Under the implementation of the “Advanced neonatal screening” Federal Program and the Ministry of Healthcare of Russia Order No. 274n “On approval of the Procedure for providing medical care to patients with congenital and/or hereditary diseases” that started jointly on Jan. 01, 2023 overall Russia, the examination of all newborns for the 29 nosologies of exchange disorders by tandem mass spectrometry as well as spinal muscular atrophy and primary immunodeficiencies by polymerase chain reaction had begun. Circa 1 million and 230 thousand newborns were examined in 85 Russia regions during 2023 with the level of births coverage exceeding 98%. As a result, a risk group that amounted to 1.86% of all examined was formed with confirming diagnostics performed for 8712 neonatal patients at risk, of which 676 have had their deceases confirmed including 379 hereditary metabolic diseases, 117 spinal muscular atrophies and 180 primary immunodeficiencies. Effective treatment and dispensary follow-up methods have been developed so far for all the screened nosologies. Thus, the introduction of the neonatal screening made it possible to initiate therapy for most of the identified patients at preclinical stages reducing the overall infant mortality and improving the quality of life for such patients and their caretakers.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency (PID) characterized by defective B cell maturation, low serum immunoglobulin concentrations and recurrent infectious episodes. The disease is caused by defects of the BTK gene, which encodes Bruton's tyrosine kinase. Along with frequent infections, autoimmune complications of XLA are an important issue. Inflammatory bowel disease-like syndromes (IBD) represent a special group of complications of XLA, their pathophysiology largely unknown. Materials and methods used: Authors conducted a retrospective data analysis of 56 patients with XLA followed at the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) in 2011-2022. Results: IBD-like disease was diagnosed in 11 of 56 (19.6%) patients with XLA, based on medical history, endoscopic picture, histological and laboratory studies. The median onset of the first clinical manifestations of IBD was 7 years (2;14). The most common symptoms were weight loss (7/11, 64%), chronic diarrhea (7/11, 64%) and recurrent abdominal pain (5/11, 45%). Blood in the stool was detected in a quarter of the patients (3/11, 27%). Upon implementation of anti-inflammatory therapy, the majority of patients available for assessment (7/10, 70%) demonstrated improvement. Complete response to therapy with mesalazine was achieved in 2 patients out of 9 who used it (22%). Complete response to treatment with adalimumab was observed in 1 out of 4, with infliximab in 1/3, and with vedolizumab in 1/2. A single patient had refractory IBD without response to all treatment modalities, which served as an indication for allogeneic hematopoietic stem cell transplantation (HSCT), which unfortunately resulted in fatal outcome due to early post-transplant complications. Conclusion: intestinal symptoms in XLA require special vigilance and a multidisciplinary approach. In the study group, the use of variable anti-inflammatory therapy in the majority of patients was shown to be effective and did not lead to the development of additional infectious complications. Analysis of a larger number of patients with XLA and IBD would allow standardization of anti-inflammatory therapy selection in this complex group.

Expanded neonatal screening (ENS) system is a crucial invention that was aimed at reducing infant mortality by enabling the early detection and treatment of severe and life-threatening conditions. Since its Russia-wide implementation in 2023 ENS had successfully identified hundreds of cases of newborns at risk allowing further timely medical intervention that often happened even at a pre-symptomatic stage. However, further optimization of patient routing algorithms within ENS is necessary in order to enhance the identification of newborns at risk and expedite their diagnosis and treatment. This manuscript focuses on optimizing of the routing algorithms specifically for newborns with suspected adenosine deaminase (ADA) deficiency, a severe form of primary immunodeficiency. Given the unique therapeutic and preventive measures required for these patients, the proposed guidelines expand the criteria for referring newborns for confirmatory diagnostics based on nucleoside metabolism data obtained from tandem mass spectrometry of dried blood spots. These improvements are aimed to the earliest detection and targeted treatment of newborns with ADA deficiency thereby enhancing the overall efficiency of primary immunodeficiency screening in Russia.

