Autoimmune Lymphoproliferative Syndrome Research Articles

Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

Looking for ALPS: The value of a combined assessment of biochemical markers.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus. We conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte-Justine Hospital over 10 years. Patients were screened using the combination of TCRαβ+ CD4- CD8- "double negative" (DN) T cells and soluble plasmatic FAS ligand (sFASL). Among the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαβ+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low. sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis.

Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

Probable Autoimmune Lymphoproliferative Syndrome with Monogenic Lupus Due to KRAS Mutation.

Autoimmune lymphoproliferative syndrome (ALPS) is a disease characterized by dysfunction of the T lymphocyte  apoptotic pathways, mostly due to dysfunctional FAS mediated signaling. However few cases can also occur independent of FAS pathway alteration. ALPS is characterized by various immuno-hematological manifestations. Monogenic lupus is an evolving entity, which describes the etiologic role of single gene modulation in systemic lupus erythematosus. In this manuscript, we describe a case of probable ALPS with monogenic lupus caused by a novel mutation in the KRAS gene.

Collage of cases and brief review of the laboratory diagnosis and molecular testing in autoimmune haemolytic anaemia.

Autoimmune haemolytic anaemia (AIHA) is an acquired heterogenous clinical entity with variable presentations like acute haemolysis or mild, chronic haemolysis compounded with acute exacerbation in winters or fatal uncompensated haemolysis. A step-wise approach to the diagnosis and characterisation of AIHA should be undertaken, firstly the diagnosis of haemolysis followed by the establishment of immune nature with the aid of direct agglutination tests (DAT). Simultaneously the other causes of immune haemolysis need to be excluded too. In light of advancements in diagnostics, a wide array of investigations can be used like absolute reticulocyte count, bone marrow responsiveness index to establish the evidence of haemolysis, sensitive gel technology, enhanced DAT assays, e.g., modified DAT with low ionic strength saline solution (LISS) at 4°C, DAT assays utilizing reagents such as anti-IgA and anti-IgM and DAT by flowcytometry, to detect RBC bound autoantibodies (Abs) and monospecific DAT to establish immune causes of haemolysis and characterisation of the autoantibodies. The compensatory role of bone marrow and synchronous pathologies like clonal lymphoproliferation, dyserythropoiesis, fibrosis are important factors in the evolution of the disease and aid in the customisation of treatment modalities. The laboratory work up should aim to diagnose underlying diseases like chronic lymphoproliferative disorders, autoimmune disorders and infectious diseases. Also, tests like autoimmune lymphoproliferative syndromes (ALPS) screening panel and Next-generation sequencing (NGS) panel for RBC membrane disorders, RBC enzymopathies, and congenital dyserythropoietic aneamia have found their place. It is incumbent upon the clinicians to use the all-available diagnostic modalities for the accurate diagnosis, prognostication and customisation of the therapy.

Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

Double-Negative T (DNT) Cells in Patients with Systemic Lupus Erythematosus.

Double-negative T (DNT) cells are a rare and unconventional T-lymphocyte subpopulation lacking both CD4 and CD8 markers. Their immunopathological roles and clinical relevance have yet to be elucidated. Beyond autoimmune lymphoproliferative syndrome (ALPS), these cells may also play a role in rheumatic disorders, including systemic lupus erythematosus (SLE); indeed, these two diseases share several autoimmune manifestations (including nephritis). Moreover, one of the main experimental murine models used to investigate lupus, namely the MRL/lpr mouse, is characterized by an expansion of DNT cells, which can support the production of pathogenic autoantibodies and/or modulate the immune response in this context. However, lupus murine models are not completely consistent with their human SLE counterpart, of course. In this mini review, we summarize and analyze the most relevant clinical studies investigating the DNT cell population in SLE patients. Overall, based on the present literature review and analysis, DNT cell homeostasis seems to be altered in patients with SLE. Indeed, most of the available clinical studies (which include both adults and children) reported an increased DNT cell percentage in SLE patients, especially during the active phases, even though no clear correlation with disease activity and/or inflammatory parameters has been clearly established. Well-designed, standardized, and longitudinal clinical studies focused on DNT cell population are needed, in order to further elucidate the actual contribution of these cells in SLE pathogenesis and their interactions with other immune cells (also implicated and/or altered in SLE, such as basophils), and clarify whether their expansion and/or immunophenotypic aspects may have any immunopathological relevance (and, then, represent potential disease markers and, in perspective, even therapeutic targets) or are just an unspecific epiphenomenon of autoimmunity.

Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing

BackgroundElevated TCRαβ+CD4-CD8- double-negative T-cells (DNT) and serum biomarkers help identifying FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified upon standard exon sequencing (ALPS-undetermined: ALPS-U). ObjectiveWe aimed to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. MethodsGenetic analysis included whole FAS gene sequencing, copy number variation analysis and sequencing of FAS cDNA and other FAS pathway related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss-of-heterozygosity (sLOH). ResultsNine of 16 ALPS-U patients lacked FAS expression on CD57+DNT predicting heterozygous “loss of expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7/9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT, one patient showed a FAS exon duplication. Three patients had reduced FAS expression, two of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the four ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. ConclusionA combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. Clinical implicationDetection of complex FAS pathway gene alterations by extended genetic analysis allows targeted therapy with sirolimus.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME: A CASE REPORT

Autoimmunelymphoproliferative syndrome (ALPS), a rare geneticdisorder, is a non-malignant, non-infectiouslymphoproliferationthatalters immune system homeostasis by altering FAS-mediated lymphocyte apoptosis. In the past few years, the diagnosis of ALPS wasalwaysconfusedwithotheridiopathicautoimmune pathologies such as Evans syndrome (which combines autoimmunehemolyticanemia and idiopathicthrombocytosis), histyocytosis or systemic lupus erythematosus. In this article, wepresenta case of a childaged 2 years and 7 months, whopresentedwithprolongedfeverassociatedwith a tumor syndrome consisting of polyadenopathy, hepatomegaly, splenomegaly and recurrentcytopenia. Aftereliminatingother diagnoses, the diagnosis of autoimmunelymphoproliferative syndrome wasretained by the demonstration of the FAS mutation on geneticstudy.

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer.

Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.

Phenotypic Variability in PRKCD: a Review of the Literature.

Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. Literature review was performed using MEDLINE. Twenty cases have been described in the literature with significant heterogeneity. The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated. We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent. We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells. We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations. The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

Guardians of Immunity: Advances in Primary Immunodeficiency Disorders and Management.

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of genetic conditions profoundly impacting immune function. The investigation spans various PID categories, offering insights into their distinct pathogenic mechanisms and clinical manifestations. Within the adaptive immune system, B-cell, T-cell, and combined immunodeficiencies are dissected, emphasizing their critical roles in orchestrating effective immune responses. In the realm of the innate immune system, focus is directed towardphagocytes and complement deficiencies, underscoring the pivotal roles of these components in initial defense against infections. Furthermore, the review delves into disorders of immune dysregulation, encompassing hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX), and autoimmunity polyendocrinopathy candidiasis-ectodermal dystrophy(APECED), elucidating the intricate interplay between immune tolerance and autoimmunity prevention. Diagnostic strategies for PIDs are explored, highlighting advancements in genetic and molecular techniques that enable precise identification of underlying genetic mutations and alterations in immune function. We have also outlined treatment modalities for PIDs, which often entail a multidisciplinary approach involving immunoglobulin replacement, antimicrobial prophylaxis, and, in select cases, hematopoietic stem cell transplantation. Emerging therapies, including gene therapy, hold promise for targeted interventions. In essence, this review encapsulates the complexity of PIDs, emphasizing the critical importance of early diagnosis and tailored therapeutic interventions. As research advances, a clearer understanding of these disorders emerges, fostering optimism for enhanced patient care and management in the future.

