Case report:: severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/mu L were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.Transplantation and immunomodulatio

Clinical and molecular characteristics of two transaldolase-deficient patients

Transaldolase (TALDO) deficiency is a rare metabolic disease in the pentose phosphate pathway, which manifests as a severe, early-onset multisystem disease. The body fluids of affected patients contain increased polyol concentrations and seven-carbon chain carbohydrates. We report the molecular and clinical findings in two recently diagnosed transaldolase-deficient children, both presented at birth. During infancy, they presented thin skin with a network of visible vessels, spider telangiectasias and multiple haemangiomas. Such unusual skin changes are characteristic of liver damage. Later, the patients developed rapidly progressive nodular liver fibrosis, tubulopathy and severe clotting disturbances. The clinical features of these patients were in line with previously studied patients with transaldolase deficiency. The diagnosis was established by detecting high concentrations of erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose and sedoheptulose-7-phosphate in the urine. Detection was made by gas chromatography and liquid chromatography-tandem mass spectrometry and then confirmed by molecular analysis of the TALDO gene. Conclusion: Transaldolase deficiency, a rare early-onset multisystem disease, should be considered by neonatologists, paediatricians, hepatologists and nephrologists in the differential diagnosis of patients presenting hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure and tubulopathy

BCG Moreau Vaccine Safety Profile and NK Cells-Double Protection Against Disseminated BCG Infection in Retrospective Study of BCG Vaccination in 52 Polish Children with Severe Combined Immunodeficiency

Objectives The aim of the study was to estimate the rate of adverse reactions to live BCG Moreau vaccine, manufactured by Biomed in Poland, in severe combined immunodeficiency (SCID) patients. Material The profiles of 52 SCID patients vaccinated at birth with BCG, hospitalized in Children's Memorial Health Institute, Warsaw (CMHI), in the years 1980-2015 were compared with those of 349 BCG-vaccinated SCID patients from other countries analyzed by Beatriz E. Marciano et al. in a retrospective study (Marciano et al. J Allergy Clin Immunol. 2014;133(4):1134-1141). Results Significantly less disseminated BCG infections (10 out of 52 SCID, 19%) occurred in comparison with Marciano study-119 out of 349, 34% (p = 0.0028), with no death in patients treated with SCID anti-TB drug, except one in lethal condition. In our study, disseminated BCG infection was observed only in SCID with T-B+NK- phenotype and significantly lower NK cell counts (p = 0.0161). NK cells do not influence on the frequency of local BCG reaction. A significantly higher number of hematopoietic stem cells transplantations (HSCT) were performed in CMHI study (p = 0.0001). Anti-TB treatment with at least two medicines was provided. Conclusion The BCG Moreau vaccine produced in Poland, with well-documented genetic characteristics, seems to be safer than other BCG substrains used in other regions of the world. Importantly, NK cells seem to play a role in protecting SCID patients against disseminated BCG complications, which NK- SCID patients are more prone to. HSCT and TB therapy could be relevant due to the patients' survival and the fact that they protect against BCG infection.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Background:Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective:We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with theRAGdefects in populations inhabiting South, West, and East Slavic countries. Methods:Demographic, clinical, and laboratory data were collected fromRAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determinedin vitroby flow cytometry-based assay. Results:Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum ofRAGdeficiencies, including SCID (n= 20), OS (n= 37), and LS/CID (n= 25) phenotypes. Sixty-seven (81.7%) patients carriedRAG1and 15 patients (18.3%) carriedRAG2biallelic variants. We estimate that the minimal annual incidence ofRAGdeficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n= 47) of patients withRAG1variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n= 18, 27%) or in compound heterozygous (n= 29, 43%) form. The majority (77%) of patients with homozygousRAG1p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygousRAG1p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion:We propose thatRAG1p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort ofRAG1founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.Transplantation and immunomodulatio

The clinical and genetic spectrum of 82 patients with RAG deficiency including a c.256_257delAA founder variant in Slavic countries

Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival