Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network

Cirillo, Emilia; Cancrini, Caterina; Azzari, Chiara; Martino, Silvana; Martire, Baldassarre; Pession, Andrea; Tommasini, Alberto; Naviglio, Samuele; Finocchi, Andrea; Consolini, Rita; Pierani, Paolo; D'Alba, Irene; Putti, Maria Caterina; Antonio, Miguel; Giardino, Giuliana; Prencipe, Rosaria; Esposito, Federica; Grasso, Fiorentino; Scarselli, Alessia; Matteo, Gigliola Di; Attardi, Enrico; Ricci, Silvia; Montin, Davide; Specchia, Fernando; Barzaghi, Federica; Cicalese, Maria Pia; Quaremba, Giuseppe; Lougaris, Vassilios; Giliani, Silvia; Locatelli, Franco; Rossi, Paolo; Aiuti, Alessandro; Badolato, Raffaele; Plebani, Alessandro; Pignata, Claudio

doi:10.3389/fimmu.2019.01908

Cited by 34 publications

(31 citation statements)

References 51 publications

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“…Overall, diagnostic delay amongst the predominant forms of PID varied from 4 months in SCID-which is similar to data reported by others (22,25)-to 141 months in XLA patients. Obviously, such long diagnostic delays lead to a number of unrecognized PAD deaths and contribute to the low proportion of humoral deficiencies in the registry.…”

Section: Discussionsupporting

confidence: 89%

Primary Immunodeficiencies in Russia: Data From the National Registry

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 89%

Primary Immunodeficiencies in Russia: Data From the National Registry

et al. 2020

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“…This is even greater than reported in large SCID cohorts from Iran (87.3%), KSA (60%) and India (36%) ( 8 , 20 , 21 ). Remarkably, in our cohort, 66% of affected children had a positive family history of SCID for which half of them (33%) reported a sibling death, much higher than what have been reported in Italy (5.6%) and Iran (3%) ( 20 , 22 ).…”

Section: Discussioncontrasting

confidence: 70%

A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening

et al. 2021

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IntroductionSevere combined immunodeficiency (SCID) results from various monogenic defects that impair immune function and brings on early severe and life-threatening infections. The main stay of treatment for SCID is hematopoietic stem cell transplant (HSCT) with near normal survival at 5 years for an early transplant done at or before the age of 3.5 months of life and the patient is maintained free of infections. Although overall rare, it constitutes a major burden on affected children, their families and on the health system especially in communities with a high rate of consanguinity where incidence and prevalence of recessive inborn errors of immunity (IEI) are expected to be high.MethodHere, we report the clinical, immunological, and molecular findings in 36 children diagnosed with SCID from a single tertiary center in Oman for the last decade.ResultsWe observed a median annual incidence rate of 4.5 per 100,000 Omani live births, and 91.7% of affected children were born to consanguineous parents. Twenty-three children (63.9%) fulfilled the criteria for typical SCID. The median age at onset, diagnosis and diagnostic delay were 54, 135, and 68 days, respectively. The most common clinical manifestations were pneumonia, septicemia, and chronic diarrhea. Eleven children (30.6%) have received hematopoietic stem cell transplant (HSCT) with a survival rate of 73%. The most frequent genetic cause of SCID in this cohort (n = 36) was (RAG-1), encoding for recombination activating gene (n = 5, 13.9%). Similarly, Major histocompatibility complex type II deficiency accounted for (n = 5, 13.9%) of our cohort.ConclusionOur report broadens the knowledge of clinical and molecular manifestations in children with SCID in the region and highlights the need to initiate newborn based screening program (NBS) program.

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“…In addition, mutations in V(D)J rearrangement and DNA repair mechanisms ( RAG‐1, RAG‐2, NHEJ, DCLRE1C and PRKDC ) genes block T‐ and B‐cell development. (Cirillo et al., 2019; Fischer et al., 2015; Notarangelo, 2010; Rivers & Gaspar, 2015; Schumacher & Notarangelo, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mutational landscape of severe combined immunodeficiency patients from Turkey

Fırtına

et al. 2020

Int J Immunogenetics

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Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next‐generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon‐based targeted NGS panel, which contained 18 most common SCID‐related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease‐causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom‐made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK− SCID). Incidence of autosomal‐recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom‐made sequencing panel was able to identify and confirm the previously known and novel disease‐causing variants with high accuracy.

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Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network

Cited by 34 publications

References 51 publications

Primary Immunodeficiencies in Russia: Data From the National Registry

Primary Immunodeficiencies in Russia: Data From the National Registry

A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening

Mutational landscape of severe combined immunodeficiency patients from Turkey

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