A rare case of Klippel-Trenaunay syndrome presenting with chronic myeloid leukemia.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome associated with capillary/venous/ lymphatic malformations with limb hypertrophy and cancer risk. Various cancers, mostly Wilms tumor, have been reported in patients with KTS, but not leukemia. Chronic myeloid leukemia (CML) is also a rare disease in children, where there is no known disease or syndrome to predispose to CML. CASE: We report a case of CML incidentally diagnosed in a child with KTS when he was bleeding from surgery of the left groin for vascular malformation. CONCLUSIONS: This case reflects the variety of cancer types that may accompany KTS and provides information about CML prognosis in such patients.

Hematological involvement in pediatric systemic lupus erythematosus: A multi-center study.

Introduction: Systemic lupus erythematosus (SLE) may present with features of several systems, including hematological manifestations. In this study, we aimed to evaluate the characteristics of hematological involvement and assess possible associations and correlations in pediatric SLE patients. Method: This is a retrospective multi-center study. The medical records of pediatric SLE patients followed between January 2000 and June 2020 were analyzed. All children fulfilled the criteria of the Systemic Lupus International Collaborating Clinics. Results: The study included 215 children with SLE, 118 of whom had hematological manifestations. Concomitant renal involvement and low C3 levels were significantly more frequent in patients with hematological involvement (p = 0.04, p = 0.008, respectively). Also, anti-cardiolipin, anti-beta-2-glycoprotein I (anti-ß2 GP1), and anti-Sm antibody positivity, and the presence of lupus anticoagulant were more common in the group with hematological findings (p = 0.001 for anti-cardiolipin antibody positivity and p < 0.001 for the positivity of anti-ß2 GP1 antibody, anti-Sm antibody, and lupus anticoagulant). The most common hematologic abnormality was anemia (n = 88, 74.5%), with autoimmune hemolytic anemia constituting the majority (n = 40). Corticosteroids followed by IVIG were the mainstay of treatment. In patients resistant to corticosteroid and IVIG treatments, the most preferred drug was rituximab. Low levels of C3, high SLEDAI score, high incidence of renal involvement, and positive antiphospholipid antibodies were associated with hematological involvement in the univariate analysis. The presence of antiphospholipid antibodies and high SLEDAI score were independently associated with hematological involvement in multivariate analysis (OR: 4.021; 95% CI: 2.041-7.921; p < 0.001 and OR: 1.136; 95% CI: 1.065-1.212; p < 0.001). Conclusion: Hematological abnormalities are frequently encountered in pediatric SLE. Positive antiphospholipid antibodies and high SLEDAI scores were associated with hematological involvement.

Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature.

Diamond Blackfan Anemia (DBA) is an inherited bone marrow (BM) failure syndrome, characterized by a paucity of erythroid differentiation. DBA is mainly caused by the mutations in ribosomal protein genes, hence classified as ribosomopathy. However, in approximately 30% of patients, the molecular etiology cannot be discovered. RPS19 germline mutations caused 25% of the cases. On the other hand, CECR1 mutations also cause phenotypes similar to DBA but not being a ribosomopathy. Due to the blockade of erythropoiesis in the BM, we investigated the transcriptomic profile of three different cell types of BM resident cells of DBA patients and compared them with healthy donors. From BM aspirates BM mononuclear cells (MNCs) were isolated and hematopoietic stem cells (HSC) [CD71-CD34+ CD38mo/lo], megakaryocyte-erythroid progenitor cells (MEP) [CD71-CD34+ CD38hi] and Proerythroblasts [CD71+ CD117+ CD38+] were sorted and analyzed with a transcriptomic approach. Among all these cells, proerythroblasts had the most different transcriptomic profile. The genes associated with cellular stress/immune responses were increased and some of the transcription factors that play a role in erythroid differentiation had altered expression in DBA proerythroblasts. We also showed that gene expression levels of ribosomal proteins were decreased in DBA proerythroblasts. In addition to these, colony formation assay (CFU-E) provided functional evidence of the failure of erythroid differentiation in DBA patients. According to our findings that all patients resembling both RPS19 and CECR1 mutations have common transcriptomic signatures, it may be possible that inflammatory BM niche may have a role in DBA pathogenesis.

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

Usage of Plasma Presepsin, C-Reactive Protein, Procalcitonin and Proadrenomedullin to Predict Bacteremia in Febril Neutropenia of Pediatric Hematological Malignancy Patients.

OBJECTIVE: To investigate the value of presepsin and proadrenomedullin (proADM) as new markers for febrile neutropenia, by comparing them with conventional markers. METHODS: Plasma specimens for presepsin, proADM, C-reactive protein (CRP), and procalcitonin (PCT) were collected every 3 days during each episode of febrile neutropenia. RESULTS: A total of 39 patients experiencing a collective 47 episodes of febrile neutropenia with hematological malignant neoplasms, as well as 40 healthy control patients without infectious disease, were enrolled in this study. Levels of the studied analytes in the presepsin 1 group (with baseline values taken at admission), presepsin 2 group (values recorded on the 3rd day of febrile neutropenia), and presepsin 3 group (values recorded on the 6th day of hospitalization) were all higher in the subgroups with bacteremia. C-reactive protein 1 (baseline value taken at admission), procalcitonin 1 (as recorded at admission), and procalcitonin 2 (recorded on the 3rd day of febrile neutropenia) were higher in the subroups with bacteremia (P =.03, P = .04, and P = .04, respectively). In multivariate logistic regression analysis, presepsin 1 and/or PCT 1/CRP 1 combined analysis was superior in predicting bacteremia. CONCLUSION: Presepsin could be used in combination with other biomarkers to detect bacteremia.

