Rare Autoinflammatory Disease Research Articles

Adult-onset familial mediterranean fever: case reports with literature review

Familial Mediterranean Fever (FMF) is a rare monogenic autoinflammatory disease that typically manifests in early childhood. The disease is characterized by its prevalence within a specific ethnic group. Nevertheless, FMF can also manifest in later stages of life among individuals with or without an ethnic background. We present two case reports of FMF patients, where the onset of the disease occurred in the third decade of life. These cases emphasize the importance of including monogenic autoinflammatory diseases in the differential diagnosis of adults presenting with fever of unknown origin and exhibiting typical FMF symptoms regardless of ethnicity.

P55 The boggy uveitis

Abstract Introduction Blau syndrome is a rare autosomal dominant autoinflammatory disease that affects young children. Typically, it causes widespread granulomatous inflammation, causing uveitis, arthritis, and dermatitis. The triad may be characteristic of the disease but is not present in all cases and may occasionally be incomplete. A characteristic finding is the presence of boggy swellings in the involved joints. Our patient presented with uveitis and boggy swellings of the wrists without arthritis. The history of dermatitis was remote. A high clinical index of suspicion and exome sequencing are imperative to make this rare diagnosis. Case description A six-year-old female was brought to an ophthalmologist with a complaint of a progressive decrease in vision in both eyes over the last four months. The vision deteriorated rapidly over the last couple of months. A detailed eye examination revealed features of granulomatous posterior uveitis with bilateral inflammatory cataracts. She was referred to the Rheumatology Outpatient Clinic. A detailed examination revealed boggy swellings on the bilateral wrist joints. As per the father, these swellings had been present for the last four years. The child never complained of pain in the wrists, or swelling and/or pain in any other joint. There was no history suggestive of arthritis or uveitis in the parents or immediate family members. The child occasionally developed an itchy red rash on the back. Such a rash has not occurred for the last many months. There was no skin lesion at the time of the examination. Suspecting Blau syndrome, a blood sample was sent for clinical exome sequencing (CES). Surgery (cataract extraction and intraocular lens implantation) was performed in the right eye. Intraoperative findings were noted, and features of granulomatous uveitis were evident. The patient was initiated on oral corticosteroids at 1 mg/kg of prednisolone by the eye surgeon. Four weeks later, the CES result was reported; it was positive for a heterozygous ‘pathogenic’ variant (detected in exon 4 of the NOD2 gene). The patient was reviewed after the report, and methotrexate was added. We started tapering the corticosteroids after six weeks of initial therapy. On the last eye examination (three months after the surgery), the uveitis had subsided. The vision was normal in the operated eye and had considerably improved in the unoperated eye. The surgery for the left eye was now deemed non-obligatory and was thus deferred. Discussion Blau syndrome is a rare autosomal dominant syndrome that causes arthritis, dermatitis, and granulomatous uveitis in children. A characteristic clinical feature of Blau syndrome is the presence of boggy swellings in the involved joints. Skin involvement usually occurs before the onset of arthritis and uveitis, presenting in the form of a rash (macro or micropapular and scaly), and occurs in infancy. Arthritis appears subsequently (between two and four years of age), followed by uveitis (around four years of age). Other uncommon manifestations of this disease are lymphadenopathy, sialadenopathy, erythema nodosum, neuropathies, leukocytoclastic vasculitis, glomerular and interstitial nephritis, interstitial lung disease, and pericarditis. A close mimic of this disease is sarcoidosis. Blau syndrome is an autosomal dominant disorder due to a mutation in the caspase recruitment domain gene CARD15/NOD2. There is no consensus on the optimal treatment for Blau syndrome. Corticosteroids and immunosuppressive agents, including methotrexate and azathioprine, have been used. Biologic agents have also been used with good results. In our case, the patient never had joint pains. He did not seek help until the child’s vision was impaired. Commonly, the ophthalmologist may be the only qualified physician of first contact. Joint pains may often be treated with self-medication or may be labelled as “growing pains” but the loss of vision is an unignorable catastrophic symptom and is invariably reported. The alert eye specialist must also enquire about fever, arthritis, and dermatitis in children with granulomatous uveitis. This correlation must be made sooner rather than later to prevent delay in diagnosis and therapy. The temporal dispersion of symptoms, i.e., the occurrence of different symptoms at different ages in the affected individual, also makes the diagnosis of Blau syndrome very challenging. Key learning points • Blau syndrome is a rare autosomal dominant disorder due to a mutation in the caspase recruitment domain gene CARD15/NOD2. • It causes arthritis, dermatitis, and granulomatous uveitis. • A characteristic clinical feature of Blau syndrome is the presence of boggy swellings in the involved joints. • A strong index of suspicion is required for diagnosis of this rare disorder.

