Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation

Abstract Background Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. Objective To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. Methods Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. Results We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. Conclusions Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

Download Full-text

AB0764 MANIFESTATIONS OF BEHCET’S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1364 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1409.1-1409

Author(s):

R. Goloeva ◽

Z. Alekberova

Keyword(s):

Behçet’S Disease ◽

Behcet’S Disease ◽

Clinical Symptoms ◽

Behçet's Disease ◽

Disease Onset ◽

Recurrent Aphthous Stomatitis ◽

Organ System ◽

Aphthous Stomatitis ◽

Behcet's Disease ◽

System Involvement

Background:Behcet’s disease (BD) is a systemic vasculitis of unknown etiology, characterized by recurrent oral and genital erosions and ulcerations, as well as involvement of joints, ocular, vascular, gastrointestinal (GI), and central nervous system (CNS).Objectives:To study the influence of such factors as patient’s gender, age at the disease onset and initial manifestations of the disease on the severity of BD.Methods:95 patients with confirmed BB were examined. The majority of patients were males (70 men, 25 women) with the 2.8:1 M:W ratio. Patients’ mean age (median [interquartile range]) was 29 years [22; 34], from 16 to 51 years, the average age at disease onset was 20 years [14; 24]; and mean disease duration was 8 years [4; 15].Results:The following clinical manifestations of BD were documented at disease onset (%): recurrent aphthous stomatitis – 63.1; skin lesions – 12.6; genital ulcers – 4.2; ocular lesions – 6.3; joint syndrome -7.4; CNS lesions -2.1; gastrointestinal tract involvement -2.1; thrombosis -1; epididymitis -1. 11.6% of all patients had signs of organ system involvement by the time of establishing BD diagnosis. Recurrent aphthous stomatitis was more common in female patients at BD onset– 76% vs. 58.6%, p=0.01, while organ system involvement was more common in males-14% vs. 4% in females, p=0.02.Progression from initial symptoms to the mature BD phenotype allowing to verify the diagnosis occurred within 4.3 years on average [1; 6], although 30.5% of patients progressed to a full-blown disease within 1 year.Analysis of potential predisposing or precipitating factors prior to BD onset identified such in only 12 patients, including frequent episodes of tonsilitis in 3 patients, cold exposure with hypothermia in 2, dental procedures in 2, stressful events - in 2, and one case of each - herpes labialis, frontal sinus puncture and appendectomy. Other patients could not recall any potential precipitator of BD.Mean age at BD onset was 20 years [14; 24], including 30.5% of patients with disease onset before 16 years, 22.1% aged from 16 to 21 years, 36.8% aged from 21 to 30 years at disease onset, and in remaining 10.5% the disease manifested after 30 years of age. BD onset in men and women was documented at approximately the same time. There were no signs or correlations indicating that patient’s age at disease onset could be associated with specific clinical symptoms in males or females. However, analysis of gender-associated differences in disease severity based on Krause’s Clinical Severity Scoring yielded the following results: mild BD was found in 15.7% men and 44% women (p=0.009), moderate disease - in 7.1% men and 16% women, (p>0.05), and severe BD - in 77% men and 40% women, respectively, (p=0.001). The risk of developing severe BD was 5-fold higher in men vs women [OR = 5.06, 95% CI 1.7-15.1].Conclusion:First BD symptoms manifested in the majority of patients before the age of 30 years, with only 10% of patients with BD onset at the age of > 30 years. In more than 50% of all patients aphthous stomatitis was the first manifestation of the disease, and was more common in women. Prognostically unfavorable BD signs were found in 11.6% of patients already at the initial stages of the disease in men. No correlation was found between the age at BD onset and clinical symptoms of the disease in both males and females.Disclosure of Interests:None declared

Download Full-text

Recurrent aphthous stomatitis. Clinical, therapeutic, histopathologic, and hypersensitivity aspects

JAMA ◽

10.1001/jama.196.7.637 ◽

1966 ◽

Vol 196 (7) ◽

pp. 637-644 ◽

Cited By ~ 46

Author(s):

E. A. Graykowski

Keyword(s):

Recurrent Aphthous Stomatitis ◽

Aphthous Stomatitis

Download Full-text

AB1059 A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ANAKINRA IN PATIENTS WITH STILL´S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2822 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1819.2-1820

Author(s):

L. Schanberg ◽

P. Nigrovic ◽

A. Cooper ◽

W. Chatham ◽

S. Akoghlanian ◽

...