An Approach to Nodal T- and NK-Cell Lymphomas—A Systemic Review

AbstractT-cell lymphomas are rare neoplasms that have complex pathology. The multiparameter approach has been recommended by World Health Organization (WHO) for the classification of T-cell lymphomas taking into account morphology, immunophenotype, genetics, and clinical features. This also includes division established on the possible cell-of-origin (COO) from T regulatory or T-follicular helper (TFH) cells. The recent WHO-HAEM5 has classified entities as precursor T-lymphoblastic neoplasms, mature T-cell neoplasms, Epstein-Barr virus (EBV)-related T- and NK/T-cell lymphomas, and tumor-like lesions with T-cells predominance. Distinct entities have been recognized within the anaplastic large cell lymphoma (ALCL) family founded on the status of anaplastic lymphoma kinase (ALK) gene rearrangement: ALK-positive and molecularly heterogeneous ALK-negative. The family of lymphomas arising from TFH cells consists of three distinct nodal TFH cell lymphoma entities: angioimmunoblastic-type, follicular-type, and not otherwise specified. These three entities show significant clinical and immunophenotypic overlap. The cases that do not qualify for ALCL or nodal TFH cell lymphomas are labelled as peripheral T-cell lymphomas-not otherwise specified after ruling out nodal EBV-positive T- and NK- cell lymphoma. The new category termed tumor-like lesions with T cell predominance has a high chance to be misdiagnosed as lymphoma. This category includes entities such as Kikuchi-Fujimoto disease, indolent T-lymphoblastic proliferation, and autoimmune lymphoproliferative syndrome. For pathologists, diagnosing nodal T-cell lymphomas may be thought-provoking due to their broad histopathologic spectrum that mimics reactive as well as other neoplastic processes. This review provides a comprehensive diagnostic criterion of the most commonly encountered nodal T-cell and NK cell lymphomas in day-to-day training and an algorithmic approach.

Autoimmune lymphoproliferative syndrome (ALPS) due to a novel dominant negative germline mutation in the FAS gene.

Autoimmune lymphoproliferative syndrome (ALPS) due to a novel dominant negative germline mutation in the FAS gene.

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p=.034) and slowed lymphocyte engraftment (r=.290; p=.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p=.021 and p=.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR=.204, p=.022). The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Caspase-8 deficiency-a rare cause of immune dysregulation – First case report from India

A 3½-year-old boy presented with generalized lymphadenopathy since 1 year of age. After 5 months of age, he had multiple infections and two episodes of pneumonia. At 2½ years, he developed chronic diarrhea. Colonoscopy showed ileal ulcers and inflammatory pan colitis with skip areas and histopathologic examination showed mild chronic ileitis, villous shortening, and diffused active colitis. Next-generation sequencing revealed a previously reported homozygous missense mutation Caspase-8. Unlike autoimmune lymphoproliferative syndrome, Caspase-8 deficiency states have immunodeficiency, autoimmunity, and early-onset inflammatory bowel disease in addition to lymphoproliferation. Early diagnosis aided by molecular confirmation is essential as haploidentical hematopoietic stem cell transplant is curative.

ALPS Diagnosis: Different Phenotype in Child and Mother

Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to malignancy. We present two cases: mother and son with different phenotype at onset.A 7-year-old child presented with anemia, thrombocytopenia and splenomegaly. In his family history: born from non-consanguineous parents, his mother had a splenectomy due to hemolytic anemia of unknown cause. In the child, initial differential diagnosis ruled out infection or malignancy. Bone marrow aspirate had erythroid hyperplasia, giant metamyelocytes and bands and low thrombopoyesis. His immunological evaluation had hypergammaglobulinemia, elevated TCRαβ+-DNT cells (10%). ALPS was suspected and he started Prednisolone and Mycophenolate.A mutation in FAS gene was identified (exon 9, c.785T > A, p.Ile262Asn). His mother, a 45-year-old female presented with a history of lymphadenopathy. In her past medical history, she had hemolytic anemia and splenomegaly, a splenectomy was performed and the anemia resolved. Initial evaluation was started because breast cancer was suspected. Lymph node biopsy was performed where malignancy was ruled out, but unspecific inflammatory infiltrate was found. An immunological evaluation was performed. The first that was identified was the history of his son with ALPS (not specified by any other physician). Due to her history, the lymphoproliferation and anemia Sanger sequencing of her sońs mutation was performed. It revealed the same mutation and treatment was started. FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype. The factors that determine the penetrance of clinical ALPS have not been entirely determined. Penetrance appears to be relatively associated with the location and type of the mutation and even varies in individuals carrying the same genetic mutation.