Adult-onset Still’s disease masquerading as acute coronary syndrome: a case report and review of the literature

IntroductionAdult-onset Still’s disease is a rare systemic autoinflammatory disease. We present a case of a young man with a constellation of symptoms and myopericarditis as a complication of this disease.CaseA 36-year-old Hispanic man with no significant past medical history developed a quotidian fever pattern following an upper respiratory tract infection. He initially presented with chest pain concerning for myocardial infarction and underwent cardiac catheterization, which revealed non-obstructive coronary artery disease. He was found to have myopericarditis, significant neutrophilic leukocytosis, and hyperferritinemia. He improved on high-dose corticosteroids but developed steroid-induced psychosis, and 4 months from symptom onset, he finally received tocilizumab, which eventually induced remission without adverse reactions.DiscussionAdult-onset Still’s disease should be considered in a patient with fevers of undetermined origin. Due to its multisystemic involvement, adult-onset Still’s disease is often a diagnosis arrived at after an extensive cardiac, hematologic, malignant, and infectious workup. Imaging, laboratory testing, and bone marrow biopsy were necessary to rule out alternative etiologies of this patient’s presentation. Steroids are the mainstay of treatment because they are easily affordable, although the high risk of adverse effects makes them less desirable. Interleukin-1 inhibitors (anakinra or canakinumab) and interleukin-6 inhibitor tocilizumab are the steroid-sparing biologic agents of choice but are cost-prohibitive.ConclusionAdult-onset Still’s disease should be considered in the differential diagnoses of fever of undetermined origin. Early identification and initiation of treatment are critical to faster recovery and prevention of progression to severe complications. Steroids remain the standard first-line therapy and should be followed by disease-modifying steroid sparing drugs. The social determinants of health may preclude their timely initiation and should alert providers of proactive ways to avoid further delays.

Maxillofacial Symptoms and Diagnosis Criteria Concerning Chronic Recurrent Multifocal Osteomyelitis: A Systematic Literature Review.

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease characterized by sterile inflammation of bony tissue. Although it has distinct clinical and radiologic features, it is often misdiagnosed, leading to inappropriate and delayed treatment. Indeed, at the origin the disease can have an exclusive maxillofacial location and so be, at least clinically, difficult to prove. The aim of this study was to summarize through a systematic literature review the clinical, laboratory, and imaging data regarding maxillofacial manifestations of CRMO. The present systematic review of the literature was designed following the standard PROSPERO eligibility criteria. Three electronic databases were searched to find clinical studies describing cases of patients diagnosed with CRMO of the orofacial area. Relevant clinical, radiographic, and laboratory results were extracted. The search strategy retrieved 95 articles. Assessment of the full text was done for 47 articles among them, 30 were included. The total patients included was 82, mean age was 8.2 years. Pain and swelling association was present in 94% of the cases, mandible was involved in 96.3% of the cases. Sclerosis, lytic lesion, and periostal reaction were the most frequent radiologic findings. Chronic recurrent multifocal osteomyelitis is often misdiagnosed as infectious osteomyelitis, practitioners should therefore be familiar of its distinct clinical course and paraclinical features. Further investigations would be beneficial to assess the extraosseous manifestations and the long-term outcome of CRMO.

Pediatric SAPHO syndrome with pleural effusion: case report of a unique finding in a rare disease.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by bone inflammation and skin manifestations including acne, palmoplantar pustulosis, psoriasis, or hidradenitis suppurativa. SAPHO syndrome is considered on the same spectrum as chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis (CNO/CRMO), the former often being the nomenclature in adults and the latter in children. The diagnosis is made on patterns of clinical manifestations and is a diagnosis of exclusion. While skin and bone manifestations are commonly described with SAPHO syndrome, pleural involvement is rare, and few cases have been described in the literature, especially in pediatric patients. Herein we present a 14-year-old female with a past medical history of hidradenitis supprtiva, eczema, psoriasis, and a prior episode of culture-negative osteomyelitis who presented to the emergency room with chief complaints of right sided pain with inspiration and back pain. Exam revealed palmoplantar pustulosis, hidradenitis supprativa, psoriasis, and tenderness of vertebrae. Imaging showed a right sided pleural effusion and multiple sites of osteitis. Laboratory evaluation revealed elevated inflammatory markers, an exudative pleural effusion with neutrophilic predominance, and no evidence of malignancy, infection, or immunodeficiency. The patient was diagnosed with SAPHO syndrome and treated with naproxen, methotrexate, and golimumab with significant improvement including resolution of the pleural effusion. Pediatric SAPHO syndrome is a rare disease that classically causes osteitis and skin manifestations. This case highlights that pleural effusion can be a rare manifestation of pediatric SAPHO syndrome. Patients with suspected SAPHO syndrome with respiratory symptoms should be evaluated for pleural effusion.

TNF-alpha blockade in Primary Chronic Non-Bacterial Osteomyelitis of the Mandible.

Primary chronic Non-Bacterial Osteomyelitis of the jaw is a rare auto-inflammatory disease of unknown aetiology that bears pathophysiological resemblance to both the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome in adults and chronic recurrent multifocal osteomyelitis (CRMO) in children. Both SAPHO and CRMO respond to TNF-alpha blockade. Previously reported treatment regimens in CNOM including non-steroidal anti-inflammatory drugs, corticosteroids, antibiotics, anti-resorptive therapy, and surgery all bear disappointing results. TNF- α blockade is suggested as a treatment option by some experts but this is not backed by any clinical data.We sought to retrospectively and exhaustively report our experience of anti-TNF alpha therapy in refractory CNOM. Fifteen patients with refractory CNOM and high disease burden were referred to our centre. TNF- α blockade was attempted in 10 cases, given its efficacy in neighbouring diseases, its good tolerance profile and failure of previous treatment strategiesWe herein retrospectively report detailed outcomes for all patients having received anti-TNF alpha therapy for this indication in our centre. TNF-α-targeting therapy resulted in a rapid and sustained remission in a majority of patients with CNOM, without serious adverse events. Treatment was tapered and stopped without relapse in some patients despite a refractory course of several years. Male sex seems to be associated with a poorer outcome. Our results suggest that blocking TNF-α is efficient and safe in CNOM.

Optical coherence tomography assessment of disease activity in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome is a rare autoinflammatory disease caused by gain-of-function mutations or variants in the NLRP3 gene. Clinically, patients suffer from a broad spectrum of both systemic and neurological symptoms. The aim of this study was to determine whether systemic inflammation demonstrated by serum amyloid A (SAA) elevation is associated with neuroinflammation assessed by optical coherence tomography (OCT). Thirty eyes of 15 patients with NLRP3 low penetrance mutations (PwNLRP3) and 20 eyes of 10 age- and sex-matched healthy controls were examined by spectral-domain OCT as part of routine clinical care. All retinal layers and clinical features were evaluated. At baseline no significant retinal neuroaxonal inflammation or degeneration was observed in all measured retinal layers amongst PwNLRP3 compared with healthy controls. In a pooled analysis of all individual OCT time points a significant difference regarding the macular retinal nerve fibre layer was detected. Increased levels of SAA showed a positive association with averaged combined outer plexiform layer and outer nuclear layer volumes (ρ < 0.0001, r2 = 0.35). In cryopyrin-associated periodic syndrome increased combined outer plexiform layer and outer nuclear layer volumes are mirrored by SAA increase, an acute phase reactant indicating systemic inflammation. Our findings identify OCT as a candidate biomarker to monitor subclinical neuroinflammation and to assess disease activity in PwNLRP3.