Keyword(s):

Early Onset ◽

Disease Onset ◽

Study Drug ◽

Placebo Patient ◽

Controlled Study ◽

Symptom Duration ◽

Newly Diagnosed ◽

Still’S Disease ◽

Research Support ◽

Still's Disease

Background:Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) are rare autoinflammatory disorders associated with an activated IL-1 pathway, characterized by spiking fever, rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. There is a growing understanding that SJIA and AOSD are one disease with different ages of onset, i.e. Still’s disease. The anaSTILLs study (anakinra inStill´sdisease) was designed to further evaluate efficacy and safety of anakinra in patients with Still´s disease across all age groups.Objectives:The primary objective was to demonstrate efficacy of anakinra versus placebo as assessed by ACR30 response with absence of fever at Week 2. Secondary objectives included: early onset of efficacy, sustained efficacy, time to study drug discontinuation, safety, pharmacokinetics, clinical signs and biomarkers.Methods:‘anaSTILLs’ was a randomized, double-blind, placebo-controlled, 12-week study including patients with active and newly diagnosed (6 months) Still´s disease according to adapted ILAR criteria if <16, or Yamaguchi criteria, if ≥16 years of age at disease onset. Patients were randomized to anakinra 2 mg/kg (max 100 mg/day), 4 mg/kg (max 200 mg/day) or placebo.Results:12 patients were randomized and received study drug: 6 anakinra (2 mg/kg n=2, 4 mg/kg n=4) and 6 placebo, the study was terminated early due to slow recruitment. 1 patient on placebo had lymphoma, not Still’s disease, and was excluded; thus in total 11 patients were analyzed for efficacy, 8 were children [median (range) age=4.0 (1-11) years] and 3 were adults [median (range) age=32.0 (25-51) years]. 55% were male and the mean symptom duration was 74.2 days. All patients on anakinra but none on placebo achieved ACR30 response with absence of fever at Week 2 (p-value=0.0022). The efficacy of anakinra was further demonstrated by superiority to placebo in ACR50/70/90 responses with absence of fever at Week 2. All placebo patients discontinued the study within 6 weeks, 2 due to progressive disease, 2 due to lack of efficacy and 1 due to withdrawal by patient. There was a numerically higher proportion with early onset of efficacy (Week 1) in the anakinra group compared to placebo. The ACR30/50/70/90 responses in the anakinra group were sustained throughout the study period. Patients in the anakinra group had a prompt and persistent decrease in CRP and ferritin levels at Week 1, which was not observed in the placebo group. There were no unexpected safety findings. All anakinra patients developed anti-drug antibodies (ADAs) at some timepoint during the study. ADAs were persistent throughout the treatment period, except in one patient. Titers were low to moderate. One placebo patient had low ADA titers at one occasion. No neutralizing antibodies were observed and the ADAs did not appear to impact clinical efficacy or safety.Conclusion:Anakinra is superior to placebo in the treatment of Still’s disease. ADAs occur frequently but do not appear to adversely impact efficacy or safety. These results confirm the benefits of anakinra treatment in patients with active, newly diagnosed Still´s disease across ages.Disclosure of Interests:Laura Schanberg Grant/research support from: Sobi, BMS, Consultant of: Aurinia, UCB, Sanofi, Peter Nigrovic Grant/research support from: Novartis, BMS, Pfizer, Consultant of: Novartis, BMS, Pfizer, Sobi, Miach Orthopedics, Simcere, XBiotech, Quench Bio, Ashley Cooper: None declared, Winn Chatham Grant/research support from: Sobi, Consultant of: Sobi, Shoghik Akoghlanian: None declared, Namrata Singh: None declared, Egla Rabinovich Grant/research support from: AbbVie, UCB Pharma, Janssen Research & Development, Akaluck Thatayatikom: None declared, Alysha Taxter: None declared, Jonathan Hausmann Consultant of: Novartis, Milan Zdravkovic Shareholder of: Sobi, Employee of: Sobi, Sven Ohlman Shareholder of: Sobi, Employee of: Former employee of Sobi, Henrik Andersson Employee of: Sobi, Susanna Cederholm Shareholder of: Sobi, Employee of: Sobi, Margareta Wikén Shareholder of: Sobi, Employee of: Former employee of Sobi, Rayfel Schneider Grant/research support from: Roche, Novartis, Sobi, Pfizer, Consultant of: Sobi, Novartis, Novimmune, Fabrizio De Benedetti Grant/research support from: AbbVie, Pfizer, Novartis, Novimmune, Sobi, Sanofi, Roche, Speakers bureau: AbbVie, Novartis, Roche, Sobi

