Molecular Characteristics, Clinical and Immunologic Manifestations of 11 Children with Omenn Syndrome in East Slavs (Russia, Belarus, Ukraine).

BACKGROUND: Omenn syndrome [Mendelian Inheritance (OMIM 603554)] is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, eosinophilia and profound immunodeficiency. OBJECTIVE: We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome. RESULTS: We collected clinical and immunologic data of 11 patients (1 from Belarus, 5--Ukraine, 5--Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis--20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/-)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/-NK+ phenotype. Eight out of 11 pts had mutation in RAG1 gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in RAG genes (p.E722Q in RAG1 and p.M459R in RAG2). At present, 7/11 were transplanted and 5 out of the transplanted are alive. CONCLUSION: This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in RAG1 gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation.

Variable CD18 expression in a 22-year-old female with leukocyte adhesion deficiency I: Clinical case and literature review.

Key Clinical Message: Partial leukocyte adhesion deficiency type 1 (LAD-1) deficiency is extremely rare condition with milder infectious manifestation and immune system imbalance leads to increased risks of autoinflammatory complications, such as pyoderma gangrenosum, that can be triggered by trauma or pregnancy. In patients with spice-site ITGB2 variants, partial expression can occur due to different ß2 integrin isophorms expression. Abstract: LAD-1, OMIM ID #116920 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene that encodes the CD18 ß2 integrin subunit. According to the CD18 expression, LAD-1 is categorized as severe (<2%), moderate (2%-30%), or mild (>30%). Here, we describe a 22-year-old female, who presented with inflammatory skin disease and oral cavity, as well as respiratory tract infections during the first year of life. LAD-1 was diagnosed at the age of 2 years by low expression of CD18 (1%). Whole-exome sequencing identified homozygous c. 59-10C>A variant in the ITGB2 gene. Despite severe phenotype, the patient survived to adulthood without hematopoietic stem cell transplantation and became pregnant at the age of 20 years, with pregnancy complicated by a pyoderma gangrenosum-like lesion. During her life, CD18 expression increased from 1% to 9%; at 22 years of age, 5% of neutrophils and 9% of lymphocytes were CD18+. All CD18+-lymphocytes were predominantly memory/effector cytotoxic T cells. However, revertant mosaicism was not being established suggesting that CD18 expression variability may be mediated by other mechanisms such as different ß2 integrin isophorms expression.

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.

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5.

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation.

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.