Familial Mediterranean fever. Report of a pediatric case

Familial Mediterranean fever or (FMF) (FMF) is a rare monogenic auto-inflammatory disease, predominantly pediatric, with autosomal recessive hereditary transmission, affecting the Mediterranean rim, linked to a mutation of the protein marinosterin, resulting in the secretion of proinflammatory cytokines, interleukin 1. These main manifestations: acute inflammatory attacks with fever and elevation of the serum protein of the inflammation yielding spontaneously in one to 3 days. These flare-ups associate abdominal, articular, cutaneous signs, sometimes polyseritis. The evolution remains favorable under colchicine, with risk of amyloidosis and death and impact on the quality of life. Our objective is to describe through a case of FMF, the clinical approach of a relapsing fever, the clinical characteristics of FMF, and to report the clinical wandering and the diagnostic delay of 4 years as well as the impact on growth and quality of life. This is a 14-year-old boy, of consanguineous marriage, who consults for a recurrent fever at 40°, a clinical and biological inflammatory syndrome, with abdominal signs, and arthralgia, weight delay of less than 3DS, contrasting with a paucity of physical signs apart from pharyngitis. negativity of the infectious, immune, tumor and resistance to antibiotics, and the spontaneous resolution of symptoms in 3 days s, made us evoke the diagnosis of FMF, confirmed by the genetic study which found the homozygous mutation of the protein. In conclusion, FMF is an autoinflammatory disease, monogenic, to evoke in consanguineous marriage, a boy, in front of a recurrent fever, with abdominal, serous, cutaneous and joint involvement; confirmed by genetic study. Colchicine reduces flare-ups, and prevents amyloidosis, and improves quality of life.

Chronic non-bacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO) with a focus on pamidronate therapy.

Chronic recurrent multifocal osteomyelitis (CRMO), also called chronic nonbacterial osteomyelitis (CNO) or nonbacterial osteomyelitis (NBO), is a rare autoinflammatory bone disease of unknown etiology. However, the number of patients properly diagnosed would increase with better knowledge of the disease. In this regard, whole-body magnetic resonance imaging (WB MRI) has been found to be a better predictor of active lesions than clinical examination. Importantly, the RINBO index (radiologic index for NBO) quantifies the involvement based on the WB MRI. Further, a chronic nonbacterial osteomyelitis MRI scoring (CROMRIS) has been developed as an online tool for assessing WB MRI. The therapy consists of non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates (pamidronate, zoledronate, etc.) and other drugs, including biologics. Pamidronate is an appropriate and safe therapy. The first pilot prospective randomised controlled trial (RCT) on pamidronate vs. placebo was carried out in adults. No RCT has been done in children yet. Besides RCTs, there are a number of issues to be explored in future, i.e. predictors of therapy effect, optimal therapy duration, predictors of therapy discontinuation and evaluation of optimal therapy protocol. Recently, the CNO clinical disease activity score (CDAS) was constructed and validated but the classification criteria are still being developed. As collaboration on this rare disease is essential, a prospective Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) was established to generate future comparative effectiveness research data.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Burden of illness and unmet needs in generalized pustular psoriasis: report of four cases

Generalized pustular psoriasis (GPP), the most severe form of pustular psoriasis, is a rare autoinflammatory skin disease that manifests with the rapid and widespread eruption of small, sterile pustules and surrounding skin erythema, often accompanied by systemic symptoms. GPP is frequently painful and distressing and adversely affects patients’ quality of life. Until recently, systemic treatment for GPP in the United States mainly involved the off-label use of agents approved to treat plaque psoriasis. In September 2022, spesolimab was approved in the United States as a first-in-class treatment for GPP flares in adults, making a GPP-specific therapy available. Here, we describe 4 cases from our respective clinical practices that highlight the difficulties faced by patients with GPP in receiving an accurate diagnosis and obtaining effective treatment and demonstrate the associated physical and psychological disease burdens. The potential severity and consequences of untreated GPP necessitate a prompt diagnosis, initiation of effective treatment, and regular follow-up and monitoring of patients’ conditions. When managing GPP, a multidisciplinary approach is recommended to ensure that patients receive appropriate social and emotional support and effective medical care.