Download Full-text

Adult systemic lupus erythematosus in Egypt: The nation-wide spectrum of 3661 patients and world-wide standpoint

Lupus ◽

10.1177/09612033211014253 ◽

2021 ◽

pp. 096120332110142

Author(s):

Tamer A Gheita ◽

Rasha Abdel Noor ◽

Esam Abualfadl ◽

Osama S Abousehly ◽

Iman I El-Gazzar ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Age Of Onset ◽

Wide Spectrum ◽

Age At Onset ◽

Disease Onset ◽

Clinical Manifestations ◽

Population Based ◽

Systemic Lupus ◽

Cross Sectional

Objective The aim of this study was to present the epidemiology, clinical manifestations and treatment pattern of systemic lupus erythematosus (SLE) in Egyptian patients over the country and compare the findings to large cohorts worldwide. Objectives were extended to focus on the age at onset and gender driven influence on the disease characteristics. Patients and method This population-based, multicenter, cross-sectional study included 3661 adult SLE patients from Egyptian rheumatology departments across the nation. Demographic, clinical, and therapeutic data were assessed for all patients. Results The study included 3661 patients; 3296 females and 365 males (9.03:1) and the median age was 30 years (17–79 years), disease duration 4 years (0–75 years) while the median age at disease onset was 25 years (4–75 years). The overall estimated prevalence of adult SLE in Egypt was 6.1/100,000 population (1.2/100,000 males and 11.3/100,000 females).There were 316 (8.6%) juvenile-onset (Jo-SLE) and 3345 adult-onset (Ao-SLE). Age at onset was highest in South and lowest in Cairo (p < 0.0001). Conclusion SLE in Egypt had a wide variety of clinical and immunological manifestations, with some similarities with that in other nations and differences within the same country. The clinical characteristics, autoantibodies and comorbidities are comparable between Ao-SLE and Jo-SLE. The frequency of various clinical and immunological manifestations varied between gender. Additional studies are needed to determine the underlying factors contributing to gender and age of onset differences.

Download Full-text

Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽

10.1007/s10048-021-00667-0 ◽

2021 ◽

Author(s):

Chiara Cavestro ◽

Celeste Panteghini ◽

Chiara Reale ◽

Alessia Nasca ◽

Silvia Fenu ◽

...

Keyword(s):

Early Onset ◽

Cerebellar Atrophy ◽

Iron Accumulation ◽

Brain Iron ◽

Causative Gene ◽

Coding Regions ◽

Aberrant Transcript ◽

Pathogenic Variants ◽

Intronic Mutation ◽

Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

Download Full-text

High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107347 ◽

2021 ◽

pp. jmedgenet-2020-107347

Author(s):

D Gareth Evans ◽

Elke Maria van Veen ◽

Helen J Byers ◽

Sarah J Evans ◽

George J Burghel ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Ductal Carcinoma ◽

Cancer Genes ◽

Early Onset Breast Cancer ◽

Younger Women ◽

Pathogenic Variants ◽

Younger Age ◽

Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Download Full-text

Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

BMC Medical Genomics ◽

10.1186/s12920-021-01001-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Beatrice Berti ◽

Giovanna Longo ◽

Francesco Mari ◽

Stefano Doccini ◽

Ilaria Piccolo ◽

...

Keyword(s):

Intellectual Disability ◽

Mitochondrial Dysfunction ◽

Early Onset ◽

Integrated Approach ◽

Compound Heterozygous ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

First Case ◽

Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

Download Full-text

P39 Longitudinal changes of cerebral white matter tissue microstructure in early-onset systemic lupus erythematosus

10.1136/lupus-2020-eurolupus.87 ◽

2020 ◽

Author(s):

Ettore Silvagni ◽

Francesca Inglese ◽

Alessandra Bortoluzzi ◽

Alfredo Revenaz ◽

Massimo Borrelli ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

White Matter ◽

Lupus Erythematosus ◽

Early Onset ◽

Cerebral White Matter ◽

Systemic Lupus ◽

Tissue Microstructure ◽

Longitudinal Changes ◽

Onset Systemic Lupus Erythematosus

Download Full-text

Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽

10.3390/cancers13153857 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3857

Author(s):

Pilar Mur ◽

Nuria Bonifaci ◽

Anna Díez-Villanueva ◽

Elisabet Munté ◽

Maria Henar Alonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Early Onset ◽

Low Risk ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Pathogenic Variants ◽

Predisposing Genes ◽

The Mean ◽

Early Onset Colorectal Cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

Download Full-text