Report and literature review of a familial case of autoinflammatory disease associated with RELA gene variant

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Otorhinolaryngological manifestations of autoinflammatory diseases. Systematic review

To explore the clinical and genetic characteristics of a boy with X-linked familial Behcet-like autoinflammatory syndrome-2 (AIFBL2). A boy who was admitted to Children's Hospital Affiliated to Zhengzhou University in December 2023 due to recurrent oral ulcers for 2 years, intermittent abdominal pain and fever for more than 1 year was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. A literature search was conducted in OMIM, PubMed, Wanfang Data Knowledge Service Platform, China Biomedical Literature Service System, and the VIP database using the keywords "ELF4 gene" "deficiency in ELF4, X-linked" "ELF4 deficiency" and "DEX" to identify recently published studies. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No.: 2023-H-K44). The patient, a 12-year-old male, presented with recurrent mouth ulcers, fever and abdominal pain. Lymphocyte subsets showed a significant decrease in NK cells. Abdominal CT showed thickening of local intestinal wall in the lower right abdomen. Colonoscopy revealed a solitary deep longitudinal ulcer in the ileocecal region. Genetic testing revealed a hemizygote missense variant c.687C>G, with his mother showing the same mutation at this locus. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was considered likely pathogenic (PP1+PP2+PM2_Supporting+PP3+PP4). Literature review has found 19 AIFBL2 patients including 1 patient from this study. Mouth ulcer, fever, rash and abdominal pain were the primary clinical manifestations, for which genetic testing is the main diagnostic method. The hemizygote c.687C>G missense variant of the ELF4 gene probably underlay the AIFBL2 in this child, which has provided a basis for his clinical diagnosis and genetic counseling.

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

Objective: To summarize the clinical phenotype and genetic characteristics of deficiency in ELF4 gene X-linked (DEX). Methods: A case series study was conducted to retrospectively analyze the clinical data and genetic testing results of 2 cases of DEX treated at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and the First Hospital of Jilin University from January 2023 to April 2024. And literature up to April 2024 was searched from the PubMed database, as well as CNKI and Wanfang databases, using keywords such as "ELF4 deficiency" "deficiency in ELF4, X-linked""ELF4 gene". The main clinical manifestations and genotypes of DEX were summarized. Results: Both patients were male, with onset ages of 3 months and 3 years, respectively. Both patients presented with recurrent oral ulcers and abdominal pain. And the laboratory examination showed a significant increase in inflammatory markers. Intestinal examinations showed multiple intestinal ulcers, and both patients developed intestinal fistulas. Whole exome sequencing found ELF4 c.799C>T, p Arg267Trp and ELF4 c. 248-7G>A, both maternal variants. Based on clinical and genetic results, DEX were diagnosed. In terms of treatment, both patients underwent surgical treatment during the acute phase of the disease and received anti-tumor necrosis factor α therapy, but recurrent gastrointestinal symptoms were still observed in Patient 1, while the clinical effect in Patient 2 was still acceptable. However, the inflammatory markers in both patients were not normal even after treatment. Literature review found 18 patients including 2 patients in this study, reported in 5 English articles and no Chinese reports. Thirteen patients had disease onset age before 5. The main clinical manifestations were fever (12/17), oral ulcers (14/18), abdominal pain (8/18), diarrhea (6/18), perianal ulcers (5/17), ileum ulcers (6/16), colon ulcers (7/16), skin involvement (7/17) and recurrent infections (7/18); laboratory examinations found increased erythrocyte sedimentation rate (13/15) as well as C-reactive protein (9/9), and anemia (13/15); in terms of immunological function, there is a decrease in natural killer cells (9/15) as well as a decrease in class switching memory B cells (8/9). The main types of gene variantions were missense variantions (6/18), nonsense variantions (4/18) or frameshift variantions (3/18). Conclusions: DEX should be considered when an early-onset male patient manifested with recurrent fever, oral ulcers or mucosal ulcers, with elevated inflammatory markers, with or without recurrent infection. It is recommended to perform lymphocyte subsets analysis, gastrointestinal endoscopy and genetic testing to support the diagnosis.

Hyper-IgD syndrome (HIDS, OMIM #260920) is a rare autosomal recessive autoinflammatory disorder caused by pathogenic variants in the mevalonate kinase (MVK) gene. HIDS has an incidence of 1:50,000 to 1:5,000, and is thought to be prevalent mainly in northern Europe. Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and high immunoglobulin levels. Using whole exome sequencing (WES) and/or Sanger capillary sequencing, we identified five distinct genetic variants in the MVK gene from nine patients belonging to six families. The variants were classified as pathogenic or likely pathogenic as per the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for annotation of sequence variants. Over 70% of patients in the present study had two recurrent mutations in MVK gene i.e. a nonsynonymous variant p.V377I, popularly known as the 'Dutch mutation', along with a splicing variant c.226+2delT in a compound heterozygous form. Identity by descent analysis in two patients with the recurrent variants identified a 6.7 MB long haplotype suggesting a founder effect in the South Indian population. Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. This has implications in clinical diagnosis, as well as in the development of cost-effective approaches for genetic diagnosis and screening. To our best knowledge, this is the first and most comprehensive case series of clinically and genetically characterized patients with HIDS from India.