Schnitzler syndrome: A rare disease with neutrophilic dermatosis and monoclonal gammopathy

Schnitzler syndrome is a rare chronic auto-inflammatory disease characterized by neutrophilic dermatosis and a monoclonal gammopathy of IgM type. The clinical features of this disease like fever, rash, arthralgias and lymphadenopathy often overlaps with the presenting symptoms of other diseases like Castleman’s disease, adultonset Still’s disease and lymphomas. But the line of treatment is different for each of these clinical conditions. Schnitzler syndrome is associated with over-production of IL-1 and therapies are directed against this interleukin. Here, we present a case of Schnitzler syndrome, who was initially diagnosed as multi-centric Castleman’s disease and was treated with only partial resolution of symptoms.

Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis.

Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (n= 103, 89.2%); median age at first symptoms 45years (range 20-73). The diagnosis was excluded in the remaining 51 "non-CNO" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (P< 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages.

Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome

Background and objectivesThe study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants.MethodsRNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines.ResultsTranscriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement.ConclusionOverproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.

Analysis of Anakinra Therapy for the Deficiency of Interleukin-1 Receptor Antagonist through Clinical Evidence.

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autosomal recessive autoinflammatory disease with symptoms including but not limited to osteomyelitis, periostitis, and systemic inflammation. DIRA is developed from the loss-of-function biallelic mutations of the IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation. Thus, anakinra as the recombinant IL-1RA has become the primary drug to treat DIRA. Although anakinra has been effective for the complete remission of DIRA, it has also shown various side effects. To confirm the efficacy and safety issues associated with DIRA treatment, we conducted a literature review and secondary data analysis to enhance our understanding on this important topic. Through comprehensive literature search, we have identified 15 papers with 25 patients studied. The demographic, clinical, and genetic data were extracted, followed by statistical analysis to support the physiological mechanisms of anakinra treatment. Through the literature review and data analysis, it was found that 88% of patients had complete clinical remission of DIRA upon continual treatment with anakinra; patients had a mean improvement of Hemoglobin (+3.18 g/dL), Erythrocyte Sedimentation Rate (-53.4 mm/h), and C-reactive Protein (-135.45 mg/L) levels, suggesting that the improvement of hematopoietic function and inflammation is a mechanism for anakinra treatment. Various genetic variants were also identified from the patient data that cause the loss of function of IL-1RA, providing real patient genomic data to support the anakinra treatment. Considering the inconsistency and certain variations from clinical research influenced by specific conditions, this review along with the data analysis confirms the efficacy and safety of anakinra treatment for DIRA.

Stellate ganglion block in the treatment of SAPHO syndrome: A case report.

Synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare and refractory autoinflammatory disease, and there is no consensus on its treatment. Stellate ganglion block (SGB) blocks sympathetic nerves, ameliorates immune dysfunction, and alleviates stress response, which has been used to treat various chronic pain syndromes, arrhythmias, and post-traumatic stress disorder (PTSD). Also, the SGB has been reported to be successfully used to treat certain skin diseases, autoinflammatory diseases, and menopausal symptoms. In this study, over 3 years of follow-up, we found that SGB successfully intervened the symptoms of SAPHO syndrome, including sternoclavicular joint arthritis and palmoplantar pustulosis.

Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin-Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti-Interleukin-1 Therapy.

Cryopyrin-associated periodic syndromes (CAPS), also known as NLRP3-associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain-of-function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin-1β (IL-1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal-dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn). We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n=10) and healthy family members (n=5). The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain-of-function variant. Administration of IL-1 receptorantagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. Our findings highlight the crucial role of early diagnosis and treatment with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high- and ultrahigh-frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Chronic Nonbacterial Osteomyelitis in Inflammatory Bowel Disease.

Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. This review presents a comprehensive analysis of the intricate relationship between CNO and inflammatory bowel disease (IBD), shedding light on shared pathophysiological mechanisms and clinical management. A thorough literature review was conducted, encompassing 24 case reports involving 40 patients. The demographic distribution of patients revealed a near-equal gender ratio, with a median age of diagnosis at 12 years. The diagnosis patterns showed a higher proportion of CNO as the initial diagnosis, while Crohn's disease was more prevalent than ulcerative colitis. The time interval between the clinical presentations varied, ranging from simultaneous detection to a substantial 15-year gap. Treatment modalities included nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, aminosalicylates, and biologic agents, such as infliximab, often overlapping in their use and suggesting shared pathophysiological pathways. Both conditions displayed systemic manifestations, and patients often responded well to immunosuppressive medications. The pathophysiology of CNO involves a genetic predisposition, cytokine dysregulation, and osteoclast activation. Dysregulated innate immunity results in immune cell infiltration into bones, causing sterile bone lesions. Notably, emerging evidence hints at a potential link between the microbiome and CNO. In contrast, IBD results from imbalanced mucosal immune responses to the intestinal microbiota. Polymorphisms in the promotor region of IL-10, common cytokines, immune cells, and genetic markers indicate shared immunological and genetic factors between CNO and IBD. Both conditions also involve extraintestinal symptoms. This analysis underscores the need for clinical awareness of the co-occurrence of CNO and IBD, especially among pediatric patients. A deepened understanding of the connections between these seemingly distinct diseases could lead to more effective management and improved patient outcomes.

Аутовоспалительные заболевания в практике врача неонатолога и педиатра: клинические наблюдения

Molecular genetic analysis in the current clinical practice is a kind of must-do standard in the diagnosis of rare (orphan) diseases and syndromes in pediatric patients, which gives the opportunity for making a diagnosis at an early stage, early period of life and followed by the initiation of a targeted pathogenetic therapy, if and when needed, that in its turn is able to improve the prognosis not only for the health, but also for the quality of life and in some cases for the survival of a patient. As for now, this is an overall accessible diagnostic method the use of which is nevertheless often associated with certain difficulties, such as the need for going through the path of a complex differential diagnosis and the awareness and targeted qualification among pediatric practitioners and neonatologists. Authors presents the description of the two clinical cases of a rare autoinflammatory disease, cryopyrin-associated periodic syndrome (CAPS) in children as a demonstration of the way to verify a clinical diagnosis in childhood and the features of diagnosing orphan diseases in a Russian regional hospital. Conclusion: the presented clinical observations demonstrate the capabilities of modern medicine in making a clinical diagnosis of an orphan disease from the group of autoinflammatory diseases, CAPS in particular, starting from the neonatal period of life of a patient.

A case ofcryopyrin-associated periodic syndrome due to somatic mosaic mutation complicated with recurrent circinate erythematous psoriasis.

Cryopyrin-associated periotic syndrome (CAPS) is a rare autoinflammatory disease caused by genetic variants in innate immunity genes. Autoinflammatory diseases, including CAPS, mediate proinflammatory cytokines such as interleukin (IL)-1 and IL-18 and result in severe systemic inflammation. A gain-of-function mutation in the NLR family pyrin domain-containing 3 (NLRP3) gene, which encodes the protein cryopyrin, was identified to be responsible for CAPS in 2001, and since then several additional pathogenic mutations have been found. Moreover, other phenotypes have been identified based on severity and symptomatology, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease/chronic neurologic cutaneous articular syndrome. Prompt diagnosis of CAPS remains challenging, however, due to unspecific, extensive clinical signs, and delayed diagnosis and treatment targeting IL-1 lead to multiorgan damage. Another factor complicating diagnosis is the existence of somatic mosaic mutations in the NLRP3 gene in some cases, resulting in symptoms and clinical courses that are atypical. The frequency of somatic mosaic mutations in CAPS was estimated to be 19% in a systematic review. Psoriasis is a chronic inflammatory skin disease that affects ∼3% of the global population. Although no reports have shown complication between CAPS and psoriasis, these diseases have several similarities and potential relationships, for instance activation of T helper 17 cells in the dermis and increased NLRP3 gene expression in psoriatic skin compared with normal skin. Here, we report a case of CAPS due to a somatic mosaic mutation with recurrent circinate erythematous psoriasis.