Publications by authors named "Peter Ciznar"

11 Publications

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Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations.

J Clin Immunol 2021 Jan 19. Epub 2021 Jan 19.

Department of Translational Medical Sciences, Pediatrics Section, Federico II University of Naples, via S. Pansini 5, 80131, Naples, Italy.

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.
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http://dx.doi.org/10.1007/s10875-021-00967-yDOI Listing
January 2021

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

Front Immunol 2020 10;11:900. Epub 2020 Jun 10.

Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus.

Variants in recombination-activating genes () 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. We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the defects in populations inhabiting South, West, and East Slavic countries. Demographic, clinical, and laboratory data were collected from -deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined by flow cytometry-based assay. Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of deficiencies, including SCID ( = 20), OS ( = 37), and LS/CID ( = 25) phenotypes. Sixty-seven (81.7%) patients carried and 15 patients (18.3%) carried biallelic variants. We estimate that the minimal annual incidence of 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% ( = 47) of patients with variants carried p.K86Vfs33 (c.256_257delAA) allele, either in homozygous ( = 18, 27%) or in compound heterozygous ( = 29, 43%) form. The majority (77%) of patients with homozygous p.K86Vfs33 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 p.K86Vfs33 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. We propose that p.K86Vfs33 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 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.
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http://dx.doi.org/10.3389/fimmu.2020.00900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325958PMC
June 2020

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

J Exp Med 2020 06;217(6)

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
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http://dx.doi.org/10.1084/jem.20191804DOI Listing
June 2020

Dynamics of allergy development during the first 5 years of life.

Eur J Pediatr 2018 Sep 22;177(9):1317-1325. Epub 2018 Jun 22.

Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.

Allergic diseases have increased in developed countries during the past decades. A cohort of Slovak children was followed from birth to track allergic symptoms dynamics in early childhood. Information on allergic symptoms (atopic dermatitis = AD, rhino conjunctivitis = RC, wheezing = Wh, urticaria = Ur) and food allergies among children was based on clinical evaluation of children by allergists at three developmental stages (infant, toddler, preschool). Out of 320 cases of allergies, 64 infants, 145 toddlers, and 195 preschool children suffered from AD, RC, Wh, Ur, or their combinations (i.e., significant increase with age, p < 0.001). AD first appeared in infants, Wh and/or RC rose mainly in toddlers, and Ur among preschool children. AD in infants or toddlers disappeared in the subsequent developmental stage in approximately one third of all cases. Single AD persistence without remission or extension was not common and accounted only for 6.9% of AD infants' allergic manifestations. In addition to single-symptom allergic diseases, this study also identified several combinations of atopic symptoms.Conclusions: The proportion of multi-symptom allergies increased while single-symptom forms decreased. The observed temporal trends of allergic symptoms correspond to the atopic march. What is Known: • The observed temporal trends of allergic symptoms correspond to the atopic march. What is New: • Allergic diseases in children were first manifested as single forms, with atopic dermatitis (AD) commonly functioning as the "entry point" to allergies. • The overall proportion of single-symptom allergic disorders decreased over time while the proportion of multi-symptom allergies increased.
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http://dx.doi.org/10.1007/s00431-018-3188-9DOI Listing
September 2018

Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia.

Clin Immunol 2017 10 10;183:41-45. Epub 2017 Jul 10.

Immunology Outpatient Clinic, Vienna, Austria; Sigmund Freud Private University - Medical School, Vienna, Austria. Electronic address:

Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulin levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.
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http://dx.doi.org/10.1016/j.clim.2017.07.003DOI Listing
October 2017

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

J Allergy Clin Immunol 2016 07 28;138(1):241-248.e3. Epub 2016 Feb 28.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, the Rockefeller University, New York, NY. Electronic address:

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.

Objective: Our objective was to assess the effect of mycobacterial disease in patients with CGD.

Methods: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.

Results: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.

Conclusion: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.
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http://dx.doi.org/10.1016/j.jaci.2015.11.041DOI Listing
July 2016

Nijmegen Breakage Syndrome: Clinical and Immunological Features, Long-Term Outcome and Treatment Options - a Retrospective Analysis.

J Clin Immunol 2015 Aug 14;35(6):538-49. Epub 2015 Aug 14.

Department of Immunology, Children's Memorial Health Institute, 04-730 Av. Dzieci Polskich 20, Warsaw, Poland.

Purpose: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation.

Methods: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed.

Results: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies.

Conclusions: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.
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http://dx.doi.org/10.1007/s10875-015-0186-9DOI Listing
August 2015

Clinical picture and treatment of 2212 patients with common variable immunodeficiency.

J Allergy Clin Immunol 2014 Jul 28;134(1):116-26. Epub 2014 Feb 28.

Center for Chronic Immunodeficiency (CCI), University Medical Centre Freiburg and University of Freiburg, Freiburg, Germany; UCL Medical School Royal Free Campus and Royal Free Hospital NHS Foundation Trust, London, United Kingdom. Electronic address:

Background: Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders.

Objective: This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe.

Methods: Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively.

Results: Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections.

Conclusion: Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.
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http://dx.doi.org/10.1016/j.jaci.2013.12.1077DOI Listing
July 2014

Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey.

Pediatr Rheumatol Online J 2010 Dec 2;8:29. Epub 2010 Dec 2.

Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Slovenia.

Objective: To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries.

Methods: Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire.

Results: Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients.

Conclusions: The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries.
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http://dx.doi.org/10.1186/1546-0096-8-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014922PMC
December 2010

Environmental and dietary risk factors for infantile atopic eczema among a Slovak birth cohort.

Pediatr Allergy Immunol 2006 Mar;17(2):103-11

Department of Family and Preventive Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Infantile atopic eczema (AE) is a risk marker for future asthma. This study assesses the contribution of modifiable exposures to infantile AE. If modifiable exposures contribute substantially to infantile AE, its prevention might be a sensible approach to asthma prevention. Pregnant women (n = 1978) were systematically recruited from maternity hospitals of the Slovak Republic; their birthed cohort of 1990 children were prospectively followed for 1 yr. Children's exposures to selected environmental and dietary factors were assessed via maternal questionnaires administered at delivery and 1 yr of age. A child was considered to have AE, based on physical examination (SCORAD index >2) or mother's report of a previous physician diagnosis. Multivariate logistic regression was used to calculate adjusted odds ratios and percent total regression scores (TRS) for each variable. At 1 yr of age 1326 (67%) of the children remained in the cohort and 207 (15.6%) developed AE. Various modifiable environmental and dietary exposures increased the likelihood of AE (ownership of cats; consumption of infant formula, eggs, and fish) while others decreased the likelihood of AE (ownership of livestock; exclusive breast feeding for > or =4 months). Overall, modifiable exposures contributed less to the TRS than did non-modifiable exposures (38% vs. 62%, respectively). The modifiable exposure category that contributed most to the TRS was infant feeding practices (27.5% TRS). Modifiable exposures -- especially those related to infant feeding practices -- significantly contribute to infantile AE, although modifiable factors contribute less overall than do non-modifiable exposures.
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http://dx.doi.org/10.1111/j.1399-3038.2005.00372.xDOI Listing
March 2006