Hyper-IgD syndrome (HIDS, OMIM #260920) is a rare autosomal recessive autoinflammatory disorder caused by pathogenic variants in the mevalonate kinase (MVK) gene. HIDS has an incidence of 1:50,000 to 1:5,000, and is thought to be prevalent mainly in northern Europe. Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and high immunoglobulin levels. Using whole exome sequencing (WES) and/or Sanger capillary sequencing, we identified five distinct genetic variants in the MVK gene from nine patients belonging to six families. The variants were classified as pathogenic or likely pathogenic as per the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for annotation of sequence variants. Over 70% of patients in the present study had two recurrent mutations in MVK gene i.e. a nonsynonymous variant p.V377I, popularly known as the ‘Dutch mutation’, along with a splicing variant c.226+2delT in a compound heterozygous form. Identity by descent analysis in two patients with the recurrent variants identified a 6.7 MB long haplotype suggesting a founder effect in the South Indian population. Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. This has implications in clinical diagnosis, as well as in the development of cost-effective approaches for genetic diagnosis and screening. To our best knowledge, this is the first and most comprehensive case series of clinically and genetically characterized patients with HIDS from India.

The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Updated recommendations for CFTR carrier screening: A position statement of the American College of Medical Genetics and Genomics (ACMG)

<p><strong>Introducción: </strong>Las aftas y ulceraciones bucales constituyen un motivo frecuente de consulta al estomatólogo. El afta es una forma particular de ulceración bucal. la aftosis se define por el carácter recidivante de aftas múltiples que evolucionan por episodios de 3-10 días y se repiten por lo menos dos veces al año.</p> <p><strong>Objetivo:</strong> Abordar los principales aspectos de la Enfermedad de Behçet que podrían ser útiles al estomatólogo.</p> <p><strong>Desarrollo:</strong> La enfermedad de Behçet es una vasculitis sistémica inmunomediada caracterizada por una triada característica de lesiones oculares, úlceras orales y genitales recurrentes. La aftosis bucal y la enfermedad de Behçet parecen deberse al mismo mecanismo patogénico, pero aún falta por encontrar las razones por las cuáles la primera se limita a la cavidad bucal y la segunda es sistémica. Debido a que las úlceras orales recurrentes se encuentran en de igual forma en esta enfermedad y la EB, debe considerarse como diagnóstico diferencial de EB.</p> <p><strong>Conclusiones:</strong> El papel de los estomatólogos es importante para establecer el diagnóstico de Enfermedad de Behçet, ya que podrían ser los primeros en detectarla. Las úlceras orales recurrentes son un síntoma inicial común de EB. Se requiere un enfoque multidisciplinario para diagnosticar y tratar la enfermedad.</p> <p> </p> <p><strong>Palabras clave: </strong>Enfermedad de Behçet; Úlceras orales; Estomatitis aftosa.</p> <p> </p> <p><strong>ABSTRACT</strong></p> <p><strong>Introduction: </strong>Aphthae and oral ulcers are a frequent reason for consulting the stomatologist. Aphthous are a particular form of oral ulceration. Aphtosis is defined by the recurrent nature of multiple aphthae that progress through episodes of 3-10 days and are repeated at least twice a year.</p> <p><strong>Objective: </strong>To describe the main aspects of the Behçet disease that could be useful to the stomatologist.</p> <p><strong>Development: </strong>Behçet's disease is an immune-mediated systemic vasculitis characterized by a characteristic triad of ocular lesions, recurrent oral and genital ulcers. Oral aphtosis and Behçet's disease seem to be due to the same pathogenic mechanism, but we still have to find the reasons why the former is limited to the oral cavity and the latter is systemic. Because recurrent oral ulcers are found in the same way in this disease and EB, it should be considered as a differential diagnosis of EB.</p> <p><strong>Conclusions: </strong>The role of stomatologists is important to establish the diagnosis of Behçet's disease, since they could be the first to detect it. Recurrent oral ulcers are a common initial symptom of EB. A multidisciplinary approach is required to diagnose and treat the disease.</p> <p><strong>Keywords: </strong>Behçet's disease; Oral ulcers, aphthous stomatitis.</p>

Recurrent Oral Ulcers: current and future therapeutic approaches

Does the law require reinterpretation and return of revised genomic results?

DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)

In oral medicine, colchicine is a therapeutic alternative for idiopathic recurrent aphthous stomatitis (RAS), Behçet disease (BD), periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, and mouth and genitals ulcers with inflamed cartilage (MAGIC) syndrome. The present review aims to evaluate reliability of colchicine against recurrent oral ulcers. A systematic review was conducted, with the following PICO (Patient, Intervention, Control, Outcome) question: "In populations with idiopathic or secondary recurrent oral ulcers, is colchicine more effective in improving pain and accelerating healing, compared to other intervention or placebo?" Seven RCTs and 3 OCTs were considered eligible. Four RCTs focused on BD, two RCTs and three OCTs on RAS, and one RCT on PFAPA syndrome. Heterogeneity between RCTs prevented from meta-analysis. Regarding BD, no significant difference between colchicine and placebo was found in two of three placebo-controlled RCTs, whereas the third RCT showed benefit. A comparative RCT found ciclosporin more effective than colchicine for oral lesions of BD. One open-label RCT showed promising but partial results on colchicine in reducing PFAPA attacks, when compared to corticosteroids. Concerning RAS, colchicine appeared less effective than clofazimine, thalidomide and dapsone, and with outcomes similar to low-dosage corticosteroids but higher gastric discomfort than prednisolone. One OCT reported positive results compared with no treatment but a RCT found no difference with placebo. Role of colchicine as treatment for idiopathic or secondary recurrent oral ulcers is still controversial. Further standardized RCTs and crossover trials are needed.