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare (orphan) autosomal-dominant disease related to primary immunodeficiencies with a defect in the complement system and is characterized by recurrent, unpredictable edema attacks involving various organs and tissues. The recurrent episodes of edema are not amenable to the usual therapy methods and often are life-threatening conditions, especially in pediatric patients. The most pressing issue for the attending physician is the choice of the drug from the available range, taking into consideration its mechanism of action, route of administration and other parameters. This Article summarizes the properties of drugs currently available for the HAE attacks relief in pediatric patients in Russia, including the results of clinical trials, and the Authors’ own experience in the use of Icatibant and a human C1-esterase inhibitor as drugs of choice for the edema relief in the pediatric patient cohort. The purpose of this retrospective study was to evaluate the equivalence and safety of Icatibant and a C1-inhibitor concentrate for the edema management. Materials and methods used: the study included 34 HAE-C1-INH patients who had experienced 302 attack episodes in total. The inclusion criteria were a registered episode of angioedema in a patient aged 0 up to 18 y/o, confirmed HAE diagnosis and one of the two studying drugs intake within 24 hours after the onset of the first edema symptoms. Patients were administered with Icatibant, subcutaneously, or with C1-esterase inhibitor, intravenously. The efficacy was evaluated by comparing the presence of relief and/or relief of symptoms during the mentioned therapy. All of the adverse reactions during the therapy were also recorded in order to assess the drugs’ safety. Results: a total of 302 attack episodes were analyzed in 34 patients in the period from 2016 to 2021. Icatibant was used in 225 (74.5%) cases in 34 patients, and human C1-esterase inhibitor was used in 77 (25.5%) cases in 27 patients. It was allowed to use both drugs in the same patient in different angioedema episodes. The age of the children included in the analysis at the time of the first episode ranged from 1 to 14 y/o (Me 4.5 y/o). The edema was peripheral in most of the studied cases. The drugs were found to be equivalent in terms of duration until the edema symptoms’ relief (Me duration was 30 min. in both drugs, p=0.005), but not in terms of duration until the symptoms cut-off, - with greater values for Icatibant compared to the C1-inhibitor human esterase (p=0.394). Conclusion: a relatively similar efficacy and safety of both drugs as well as the possibility for their use in all age groups were recorded. It is therefore necessary to take into consideration the availability of the satisfactory venous access when choosing a drug for stopping the edema; the patient’s age (in order to ensure the fastest possible administration of the drug counting from the onset of edema); the remoteness of a patient’s location during the attack from the nearest available and satisfying medical facility; the patient’s and/or his/her parent(s)/caretaker(s) preferences. The study demonstrated that both Icatibant and the C1-inhibitor concentrate have high safety profile.

For citation: A.Yu. Shcherbina, A.A. Mukhina, A.G. Rumyantsev. Congenital immunity defects as a human pathology studying pattern. Pediatria n.a. G.N. Speransky. 2023; 102 (2): 8-10. DOI: 10.24110/0031-403X-2023-102-2-8-10.

For citation: S.V. Voronin, R.A. Zinchenko, I.Yu. Efimova, S.I. Kutsev, A.V. Marakhonov, A.A. Mukhina, G.A. Novichkova, D.E. Pershin, Yu.A. Rodina, A.G. Rumyantsev, A.Yu. Shcherbina. Neonatal screening, postnatal diagnosis and tactics of preclinical treatment and prevention of primary immunodeficiencies in children. Guidelines by the experts from the National Association of Experts in Primary Immunodeficiencies (NAEPID) and the Association of Medical Genetics (AMG) of Russia. Pediatria n.a. G.N. Speransky. 2023; 102 (2): 11-33. DOI: 10.24110/0031-403X-2023-102-2-11-33.

Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (AT; Louis–Bar syndrome) are primary immunodeficiencies (PID) associated with chromosome instability and DNA repair defects that predispose individuals to an increased risk of various malignancies. In our study, we retrospectively analyzed clinical characteristics and outcomes of 28 cancer cases in 14 patients with AT and 10 patients with NBS who had been treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between January 2007 and December 2022. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The most common type of malignancy was mature B-cell non-Hodgkin lymphoma (B-NHL) (42%), with diffuse large B-cell lymphoma (DLBCL) accounting for 91% of all B-NHL cases. Other cases included T-cell acute lymphoblastic leukemia (ALL) ( n = 3), B-cell ALL ( n = 2), Hodgkin lymphoma ( n = 3), NK/T-cell lymphoma ( n = 1), T-cell lymphoblastic lymphoma ( n = 1), peripheral T- cell lymphoma ( n = 2), medulloblastoma ( n = 1) epithelioid rhabdomyosarcoma ( n = 1), T-cell prolymphocytic leukemia ( n = 2). A total of 4 patients were diagnosed with second malignancies (2 children with AT and 2 children with NBS. The diagnosis of PID was suspected or confirmed before the initiation of cancer therapy in 62% of AT patients and in 100% of NBS patients. Treatment was given in accordance with standard protocols with chemotherapy dose modifications. A total of 93% of patients with AT and 80% of patients with NBS required dose reduction. The level of response was quite high: 81% of patients with AT and 58% of patients with NBS achieved complete remission. According to our data, the use of reduced-dose chemotherapy regimens helps to achieve an acceptable toxicity profile without reducing the overall effectiveness of treatment.

The aim of this study was to analyze the clinical and laboratory data of 101 patients (61 boys, 40 girls) diagnosed with PFAPA syndrome. The age of onset of PFAPA syndrome ranged from 8 to 36 months (the median age of onset was 18 months). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. In most cases, clinical manifestations included recurrent fevers, acute tonsillitis (in 84% of cases, the tonsils were covered with a whitish coating), and cervical lymphadenitis. More rarely, the patients had diarrhea, vomiting, myalgia, arthralgia, and rash. All of the patients met the criteria proposed by G.S. Marshall. Our management strategies for patients with PFAPA syndrome include symptomatic treatment with antipyretics, short-term glucocorticosteroid therapy, and tonsillectomy. The majority of patients have complete resolution of PFAPA symptoms by the age of 7 regardless of the type of therapy.

This paper presents a case of rare primary immunodeficiency belonging to the group of monogenic autoinflammatory diseases with PLCy2-associated antibody deficiency and immune dysregulation (APLAID). Here we describe our experience in the management of a 7-year-old child with this syndrome and discuss key information about the pathogenesis and clinical manifestations of APLAID based on the analysis of the known cases. Due to the rarity and novelty of the disease, there is a lack of established criteria for the identification and diagnosis of APLAID and no established standard of care. We report our experience of treating APLAID with a tumor necrosis factor-a inhibitor and our analysis of the effectiveness of treatment and adverse events. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

One of the main goals of newborn screening is the early detection of a number of severe disorders for which effective treatment is available, and early diagnosis prevents serious consequences. Primary immunodeficiencies (PIDs) are a heterogeneous group of congenital immune disorders and are urgent immunological conditions requiring prompt diagnosis and treatment. Screening for primary immunodeficiencies using T-cell receptor excision circles (TREC) is used in many countries around the world. However, in addition to severe combined immunodeficiency, other forms of PIDs with T cell deficiency such as 22q11.2 deletion syndrome (22q11.2DS), CHARGE syndrome, trisomy 21, etc., can be detected during newborn screening. 22q11.2DS syndrome is one of the most common chromosomal microdeletion syndromes with an estimated prevalence of 1 in 3000–6000 births. The clinical manifestations of 22q11.2DS are quite variable. Neonatal diagnosis is traditionally based on the recognition of classic features and cytogenetic testing but many patients only come to medical attention after later symptoms have been identified. Still, the early diagnosis of 22q11.2DS ensures adequate treatment and the highest possible quality of life in such patients. Here, we report a clinical case of 22q11.2DS syndrome identified during a pilot project of newborn screening for primary immunodeficiencies in the Russian Federation in 2022. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 20 patients (9 boys, 11 girls) diagnosed with cryopyrin-associated periodic syndrome (CAPS) with an assessment of the efficacy and safety of therapy in 6 patients with an inhibitor of the interleukin-1 receptor – anakinra. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. The age of CAPS manifestation ranged from 0 to 27.0 months (median – 2 months). The clinical manifestations were dominated by fever, rash, lesions of the central nervous system, musculoskeletal system. During the attack, all 20 patients had an increase acute phase proteins of blood. All patients had heterozygous mutation in the NLRP3 gene, with the highest frequency of localization in exon 3 (17/20). 6/20 patients were initiated on anakinra therapy. All 6 patients who have been treated of anakinra enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 5/6 patients achieved full remission.

