to Sanger sequencing.For the newly discovered NOD2 missense mutation,its pathological predictions were conducted online by adopting polyphen software.Clinical data of affected cases diagnosed by NOD2 analysis were collected to analyze illustrate the clinical features.Results (1)The proband of the family was a 5-year-old Chinese Han boy,who had the clinical triad of dermatitis,polyarthritis and uveitis.The body temperature and C-reactive protein (CRP) was normal.Besides the proband,2 members were diagnosed as BS by means of NOD2 analysis.The coexistence of 2 missense mutations was detected.One novel mutation was c.1981G ＞ C,p.A661 P,and another previously reported one was c.2006A ＞ G,p.H669A.(2) Mutations identified in the male proband were inherited from his father.Tracing the other pedigree members,it was disclosed that his grandmother had the heterozygous dual NOD2 mutations.The proband displayed a phenotype featuring the symptom triad of granulomatous dermatitis,symmetric arthritis,and recurrent uveitis,with normal temperature and CRP level.Conclusions The coexistence of A661P and H669A mutations in NOD2 caused BS in a Chinese pedigree,which derived from the proband's grandmother.This is the first report of A661P mutation in NOD2 in a Chinese pedigree of this disease.The proband has multi hydatoncus surrounding multi-joints,but no persistent fever and no elevated CRP,which may help to differentiate BS from other inherited autoinllammatory diseases in clinical settings.

A familial case of Blau syndrome caused by a novel NOD2 genetic mutation / 소아과

Blau syndrome (BS) is a rare autosomal dominant, inflammatory syndrome that is characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are responsible for causing BS. To date, up to 30 Blau-associated genetic mutations have been identified within this gene. We report a novel NOD2 genetic mutation that causes BS. A girl, aged 8 years, and her brother, aged 10 years, developed erythematous skin rashes and uveitis. The computed tomography angiogram of the younger sister showed features of midaortic dysplastic syndrome. The brother had more prominent joint involvement than the sister. Their father (38 years) was also affected by uveitis; however, only minimal skin involvement was observed in his case. The paternal aunt (39 years) and her daughter (13 years) were previously diagnosed with sarcoidosis. Mutational analysis revealed a novel c.1439 A>G mutation in the NOD2 gene in both siblings. The novel c.1439 A>G mutation in the NOD2 gene was found in a familial case of BS. Although BS is rare, it should always be considered in patients presenting with sarcoidosis-like features at a young age. Early diagnosis of BS and prompt multisystem workup including the eyes and joints can improve the patient's outcome.

Blau syndrome: a case report and review of literature / 中华皮肤科杂志

A 4-year-old girl presented with generalized papules, erythema, desquamation, subcuta-neousnodules around large joints, as well as a 3-year-history of progressive eye damage. Three months after her birth, papules developed on the lower limbs, and gradually spread to involve the whole body. Eye damage appeared after a high fever and she was diagnosed with keratoleukoma, old iritis, and posterior synechia. Physical examination revealed sharply demarcated corneal opacity, shallow anterior chamber, obscure irides, and posterior synechia; pupils were not round. No superficial lymphadenectasis was observed. Dermatological examination showed ichthyosis-like coarse skin with generalized papules, erythema and desquamation, increased wrinkles and absence of sweat. Skin temperature was higher than normal. There were soft, irregu-larly sized, non-tender, movable subcutaneous masses at the wrist, ankle and knee joints without inflamma-tion or warmth. Type-B uitrasonography of both eyes disclosed vitreous opacification, posterior detachment of vitreous, extravasation at the posterior vitreous membrane, and decreased intraocular pressure. Histopathology of lesions on the back, waist, and back of hands as well as subcutaneous nodules on the wrists showed epidermal acanthosis and infiltration with a large number of histiocytes, foam cells and multi-nucleated giant cells in the dermis. No abnormal findings were observed from other examinations. This case was diagnosed as Blau syndrome, which is an autosomal dominant inherited disease; currently, there is no effective therapy for it.