Malignancies and Lymphoproliferations in Children With Primary Immune Deficiency-A Single-center Experience.

Primary immune deficiencies (PIDs) are rare genetic disorders characterized by impaired immune function, leading to frequent infections and immune dysregulation. Studies have shown that individuals with PID are at an increased risk of developing malignancies and lymphoproliferative disorders compared with the general population. In this single-center study, we aimed to analyze the occurrence of malignancies and lymphoproliferations in children diagnosed with PID. We retrospectively analyzed the medical records of 550 pediatric patients diagnosed with PIDs at our center. Among them, 17 (3,0%) patients were identified with malignancy and/or benign lymphoproliferation. Eight of the 17 patients (47.0%) had immune dysregulatory diseases, whereas ataxia-telangiectasia was the second most common PID associated with malignancy and/or benign lymphoproliferation (n = 5, 29.4%). Lymphoma was the predominant malignancy (n = 11, 64.7%), and Epstein-Barr virus was identified as the most common viral agent associated with malignancy and/or benign lymphoproliferation in patients with PID (n = 8, 47.0%). Our study highlights the association between PID and malignancies/lymphoproliferations, with immune dysregulation syndromes being the most common subclass associated with malignancies/lymphoproliferations. Early diagnosis, multidisciplinary management, and regular surveillance are crucial in improving patient outcomes and saving lives.

Neurologic Status of Patients with Purine Nucleoside Phosphorylase Deficiency Before and After Hematopoetic Stem Cell Transplantation.

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. METHODS: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. RESULTS: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. DISCUSSION: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.

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

INTRODUCTION: 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. METHODS: Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. RESULTS: 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). CONCLUSION: 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.

Evaluation of the risk factors for BK virus-associated hemorrhagic cystitis in pediatric bone marrow transplantation patients: Does post-transplantation cyclophosphamide increase the frequency?

BACKGROUND: BKV-HC is one of the most significant complications of HSCT. This retrospective study aimed to determine the frequency of BKV-HC in pediatric patients undergoing HSCT, detect the associated risk factors for the development of BKV-HC, and explore the effects of post-transplantation Cy use. METHODS: Three hundred twenty-seven patients (girls: 121, boys: 206) were analyzed according to sex, conditioning regimen, transplantation type, donor relatedness, stem cell source, the presence and grade of aGVHD, CMV co-existence, and Cy use. RESULTS: Multivariate analysis confirmed the prognostic importance of age (OR: 4.865), TBI use, the presence of aGVHD (OR: 2.794), CMV coinfection (OR: 2.261), and Cy use (OR: 27.353). A statistically significant difference was found between the mean BKV-HC follow-up times compared with post-transplantation Cy intake (p < .001). The BKV-HC rate increased as the number of risk factors of the patient increased. CONCLUSION: BKV-HC is an essential complication of HSCT primarily associated with Cy use, the presence of aGVHD, and donor relatedness. The present study shows that the use of Cy in the post-transplantation period further increases BKV-HC risk in pediatric patients, regardless of dose.

Hepatocellular Carcinoma in ADA-SCID Patient After Hematopoietic Stem Cell Transplantation.

Adenosine deaminase (ADA) deficiency is one of the most prevalent forms of severe combined immunodeficiency and results in the accumulation of toxic substrates which creates a systemic metabolic disease. It predisposes patients to the development of malignancies, most commonly lymphoma. We report an 8-month-old infant with ADA deficient severe combined immunodeficiency who developed progressive liver dysfunction and hepatocellular carcinoma after successful hematopoietic stem cell transplantation. This is the first case report of an ADA-deficient patient who presented with hepatocellular carcinoma and gives an insight into the complex etiology that can lie behind liver dysfunction in these patients.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

A set of clinical and laboratory markers differentiates hyper-IgE syndrome from severe atopic dermatitis.

Hyper-IgE syndrome (HIES) patients may share many features observed in severe atopic dermatitis (SAD), making a diagnostic dilemma for physicians. Determining clinical and laboratory markers that distinguish both disorders could provide early diagnosis and treatment. We analyzed patients (DOCK8 deficiency:14, STAT3-HIES:10, SAD:10) with early-onset SAD. Recurrent upper respiratory tract infection and pneumonia were significantly frequent in HIES than SAD patients. Characteristic facial appearance, retained primary teeth, skin abscess, newborn rash, and pneumatocele were more predictable for STAT3-HIES, while mucocutaneous candidiasis and Herpes infection were common in DOCK8 deficiency, which were unusual in SAD group. DOCK8-deficient patients had lower CD3+ and CD4+T cells with a senescent phenotype that unique for this form of HIES. Both DOCK8 deficiency and STAT3-HIES patients exhibited reduced switched memory B cells compared to the SAD patients. These clinical and laboratory markers are helpful to differentiate HIES from SAD patients.

Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis.

PURPOSE: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease. METHODS: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected. RESULTS: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation. CONCLUSION: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.

Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes.

Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains untreated, patients succumb to infections during the first 2 years of life. PURPOSE AND METHODS: This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997-2017). RESULTS: Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T - B - NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997-2006) to 85% (2007-2017) during the last 10 years. CONCLUSIONS: This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study.

Primary immunodeficiencies: HSCT experiences of a single center in Turkey.

BACKGROUND: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases. METHODS: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID. RESULTS: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients. CONCLUSIONS: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.