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

Correspondence: Natalia B. Kuzmenko, MD, PhD, Head of the Department of Epidemiology and Monitoring of Immunodeficiencies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation Address: 1 Samory Mashela St., Moscow 117997, Russia E-mail: plunge@list.ru DOI: 10.24287/1726-1708-2020-19-4suppl-62-67 Хромосомные аберрации как причина комплексного фенотипа у детей с первичными иммунодефицитами

Most of known primary immunodeficiencies (PID) are monogenic diseases, mainly due to the point defects in the immune system genes. However, in some rare cases the immunodeficiency is caused by various chromosomal aberrations. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. A retrospective analysis was performed on a group of 15 patients with clinical and laboratory signs of immunodeficiency, whose chromosomal aberrations were detected by various methods. In six patients from four different families, microdeletions with inclusion of a gene ( CTLA4 , NFKB1 ) or a part of a known PID gene ( NBAS , DCLRE1C ) were detected. Four patients had a complex phenotype, where a mutation in the known PID genes ( BTK , CYBB , STAT1 GOF , ATM ) was combined with a chromosomal defect. In one case, a homozygous damage in the  USB1 gene was confirmed by detection of dysomy chromosome 16 from the father`s side. Two patients were diagnosed with known chromosomal defects – DiGeorge2 and Jacobsen syndrome. Two other patients had various chromosome abnormalities not previously described in PID`s patients. 12/15 (80%) patients had syndromic features – various skeletal dysmorphisms, malformations, and developmental delay. Immunodeficiency genes can be damaged within the chromosomal aberrations. The combination of the various methods of genetic testing is important for patients with PID. Even in PID patients without syndromic features the chromosomal analysis methods or PID diagnosis are necessary.

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

Primary immunodeficiencies (PID) are caused by defects in genes of immune system. The mutations may occur de novo or can be inherited. The frequency of familial PID cases varies in different populations and depends on multiple factors. The aim of this study was to analyze familial PID cases among pediatric patients from NMRCPHOI D. Rogachev. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. 1075 children from 1020 families with molecular PID diagnosis were analyzed retrospectively. One hundred and forty-six children had at least one relative with the same disorder; mutations were identified in 31 PID’s genes. The frequency of familial cases was 13.6%. The proportion of families with two or more affected children was 5.4%. Patients born in a consanguineous marriage made up 3% of the observed children. Autosomal dominant PID were typical for families with affected adult relatives. Because of the high amount of familial cases, all parents of children with PID as well as adult PID patients of childbearing age should seek a familial genetic counselling immediately after the corresponding diagnosis. Patients whose PID diagnosis has not been genetically verified, should be urgently tested to find an underlying molecular genetic cause of the disease. Prenatal/preimplantation diagnostic and screening of their close relatives are very important in these families.

Evans syndrome (ES) is a rare disorder accompanied by autoimmune hemolytic anemia and immune thrombocytopenia. ES in children is often associated with the defect of immune system regulation. This article presents an analysis of the results of investigation of 54 children with ES admitted to the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology during the period 2012–2019. The male-to-female ratio was 1.07:1 and the median age of the disease onset was 4 years (0 months – 16 years). Based on the results of molecular genetic testing, the diagnosis was changed in three patients to congenital TTP. Thus, for further analysis 51 patients were available. Thirty-nine out of 51 children (76.5%) had secondary ES, the median age of the disease onset was 4 years (2 months – 12 years), the male-to-female ratio was 1.05:1. PID was genetically confimed in 25 out of 39 patients, in the remaining 14 cases the diagnosis of PID was based on clinical and laboratory fidings only. Twelve patients (22.2%) had idiopathic (primary) ES, the median age of the disease onset was 8 years (7 months – 16 years) and the male-to-female ratio was 1:1. The disease onset in ES was more often accompanied by isolated cytopenia: ITP – 22 (43.1%) patients, AIHA – 15 (29.4%) patients, immune neutropenia – 1 (2%) patient, simultaneously with AIHA and ITP – 8 (15.7%) patients, pancytopenia – 5 (9.8%) patients. The second cytopenia developed on average after 2 years (1 month – 9 years). Neutropenia was observed only in secondary ES. The mortality rate for ES was 9.8%. First-line therapy (IVIG, glucocorticoids) for ES showed low effctiveness and sustained remission was observed only in 5.9% of patients. Thirty-four (87%) patients with secondary ES and 9 (75%) patients with idiopathic ES required other lines of therapy. The next-line drugs that showed good effctiveness were rituximab (76.5%), MMF (94%), and sirolimus (83%). Combinations of rituximab and MMF, rituximab and sirolimus were also effctive and induced sustained remission without other therapy in 83.3% and 75% of patients respectively. Children with ES need thorough examination, including genetic testing, for the early diagnosis of PID and the exclusion of congenital TTP. The combination of rituximab and MMF proved to be the most effctive treatment for ES.

