Clinical Spectrum of Ras-Associated Autoimmune Leukoproliferative Disorder (RALD).

Ras-associated autoimmune leukoproliferative disorder (RALD) is a clinical entity initially identified in patients evaluated for an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. It remains a matter of debate whether RALD is a chronic and benign lymphoproliferative disorder or a pre-malignant condition. We report the case of a 7-year-old girl diagnosed with RALD due to somatic KRAS mutation who progressed to a juvenile myelomonocytic leukemia phenotype and finally evolved into acute myeloid leukemia. The case report prompted a literature review by a search for all RALD cases published in PubMed and Embase. We identified 27 patients with RALD. The male-to-female ratio was 1:1 and median age at disease onset was 2 years (range 3 months-36 years). Sixteen patients (59%) harbored somatic mutations in KRAS and 11 patients (41%) somatic mutations in NRAS. The most common features were splenomegaly (26/27 patients), autoimmune cytopenia (15/16 patients), monocytosis (18/24 patients), pericarditis (6 patients), and skin involvement (4 patients). Two patients went on to develop a hematopoietic malignancy. In summary, the current case documents an additional warning about the long-term risk of malignancy in RALD.

A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand Functions.

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies. The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The recognition of these genetic diseases brought new information on the role of this apoptotic pathway in controlling the adaptive immune response in humans.

Autoimmune and Lymphoproliferative Complications of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is frequently complicated by the development of autoimmune and lymphoproliferative diseases. With widespread use of immunoglobulin replacement therapy, autoimmune and lymphoproliferative complications have replaced infection as the major cause of morbidity and mortality in CVID patients. Certain CVID complications, such as bronchiectasis, are likely to be the result of immunodeficiency and are associated with infection susceptibility. However, other complications may result from immune dysregulation rather than immunocompromise. CVID patients develop autoimmunity, lymphoproliferation, and granulomas in association with distinct immunological abnormalities. Mutations in transmembrane activator and CAML interactor, reduction of isotype-switched memory B cells, expansion of CD21 low B cells, heightened interferon signature expression, and retained B cell function are all associated with both autoimmunity and lymphoproliferation in CVID. Further research aimed to better understand that the pathological mechanisms of these shared forms of immune dysregulation may inspire therapies beneficial for multiple CVID complications.

Strict 3' splice site sequence requirements for U2 snRNP recruitment after U2AF binding underlie a genetic defect leading to autoimmune disease.

We report that the 3' splice site associated with the alternatively spliced exon 6 of the Fas receptor CD95 displays strict sequence requirements and that a mutation that disrupts this particular sequence arrangement leads to constitutive exon 6 skipping in a patient suffering from autoimmune lymphoproliferative syndrome (ALPS). Specifically, we find an absolute requirement for RCAG/G at the 3' splice site (where R represents purine, and / indicates the intron/exon boundary) and the balance between exon inclusion and skipping is exquisitely sensitive to single nucleotide variations in the uridine content of the upstream polypyrimidine (Py)-tract. Biochemical experiments revealed that the ALPS patient mutation reduces U2 snRNP recruitment to the 3' splice site region and that this effect cannot be explained by decreased interaction with the U2 snRNP Auxiliary Factor U2AF, whose 65- and 35-kDa subunits recognize the Py-tract and 3' splice site AG, respectively. The effect of the mutation, which generates a tandem of two consecutive AG dinucleotides at the 3' splice site, can be suppressed by increasing the distance between the AGs, mutating the natural 3' splice site AG or increasing the uridine content of the Py-tract at a position distal from the 3' splice site. The suppressive effects of these additional mutations correlate with increased recruitment of U2 snRNP but not with U2AF binding, again suggesting that the strict architecture of Fas intron 5 3' splice site region is tuned to regulate alternative exon inclusion through modulation of U2 snRNP assembly after U2AF binding.

EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency.

Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.

Autoimmune Lymphoproliferative Syndrome-FAS Patients Have an Abnormal Regulatory T Cell (Treg) Phenotype but Display Normal Natural Treg-Suppressive Function on T Cell Proliferation.

