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1.
Blood Adv ; 6(18): 5403-5414, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-35687490

RESUMEN

Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.


Asunto(s)
Linfoma de Células B Grandes Difuso , Fosfatidilinositol 3-Quinasas , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Genómica , Humanos , Linfoma de Células B Grandes Difuso/genética , Fosfatidilinositol 3-Quinasa
2.
J Clin Immunol ; 41(8): 1878-1892, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34477998

RESUMEN

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).


Asunto(s)
Ataxia Telangiectasia/inmunología , Ataxia Telangiectasia/mortalidad , Linfocitos B/inmunología , Deficiencia de IgA/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Deficiencia de IgA/mortalidad , Deficiencia de IgG/inmunología , Deficiencia de IgG/mortalidad , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lactante , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Adulto Joven
3.
Clin Cancer Res ; 27(2): 575-584, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33082212

RESUMEN

PURPOSE: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. EXPERIMENTAL DESIGN: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. RESULTS: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10-5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); P < 0.0001]. CONCLUSIONS: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Neoplasias/epidemiología , Neoplasias/terapia , Síndrome de Nijmegen/epidemiología , Adolescente , Adulto , Niño , Estudios de Cohortes , Comorbilidad , Estudios de Seguimiento , Humanos , Incidencia , Estimación de Kaplan-Meier , Polonia/epidemiología , Prevalencia , Adulto Joven
4.
Br J Haematol ; 192(2): 366-374, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33131064

RESUMEN

Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the thrombocytopenia is of paramount importance for most WAS patients. We report a retrospective analysis of the safety and efficacy of romiplostim treatment in reducing thrombocytopenia and bleeding tendency in 67 children (median age 1·3 years) with genetically confirmed WAS, followed in eight months (range, 1-12 months). Complete or partial primary responses regarding platelet counts were observed in 22 (33%) and 18 (27%) subjects, respectively. Yet, even in the non-responder group, the risk of haemorrhagic events decreased significantly, to 21%, after the first month of treatment. The responses tended to be durable and stable over time, with no significant fluctuations in platelets counts. The results of this retrospective study of a large cohort of WAS patients demonstrates that romiplostim can be used to increase platelet counts and reduce the risks of life-threatening bleeding in WAS patients awaiting haematopoietic stem cell transplantation or forgoing the procedure for various reasons.


Asunto(s)
Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombocitopenia/complicaciones , Trombocitopenia/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Síndrome de Wiskott-Aldrich/complicaciones , Adolescente , Niño , Preescolar , Hemorragia/complicaciones , Hemorragia/tratamiento farmacológico , Humanos , Lactante , Recuento de Plaquetas , Proteínas Recombinantes de Fusión/efectos adversos , Estudios Retrospectivos , Trombopoyetina/efectos adversos , Resultado del Tratamiento
5.
Front Immunol ; 11: 1491, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32849507

RESUMEN

Introduction: Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. Materials and Methods: The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. Results: The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Conclusions: Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment.


Asunto(s)
Enfermedades de Inmunodeficiencia Primaria/epidemiología , Sistema de Registros , Adulto , Niño , Bases de Datos Factuales , Diagnóstico Tardío , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Patología Molecular , Prevalencia , Enfermedades de Inmunodeficiencia Primaria/terapia , Federación de Rusia/epidemiología
6.
J Clin Immunol ; 40(6): 861-871, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32602054

RESUMEN

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to malignancies. HSCT appears to cure immunodeficiency, but remains challenging due to limited experience in long-term risks of transplant-associated toxicity and malignancies. Twenty NBS patients received 22 allogeneic HSCTs with TCRαß/CD19+ graft depletion with fludarabine 150 mg/m2, cyclophosphamide 20-40 mg/kg and thymoglobulin 5 mg/kg based conditioning regimens (CRs). Twelve patients additionally received low-dose busulfan 4 mg/kg (Bu group) and 10 patients (including 2 recipients of a second HSCT) treosulfan (Treo group) 30 g/m2. Overall and event-free survival were 0.75 vs 1 (p = 0.16) and 0.47 vs 0.89 (p = 0.1) in the Bu and Treo groups, respectively. In the Bu group, four patients developed graft rejection, and three died: two died of de novo and relapsed lymphomas and one died of adenoviral hepatitis. The four living patients exhibited split chimerism with predominantly recipient myeloid cells and predominantly donor T and B lymphocytes. In Treo group, one patient developed rhabdomyosarcoma. There was no difference in the incidence of GVHD, viral reactivation, or early toxicity between either group. Low-dose Bu-containing CR in NBS leads to increased graft failure and low donor myeloid chimerism. Treo-CR followed by TCRαß/CD19-depleted HSCT demonstrates a low level of early transplant-associated toxicity and enhanced graft function with stable donor chimerism.