According to the data from Russian primary immunodeficiencies (PID) registry 71% of registered patients were treated with immunoglobulins (IG). Regular immunoglobulin substitutions were reported in 90% of patients with primary antibody deficiencies (PAD), 86% - with syndromic PID and 91% of patients with combined T and B cell defects. The study was supported by Academic Council of Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology and approved by Local Ethical Committee within the Russian PID registry. Regular IG substitution was analyzed in the representative cohort of 235 PID patients from 12 Russian regions. Of these 121 were children, 114 – adults. In 78% cases IG treatment has been started during the first 10 years of life. 80% patients were treated with highly safe products (Octagam 5% and 10%, Privigen, IG VENA, Gamunex) reaching therapeutic median pre-infusion level of serum IgG of 7 g/l. Significantly lower levels of pre-infusion serum IgG were observed in patients treated with Gabreglobin-IgG. Irregular treatment was observed in 61% of patients mainly due to the poor drug supply (lack of medication in the health care centers). Infections were reported in 90% percent of patients with irregular treatment. Unscheduled hospitalizations were two times more frequent in the group of patients with irregular IVIG treatment. Additionally, we assessed quality of life of patients with regular IVIG treatment, which significantly improved in comparison with the pretreatment period and became comparable to the group of healthy controls.

Evans syndrome (ES) is a rare disorder accompanied by autoimmune hemolytic anemia and immune thrombocytopenia. ES in children is often associated with the defect of immune system regulation. This article presents an analysis of the results of investigation of 54 children with ES admitted to the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology during the period 2012–2019. The male-to-female ratio was 1.07:1 and the median age of the disease onset was 4 years (0 months – 16 years). Based on the results of molecular genetic testing, the diagnosis was changed in three patients to congenital TTP. Thus, for further analysis 51 patients were available. Thirty-nine out of 51 children (76.5%) had secondary ES, the median age of the disease onset was 4 years (2 months – 12 years), the male-to-female ratio was 1.05:1. PID was genetically confimed in 25 out of 39 patients, in the remaining 14 cases the diagnosis of PID was based on clinical and laboratory fidings only. Twelve patients (22.2%) had idiopathic (primary) ES, the median age of the disease onset was 8 years (7 months – 16 years) and the male-to-female ratio was 1:1. The disease onset in ES was more often accompanied by isolated cytopenia: ITP – 22 (43.1%) patients, AIHA – 15 (29.4%) patients, immune neutropenia – 1 (2%) patient, simultaneously with AIHA and ITP – 8 (15.7%) patients, pancytopenia – 5 (9.8%) patients. The second cytopenia developed on average after 2 years (1 month – 9 years). Neutropenia was observed only in secondary ES. The mortality rate for ES was 9.8%. First-line therapy (IVIG, glucocorticoids) for ES showed low effctiveness and sustained remission was observed only in 5.9% of patients. Thirty-four (87%) patients with secondary ES and 9 (75%) patients with idiopathic ES required other lines of therapy. The next-line drugs that showed good effctiveness were rituximab (76.5%), MMF (94%), and sirolimus (83%). Combinations of rituximab and MMF, rituximab and sirolimus were also effctive and induced sustained remission without other therapy in 83.3% and 75% of patients respectively. Children with ES need thorough examination, including genetic testing, for the early diagnosis of PID and the exclusion of congenital TTP. The combination of rituximab and MMF proved to be the most effctive treatment for ES.