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.

A Nationwide Study of GATA2 Deficiency in Italy Reveals Novel Symptoms and Genotype-phenotype Association.

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency.

Extensive dental caries and periodontal disease in a child with GATA2 deficiency.

Background: GATA2 deficiency is an inborn error of immunity (IEI) characterized by infectious susceptibility and increased risk of myelodysplasia leading to acute myeloid leukaemia (AML). Oral anomalies already described in this disorder include recurrent viral and fungal infections and oral ulcers.

Material And Methods: We report a 9-year-old girl presenting with AML with myelodysplasia-related changes, monosomy 7 karyotype on marrow aspirate, numerous flat warts on her hands and multiple dental caries at oral cavity inspection.

Unbalanced serum immunoglobulins in clinical subtypes of pediatric tuberculosis disease.

Immune response to tuberculosis (TB) has been extensively studied in the past decades and classically involves cellular immunity. However, evidence suggests that humoral immunity may play a relevant role. Past studies regarding serum immunoglobulin (Ig) levels in TB are dated and only involve adult subjects.

STAT3-confusion-of-function: Beyond the loss and gain dualism.

Background: Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant.

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy.

IL-2 Signaling Axis Defects: How Many Faces?

CD25, Signal transducer and activator of transcription 5B (STAT5B) and Forkhead box P3 (FOXP3) are critical mediators of Interleukin-2 (IL-2) signaling pathway in regulatory T cells (Tregs). CD25 (i.e.

Atypical Presentations of IPEX: Expect the Unexpected.

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema.

Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders.

Purpose Of Review: To describe primary immunodeficiencies caused by gain-of-function (GOF) mutations of signal transducer and activator of transcription (STAT) genes, a group of genetically determined disorders characterized by susceptibility to infections and, in many cases, autoimmune manifestations.

Recent Findings: GOF mutations affecting STAT1 result in increased STAT tyrosine phosphorylation and secondarily increased response to STAT1-signaling cytokines, such as interferons. In contrast, STAT3 hyperactivity is not usually related to hyperphosphorylation but rather to increased STAT3-mediated transcriptional activity.