Comparison of Hematopoietic Stem Cell Transplantation Results in Patients with ß-Thalassemia Major from Three Different Graft Types.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative therapy for ß-thalassemias that induces severe life-threatening complications. The human leukocyte antigen (HLA) registries and umbilical cord blood banks have carried out diligent searches to find matched unrelated donors (MUDs) for about 70.0% of patients from 2000 onwards. The chance of finding a non-sibling fully matched family donors is higher in some ethnic groups in which consanguineous marriages are common. We have studied and compared transplant complications and outcomes in different graft types (sibling, non-sibling family and unrelated). The non-sibling matched family donor (MFD) group consisted of four mothers, three fathers, five cousins, one paternal uncle and one paternal aunt. There was no significant difference in the mean transfused CD34+ cells, engraftment, median days of neutrophil and platelet recovery were achieved (p > 0.05). The distribution of postttransplant complication did not show any significant difference between groups (p > 0.05). In univariate analysis and multivarite analyses, age, gender, Pesaro risk group (I-II vs. III) and ABO incompatibilty demonstrated a significant difference in disease free survival (p < 0.05). Furthermore, in the second step of investigating overall survival (OS), age, gender and Pesaro risk group (I-II vs. III) showed a significant difference (p < 0.05). There was no significant difference in transplant-related mortality (TRM) between groups. Non-sibling related donor transplants are important for populations where consanguineous marriages are common. Transplant groups according to graft type had similar thalassemia-free survival (TFS) and OS when using a treosulfan-based regimen in our study.

Invasive Saprochaete capitata Infection in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature.

PURPOSE: Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct. METHODS: The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents. RESULTS: S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing. CONCLUSIONS: This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.

ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS: DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION: DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Mutational landscape of severe combined immunodeficiency patients from Turkey.

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.

PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects.

BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. OBJECTIVE: We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. METHODS: We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. RESULTS: The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. CONCLUSION: Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.

Very high IgE levels in children: when from pediatrician to immunologist?

BACKGROUND: Total serum immunoglobulin E (IgE) is increased in many situations such as allergic diseases, primary immunodeficiencies (PID), parasitosis, infections and malignancies. When IgE levels >1000 kU/L are suspected PID by pediatricians. We tried to define some clinical and laboratory parameters to distinguish PID from the others. METHODS: We evaluated 158 children between 1.7 - 17 years (Mean: 6.6 ±3.4) for allergic diseases, PID, parasitosis and others. Total IgE, specific IgE, immunoglobulin levels and skin prick tests were performed to all patients. Parasite investigations, viral serological tests and detailed immunologic tests were analyzed in only patients who had suspected complaints. Hyper IgE syndrome (HIES) scoring sheet was filled out for all patients. RESULTS: Among all patients, 114 were diagnosed as bronchial asthma, allergic rhino-conjunctivitis or atopic dermatitis. PID diagnosis was established in totally 32 patients. Immunological evaluations were normal in 126 patients. Eleven patients were accepted as parasitosis. Median HIES score was 18 (5-44 points). CONCLUSIONS: Pediatricians may use HIES scoring sheet when they suspect a patient with PID. If the patient has very low points, they may follow the patient. If there are about 18-20 points, they should get an opinion from an immunologist for detailed immunologic tests.

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

Novel Mutation in CECR1 Leads to Deficiency of ADA2 with Associated Neutropenia.

PURPOSE: Adenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa (PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2. METHODS: We reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives. RESULTS: Genetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives. CONCLUSION: This is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.

Cyclic manner of neutropenia in a patient with HAX-1 mutation.

Introduction: Severe congenital neutropenia (SCN) includes a group of genetic disorders which cause to arrest of neutrophil maturation. SCN can be associated with heterogenous group of genetic defects in ELANE, GFI1, HAX1, G6PC3, JAGN1, VPS45 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene. Aim: Here we report a patient who has a HAX1 mutation presented with cyclic manner. Case Report: A 6 year old female patients was admitted with recurrent apthous stomatitis. We followed the patient as cyclic neutropenia according to complete blood count results 2 times for 6 weeks. After persistant neutropenia developed during a severe varicella infection, we analysed HAX1 mutation, the result was interesting and incompatible with reported cyclic neutropenia patients. Conclusion: We suggest that HAX1 deficiency should be thought in patients who have normal neutrophil counts in the between of infections.

HAX-1 deficiency: Characteristics of five cases including an asymptomatic patient.

BACKGROUND: Mutations in the HAX-1 gene cause an autosomal recessive form of severe congenital neutropenia (SCN), which particularly manifests with recurrent skin, lung and deep tissue infections from the first few months of life. OBJECTIVE: We retrospectively evaluated the clinical and laboratory findings of the patients diagnosed with SCN carrying HAX1 gene mutations. METHODS: A total of five patients with SCN, carrying a HAX1 gene mutation, were evaluated in terms of clinical and laboratory findings. Mutation analysis of the candidate genes (HAX1, ELANE and CSF3R) was performed. RESULTS: All of the patients lived in Turkey; four of them were of Kurdish origin and one was Turkish. Of the five patients, three were girls and two were boys, and the mean age of the patients was 8.8 years old (range 4-15 years). The mean age of diagnosis was 25.8 months (range 2 months-5 years). The infections diagnosed included recurrent gingivitis, stomatitis, and skin and soft tissue abscesses. Developmental retardation and epilepsy were present in only one patient, whereas speech retardation was present in two. All of our patients had a HAX1 mutation, and are still alive and none of them has shown malignant transformation yet. CONCLUSION: Complete blood count should be performed and absolute neutrophil count should be evaluated in patients with recurrent severe infections. In the event that neutropenia is detected, they should be investigated in terms of SCN and mutation analysis should be performed.