Asunto(s)
Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/métodos , Depleción Linfocítica , Agonistas Mieloablativos/uso terapéutico , Síndrome de Nijmegen/terapia , Acondicionamiento Pretrasplante/métodos , Antígenos CD19/metabolismo , Busulfano/administración & dosificación , Busulfano/efectos adversos , Busulfano/uso terapéutico , Femenino , Rechazo de Injerto , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Depleción Linfocítica/métodos , Masculino , Agonistas Mieloablativos/administración & dosificación , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/mortalidad , Cuidados Posoperatorios , Pronóstico , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Estudios Retrospectivos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Resultado del Tratamiento
7.
Orphanet J Rare Dis ; 14(1): 97, 2019 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-31053147

RESUMEN

BACKGROUND: Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients. RESULTS: We report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαß+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient's death on day + 156 after HSCT. CONCLUSIONS: In conclusion, we demonstrate that RIC HSCT with TCRαß+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients.


Asunto(s)
Antígenos CD19/metabolismo , Trastornos de los Cromosomas/metabolismo , Trasplante de Células Madre Hematopoyéticas , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Inestabilidad Cromosómica/genética , Inestabilidad Cromosómica/fisiología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/terapia , Humanos , Mosaicismo , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
8.
J Clin Immunol ; 39(1): 112-117, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30680653

RESUMEN

PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy. METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project. RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation. CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.


Asunto(s)
Granuloma/tratamiento farmacológico , Síndromes de Inmunodeficiencia/virología , Virus de la Rubéola/efectos de los fármacos , Rubéola (Sarampión Alemán)/tratamiento farmacológico , Tiazoles/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Granuloma/virología , Humanos , Lactante , Masculino , Nitrocompuestos , Estudios Retrospectivos , Rubéola (Sarampión Alemán)/virología , Linfocitos T/efectos de los fármacos , Linfocitos T/virología , Vacunación/métodos
9.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30607663

RESUMEN

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Asunto(s)
Reparación del ADN/genética , Granuloma/complicaciones , Granuloma/virología , Síndromes de Inmunodeficiencia/complicaciones , Virus de la Rubéola/patogenicidad , Enfermedades de la Piel/etiología , Enfermedades de la Piel/virología , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virología , Niño , Preescolar , Femenino , Granuloma/genética , Cabello/anomalías , Cabello/virología , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/virología , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/virología , Masculino , Síndrome de Nijmegen/genética , Síndrome de Nijmegen/virología , Osteocondrodisplasias/congénito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virología , Enfermedades de Inmunodeficiencia Primaria , Rubéola (Sarampión Alemán)/genética , Rubéola (Sarampión Alemán)/virología , Piel/virología , Enfermedades de la Piel/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/virología
10.
J Allergy Clin Immunol ; 141(1): 322-328.e10, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28392333

RESUMEN

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.


Asunto(s)
Roturas del ADN de Doble Cadena , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/terapia , Reparación del ADN , Trasplante de Células Madre Hematopoyéticas , Adolescente , Alelos , Niño , Preescolar , Trastornos por Deficiencias en la Reparación del ADN/diagnóstico , Trastornos por Deficiencias en la Reparación del ADN/mortalidad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Mutación , Pronóstico , Resultado del Tratamiento , Virosis , Adulto Joven
11.
Front Immunol ; 8: 807, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28791007

RESUMEN

BACKGROUND: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients. METHODS: 35 Russian NBS patients of ages 1-19 years, referred to our Center between years 2012 and 2016, were prospectively studied. RESULTS: Despite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies-in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group. CONCLUSION: Based on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

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