Objective: Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS. Results: The proportion of CD25highCD127low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3+CD4+ T cells from ALPS patients and thus an abnormally low proportion of CD25highFOXP3+ Helios+ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3lowCD45RA+) and an unusual subpopulation (CD4+CD127lowCD15s+CD45RA+). Despite this abnormal phenotype, the CD25highCD127low Tregs' suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression. Conclusion: An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.

Updated Understanding of Autoimmune Lymphoproliferative Syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS), a disorder characterized by immune dysregulation due to disrupted lymphocyte homeostasis, is mainly resulted from the mutations in FAS-mediated apoptotic pathway. In addition, other mutations of the genes such as Fas-ligand (FASLG), Caspase 10 (CASP10) and Caspase 8 (CASP8), NRAS and KRAS have also been observed in a small number of patients with ALPS or ALPS-related disorders. However, approximately 20-30% of patients with ALPS have unidentified defect. Its clinical manifestations observed in multiple family members include unexplained lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias such as thrombocytopenia, neutropenia, and anemia due to excessive production of antibodies by lymphocytes, elevated number of double-negative T (DNT) cells, and increased risk of lymphoma. As a very rare disease, ALPS was first characterized in the early 1990s. More than 300 families with hereditary ALPS have been reported till now; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years. ALPS has historically considered as a primary immune defect presenting in early childhood, however, recent studies have shown that it may be more common than previous thought because adult onset presentation is increasingly becoming recognized and more adult ALPS patients are diagnosed. The new genetic and biological insights have improved the understanding of ALPS and a number of targeted therapeutic strategies such as mycophenolate mofetil, sirolimus, and pentostatin have been successfully applied in ALPS patients with promising treatment efficacy. This article comprehensively reviews the clinical and laboratory manifestations, new research advances in the molecular pathogenesis, diagnosis and treatments of this disorder.

Síndrome linfoproliferativo postrasplante con compromiso cerebral: reporte de un caso / Post-transplantation lymphoproliferative disorder with brain involvement: a case report

Abstract. Post-transplantation lymphoproliferative disorder is a low incidence complication of transplant recipient patients. However, mortality is high if the diagnosis and management are not appropriate. For this reason the radiologist should be aware when dealing with images of these patients, particularly in the first year following the transplantation. In this article the case is presented of a woman who was recipient of a kidney, and developed post-transplantation lymphoproliferative disorder, affecting the central nervous system.

Resumen. El síndrome linfoproliferativo postrasplante es una complicación que se presenta con una baja incidencia en los pacientes que han sido trasplantados. Sin embargo, si el diagnóstico y manejo no son oportunos su mortalidad es alta. Por esta razón el radiólogo debe estar atento al diagnóstico al interpretar estudios de este tipo de pacientes, especialmente en el año siguiente al trasplante. Presentamos el caso de una paciente con antecedente de trasplante renal y síndrome linfoproliferativo postrasplante con afección del sistema nervioso central.

Primary immunodeficiencies (PIDs) presenting with cytopenias.

Autoimmune manifestations are increasingly being recognized as a component of several forms of primary immunodeficiencies (PID). Defects in purging of self-reactive T and B cells, impaired Fas-mediated apoptosis, abnormalities in development and/or function of regulatory T cells, and persistence of immune activation as a result of inability to clear infections have been shown to account for this association. Among autoimmune manifestations in patients with PID, cytopenias are particularly common. Up to 80% of patients with autoimmune lymphoproliferative syndrome (ALPS) have autoantibodies, and autoimmune hemolytic anemia and immune thrombocytopenia have been reported in 23% and 51% of ALPS patients, and may even mark the onset of the disease. ALPS-associated cytopenias are often refractory to conventional treatment and represent a therapeutic challenge. Autoimmune manifestations occur in 22% to 48% of patients with common variable immunodeficiencies (CVIDs), and are more frequent among CVID patients with splenomegaly and granulomatous disease. Finally, autoimmune cytopenias have been reported also in patients with combined immunodeficiency. In particular, autoimmune hemolytic anemia is very common among infants with nucleoside phosphorylase deficiency. While immune suppression may be beneficial in these cases, full resolution of the autoimmune manifestations ultimately depends on immune reconstitution, which is typically provided by hematopoietic cell transplantation.