Autoimmunity Including Intestinal Behçet Disease Bearing the <i>KRAS</i> Mutation in Lymphocytes: A Case Report

Moritake, Hiroshi; Takagi, Motoki; Kinoshita, Mariko; Ohara, Osamu; Yamamoto, Shojiro; Moriguchi, Sayaka; Nunoi, Hiroyuki

doi:10.1542/peds.2015-2891

Cited by 11 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Autoimmune diseases are well reported in children with Noonan syndrome, 43 as well as in patients with sporadic JMML. 44,45 Furthermore, somatic mutations in KRAS and NRAS are the cause of RALS (Ras-associated lymphoproliferative syndrome), [46][47][48] an entity characterized by severe autoinflammatory manifestations without evidence of malignancy. Of note, the only pediatric case of MDS with IM reported to be tested for somatic mutations also demonstrated a PTPN11 mutation, while another patient had a clinical diagnosis of NF1, another member of the Ras pathway diseases (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

Yanir

Krauss

Stein

et al. 2021

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Background Inflammatory manifestations (IM) are well described in adult patients with myelodysplastic syndrome (MDS), but the presentation is highly variable and no standardized treatment exists. This phenomenon is rarely reported in children. As more pediatric patients are hematopoietic stem cell transplantation (HSCT) candidates, the role of anti‐inflammatory treatment in relation to HSCT should be defined. Procedure Here, we report a series of five children from a tertiary center. We describe the clinical presentation, molecular findings, and treatment options. Results All patients presented with advanced MDS with blast percentages ranging 10–30%, all had severe IM. One patient had MDS secondary to severe congenital neutropenia, the other four patients had presumably primary MDS. All four were found to harbor a PTPN11 gene driver mutation, which is found in 35% of cases of juvenile myelomonocytic leukemia (JMML). The mutation was present in the myeloid lineage but not in T lymphocytes. Three had symptoms of Behcet's‐like disease with trisomy 8 in their bone marrow. All patients were treated with anti‐inflammatory medications (mainly systemic steroids) in an attempt to bring them to allogeneic HSCT in a better clinical condition. All demonstrated clinical improvement as well as regression in their MDS status post anti‐inflammatory treatment. All have recovered from both MDS and their inflammatory symptoms post HSCT. Conclusion Primary pediatric MDS with IM is driven in some cases by PTPN11 mutations, and might be on the clinical spectrum of JMML. Anti‐inflammatory treatment may reverse MDS progression and improve the outcome of subsequent HSCT.

show abstract

Section: Discussionmentioning

confidence: 99%

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

Yanir

Krauss

Stein

et al. 2021

Pediatric Blood & Cancer

View full text Add to dashboard Cite

show abstract

“…More rarely, somatic mosaicism has been reported to associate with a combination of autoimmune diseases. For example, a KRAS mutation was detected in T and B lymphocytes but not in natural killer cells of a patient with multiple autoimmunity, including thrombocytopenia, recurrent Henoch-Schonlein purpura and intestinal Behçet disease [ 62 ]. Further analyses are required to determine whether rare genetic variations such as rDELs and somatic mosaicism have significant additional value to SNPs in missing heritability of autoimmune diseases or if their effects are negligible.…”

Section: The Role Of Complex Loci At Genetic Levelmentioning

confidence: 99%

Unravelling the Roles of Susceptibility Loci for Autoimmune Diseases in the Post-GWAS Era

Gillespie

Rodriguez

2018

Genes

View full text Add to dashboard Cite

Although genome-wide association studies (GWAS) have identified several hundred loci associated with autoimmune diseases, their mechanistic insights are still poorly understood. The human genome is more complex than single nucleotide polymorphisms (SNPs) that are interrogated by GWAS arrays. Apart from SNPs, it also comprises genetic variations such as insertions-deletions, copy number variations, and somatic mosaicism. Although previous studies suggest that common copy number variations do not play a major role in autoimmune disease risk, it is possible that certain rare genetic variations with large effect sizes are relevant to autoimmunity. In addition, other layers of regulations such as gene-gene interactions, epigenetic-determinants, gene and environmental interactions also contribute to the heritability of autoimmune diseases. This review focuses on discussing why studying these elements may allow us to gain a more comprehensive understanding of the aetiology of complex autoimmune traits.

show abstract

“…RALD patients exhibit ALPS- and/or juvenile myelomonocytic leukemia-like symptoms, including autoimmune cytopenia, lymphadenopathy, and hepatosplenomegaly ( Niemela et al., 2011 , Shiota et al., 2015 , Takagi et al., 2011 ). Moreover, a RALD patient exhibiting intestinal Behcet's disease-like phenotypes was reported ( Moritake et al., 2016 ). In RALD, individual patients have clones with KRAS or NRAS mutation and wild-type clones together in hematopoietic lineage cells in a mosaic state, allowing the generation of a set of isogenic induced pluripotent stem cell (iPSC) clones from the same patients.…”

Section: Introductionmentioning

confidence: 99%

Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity

et al. 2018

Self Cite

View full text Add to dashboard Cite

SummaryOncogenic KRAS mutations in hematopoietic stem cells cause RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). KRAS plays essential roles in stemness maintenance in some types of stem cells. However, its roles in pluripotent stem cells (PSCs) are poorly understood. Here, we investigated the roles of KRAS on stemness in the context of induced PSCs (iPSCs). We used KRAS mutant (G13C/WT) and wild-type isogenic (WT/WT) iPSCs from the same RALD patients, as well as wild-type (WTed/WT) and heterozygous knockout (Δed/WT) iPSCs, both obtained by genome editing from the same G13C/WT clone. Compared with WT iPSCs, G13C/WT iPSCs displayed enforced retention of self-renewal and suppressed capacity for neuronal differentiation, while Δed/WT iPSCs showed normalized cellular characteristics similar to those of isogenic WTed/WT cells. The KRAS-ERK pathway, but not the KRAS-PI3K pathway, was shown to govern these G13C/WT-specific phenotypes, indicating the strong impact of the KRAS-ERK signaling upon self-renewal and differentiation propensity in human iPSCs.

show abstract

Autoimmunity Including Intestinal Behçet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report

Cited by 11 publications

References 18 publications

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

Pediatric myelodysplastic syndrome with inflammatory manifestations: Diagnosis, genetics, treatment, and outcome

Unravelling the Roles of Susceptibility Loci for Autoimmune Diseases in the Post-GWAS Era

Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity

Contact Info

Product

Resources

About