Expanding the spectrum of IPEX: from new clinical findings to novel treatments.

Purpose Of Review: This review aims to provide an overview of recent research findings regarding immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, focusing on clinical and immunological novelties, as well as emerging treatment strategies, based on the published literature of the last few years.

Recent Findings: While it is well known that IPEX can present with a wide range of atypical clinical manifestations, new and unique phenotypes continue to emerge, making it essential to maintain a high level of clinical suspicion both at the time of diagnosis and during follow-up. This unpredictability in clinical presentation is further compounded by the lack of a clear genotype-phenotype correlation.

Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH.

Refractory Thrombocytopenia is the Earliest Diagnostic Criterion for Sinusoidal Obstruction Syndrome in Children.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), whose diagnostic criteria changed over time to achieve a timelier diagnosis. Recently, pediatric-specific criteria presented by the European Society for Blood and Marrow Transplantation (pEBMT) incorporated transfusion-refractory thrombocytopenia (RT) as an early indicator of SOS in children. However, a comparison of all individual diagnostic parameters belonging to pEBMT and former SOS diagnostic criteria has never been performed.