Molecular profile of patients with inborn errors of immunity from Nepal

Background and AimsInborn errors of immunity (IEIs) are increasingly being diagnosed in various regions of the world. There are significant challenges in the diagnosis and treatment of IEIs in resource-limited countries. With the availability of one immunologist and increasing awareness, IEIs are diagnosed with increasing frequency and accuracy in Nepal. IEIs are also being evaluated in children presenting with autoimmune manifestations. We describe the profile of patients diagnosed with IEIs in Nepal during 2020–2022. MethodsRecords of all patients with IEIs who were diagnosed and treated at our tertiary care center in Nepal from August 2020 to April 2022 were analysed. Lead author (DB) has examined and diagnosed all cases. IEIs were diagnosed based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and genetic analysis. ResultsThirty-two patients with IEI (19 boys; 13 girls) and 801 children with autoimmune disorders were diagnosed during the study period. Genetic analysis was done on 18 patients. The diagnostic profile of the patients includes patients with chronic granulomatous disease, X-linked agammaglobulinemia, severe combined immunodeficiency, Job syndrome, selective IgA deficiency, specific antibody deficiency, Wiskott-Aldrich Syndrome, CTLA4 deficiency, IPEX syndrome, IFN-IL12 axis defect, hereditary angioedema, MonoMac syndrome, ARPC1B deficiency, leukocyte adhesion defect, PAPA syndrome, autoimmune lymphoproliferative syndrome, ADA2 deficiency, early-complement deficiency lupus, familial cold auto-inflammatory syndrome, A20 haploinsufficiency, and Blau syndrome. Some patients succumbed before the scope of diagnosis. HSCT is planned for 3 patients. ConclusionsOur is the first report of genetically proven IEIs in Nepal. Logistic constraints coupled with a lack of awareness of IEIs among laity and pediatrician accounted for a missed diagnosis, late diagnosis, and poor outcomes in resource-limited settings. Antimicrobial prophylaxis reduced the incidence of breakthrough infections. The lack of HSCT facilities precludes definitive treatment of many IEIs.

Focal Segmental Glomerulosclerosis and Renal Failure Secondary to Protein Kinase C Delta Deficiency in an Adolescent Male

Introduction: The autoimmune lymphoproliferative syndrome (ALPS)-like condition, Protein Kinase C-delta (PRKCD) deficiency, is associated with a lupus-like presentation, recurrent infections, and reduced B-cell function with hypogammaglobulinemia in addition to prominent lymphadenopathy and splenomegaly. Renal manifestations previously reported include nephrotic syndrome and glomerulonephritis. Focal segmental glomerulosclerosis (FSGS) and significant end-stage renal disease requiring dialysis have not been previously described in those with PRKCD deficiency.Case Study: We describe a now 21-year-old male of Palestinian descent with consanguineous parents who initially presented at 15 months of age with arthritis, splenomegaly, neutrophilic rash, and recurrent fevers. At 7 years of age, the patient was hospitalized with hepatosplenomegaly, diffuse adenopathy, and post-obstructive pneumonitis secondary to hilar adenopathy. He was subsequently given a diagnosis of presumed ALPS, although FAS mutation testing was negative, and started on mycophenolate with improvement in symptomology. He underwent additional comprehensive genetic testing when he was 18 years old with results revealing a novel homozygous PRKCD variant (c. 1872 1 G > A) leading to a presumed donor splice site defect. [Display omitted] Starting at 19 years of age, the patient was noted to have a steadily rising serum creatinine and profound proteinuria. Kidney biopsy revealed chronic immune complex glomerulonephritis with capillary loop and mesangial immune deposits and changes consistent with secondary FSGS. (Figure 1A&B). He was started on an angiotensin-converting enzyme (ACE) inhibitor for antiproteinuric effects, though this was discontinued due to persistent hyperkalemia. A subsequent renal biopsy performed 5 months later in the clinical setting of rapid deterioration of GFR and worsening proteinuria showed worsening FSGS with prominent podocytopathy (Figure 1 C&D). Mycophenolate and IVIG therapy were discontinued given a lack of efficacy and to preserve renal function. Unfortunately, his creatinine continued to rise, and he progressed to end-stage renal disease necessitating dialysis. He is currently being considered for kidney transplantation. ConclusionSevere FSGS leading to renal failure is an uncommon diagnosis in adolescents and has not previously been described in those with PRKCD deficiency. Our case thus broadens the phenotypic and pathologic renal manifestations of the disorder and emphasizes the need for comprehensive multidisciplinary care of individuals affected by ALPS-like conditions.