Transplacental hemophilia A and prophylactic treatment with intravenous immunoglobulin and recombinant factor VIIa in the newborn period: a case report.

Acquired hemophilia due to inhibitor antibodies to factor VIII (FVIII) is a very rare entity in neonatal period. Maternal IgG antibodies may cross the placenta and can cause life-threatening hemorrhages in newborns. Here, we represent a newborn who diagnosed as a transplacental acquired hemophilia A. A very high titer of inhibitor level (320 Nijmegen-Bethesda unit) was detected in plasma due to transplasental transfer in this case. According to the best of our knowledge the baby had the highest inhibitor level in neonatal period in the literature. Bleeding complications including intracranial hemorrhage secondary to this condition were reported before. Therefore, to prevent possible life complications, prophylactic recombinant FVIIa was administered in the presenting case and any bleeding event was not observed during follow-up. In conclusion, using prophylactic recombinant FVIIa in newborns is a safe choice for transplacental acquired hemophilia A.

Central nervous system lesions in Fanconi anemia: Experience from a research center for Fanconi anemia patients.

BACKGROUND: Brain atrophy, abnormal pituitary morphology, corpus callosum, and posterior fossa abnormalities have been described in patients with Fanconi anemia (FA). We aimed to provide an overview of cranial neuroimaging findings and to evaluate the clinical implications in FA patients. PROCEDURE: Cranial magnetic resonance imaging (MRI) studies of 34 patients with FA were retrospectively evaluated, and patients' clinical data were correlated with the imaging findings. RESULTS: The patients' median age was 17.6 (range, 3.9-28) years. At least one pathological brain imaging finding was demonstrated in 22 (65%) patients. These findings included corpus callosum abnormalities and other related supratentorial malformations in nine, pituitary abnormalities in eight, craniovertebral junction and posterior fossa abnormalities in eight, vascular lesions in six, and intracerebral calcifications in two patients. Among the 22 patients who had abnormal cranial MRI findings, six (27%) had mild to moderate intellectual disability (ID), three (14%) had epilepsy, one (5%) had mild hearing loss, and one patient (5%) had hemiplegia. Among these 34 patients, 14 (41%) were transfusion dependent. There was no significant difference between patients with congenital and acquired neuroimaging findings and patients with normal neuroimaging regarding transfusion dependency. CONCLUSIONS: Acquired abnormalities in brain tissue, such as white matter intensity changes, white matter T2 hyperintense discrete foci, or infarcts along with congenital abnormalities, were identified in this study. Variable abnormal brain imaging findings in FA patients, although some were not associated with clinical neurological manifestations, suggest that brain imaging could be part of screening in FA.

Three patients with glucose-6 phosphatase catalytic subunit 3 deficiency.

Objectives Severe congenital neutropenia (SCN) is a primary immunodeficiency (PID) characterized by persistent severe neutropenia, recurrent infections, and oral aphthous lesions. Severe congenital neutropenia is caused by various genetic defects such as ELANE, GFI, HAX-1, JAGN1, SRP54, and glucose-6 phosphatase catalytic subunit 3 (G6PC3) deficiency. Clinical features of the patients with G6PC3 deficiency vary from neutropenia to several systemic features in addition to developmental delay. Case presentation In this report, we presented three unrelated patients diagnosed with G6PC3 deficiency. All these patients had short stature, prominent and superficial vascular tissue, cardiac abnormalities (Atrial septal defect (secondary), mitral valve prolapse with mitral insufficiency, pulmonary hypertension) and lymphopenia. Patient 1 (P1) and 2 (P2) had urogenital abnormalities, P2 and P3 had thrombocytopenia. Conclusions We have shown that lymphopenia and CD4 lymphopenia do not rarely accompany to G6PC3 deficiency. Characteristic facial appearance, systemic manifestions, neutropenia could be the clues for the diagnosis of G6PC3 deficiency.

The remarkable response to ponatinib therapy in a child with blastic phase of chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia (CML) rarely occurs in children and adolescents, which shows more aggressive features like high risk of more advanced disease at the time of diagnosis. Suboptimal response to tyrosine kinase inhibitors (TKIs), adverse events, or advanced disease may impede the treatment. CASE: Herein we present a nine-year-old chronic phase CML case. He had no major molecular response (MMR) to imatinib, which was switched to dasatinib. MMR was ensured for 24 months, yet he developed a lymphoid blastic phase under dasatinib. He obtained a remarkable response to ponatinib when administered in parallel to multiagent induction chemotherapy. CONCLUSION: Ponatinib therapy is effective and promising as a bridge to hematopoietic stem cell transplantation in children. Although more studies are necessary to determine indications, dose, efficacy, and safety data.

Hb H Disease Diagnosed During Adolescent Pregnancy.

Hb H disease is a moderate to severe form of α-thalassemia (α-thal). Patients with Hb H disease may become symptomatic, especially during infections and pregnancy, and may require transfusions. Herein, we present a 16-year-old female with Hb H disease who was initially diagnosed during adolescent pregnancy and was found to carry the -α3.7/-(α)20.5 deletions. The relatively mild presentation of this case highlights the milder phenotypic consequences of deletional α mutations. The case describes the screening and management of pregnancy with Hb H disease. Additionally, this case demonstrates that screening of some undiagnosed inherited blood disorders is important during pregnancy.

Hemophagocytic Lymphohistiocytosis in Patients With Primary Immunodeficiency.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.

Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect.

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients. METHODS: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. RESULTS: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients. CONCLUSION: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

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.