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Summary Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells.

Shwachman-Diamond syndrome (SDS) is a rare, autosomal recessive multisystemic disorder characterized by pancreatic insufficiency and bone marrow failure. Short stature is a recognized feature of SDS syndrome; however, systemic data concerning recombinant human growth hormone (rGH) treatment are limited. Aim of the study: To assess the effect of rGH treatment in patients with SDS.Retrospective data were collected from patients with SDS and growth hormone deficiency (GHD) treated with rGH in the Children's Memorial Health Institute in Warsaw. The annual growth velocity (GV) and height standard deviation score (SD) were compared for up to 2 years of rGH treatment.Six SDS patients (M : F = 1 : 5) treated with rGH were identified. The median age of starting rGH therapy was 7.5 years, with a mean baseline height SD of -4.06 (range: -6.3 to -2.3 SD). The height SD significantly improved to -3.3 (p = 0.002) and then -3.03 (p = 0.002), following 1 and 2 years of treatment, respectively. The average GV for the patients prior to starting treatment was 4.9 cm/year (range: 3.1-6.5 cm/year), which significantly improved to 7.6 cm/year (range: 5.7-9.6 cm/year) after 1 year of rGH treatment (p = 0.020) and to 6.7 cm/year at the end of 2 years.Our study has shown that rGH treatment significantly improves the height SDS and GV of patients with SDS and GHD without any side effects. Further research is required to analyse the long-term effect of rGH therapy in patients with SDS.Zespół Shwachmana-Diamonda (SDS) jest rzadką, genetycznie uwarunkowaną wieloukładową chorobą, charakteryzującą się niewydolnością zewnątrzwydzielniczą trzustki, zaburzeniami hematologicznymi oraz wadami kośćca. Niskorosłość jest częstą cechą SDS, jednak dane dotyczące leczenia rekombinowanym ludzkim hormonem wzrostu (rGH) są ograniczone. Cel pracy: Ocena efektów leczenia rGH dzieci z zespołem Shwachmana-Diamonda.Retrospektywne dane zebrano od pacjentów z SDS i niedoborem hormonu wzrostu (GHD) leczonych rGH w Instytucie „Pomnik – Centrum Zdrowia Dziecka” w Warszawie. Roczne tempo wzrastania (GV) i odchylenie standardowe (SD) wzrostu oceniono przez okres 2 lat leczenia rGH.Zidentyfikowano sześciu pacjentów z SDS (M : K = 1 : 5) leczonych rGH. Mediana wieku, w którym rozpoczęto terapię rGH, wynosiła 7,5 roku, ze średnim początkowym SD wzrostu wynoszącym –4.06 (zakres: od –6.3 do –2.3 SD). SD wzrostu istotnie poprawiło się do –3.3 SD (p = 0,002), a następnie –3.03 SD (p = 0,002), odpowiednio po roku i dwóch latach leczenia. Średnie GV pacjentów przed rozpoczęciem leczenia wynosiło 4,9 cm/rok (zakres: 3,1–6,5 cm/rok), następnie istotnie wzrosło do 7,6 cm/rok (zakres: 5,7–9,6 cm/rok) po roku leczenia hormonem wzrostu (p = 0,020) i do 6,7 cm/rok po 2 latach leczenia.Analiza wykazała, że leczenie rGH znacząco poprawia SD wzrostu i GV u pacjentów z SDS i GHD, bez żadnych skutków ubocznych. Konieczne są dalsze badania, aby przeanalizować długoletnie efekty terapii rGH u pacjentów z SDS.

Introduction: Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by pancreatic exocrine insufficiency, immune deficiency, bone marrow failure, and bone malformations. Systematic data concerning endocrine function in SDS are limited. We studied patients diagnosed in The Children’s Memorial Health Institute in Warsaw, Poland, to assess the prevalence of various endocrinopathies. Material and methods: In the pilot study, retrospective data were collected for 5 patients with SDS. Subsequently, patients with SDS aged 3–16 years were recruited prospectively. In total, 19 patients with mutations in the SBDS gene were studied. Data were collected on anthropometric measurements, systemic screening tests of pituitary, thyroid, adrenal, pancreatic, and gonadal function, as well as bone mineral density. Descriptive statistics were tabulated and group differences assessed. Results: Twelve patients (63%) had ≥ 1 endocrine disorder, including growth hormone dysfunction (10 patients, 53%), hypothyroidism (2 patients, 10%), congenital hypopituitarism (1 patient, 5%), and/or type 1 diabetes mellitus (T1DM) (1 patient, 5%). The group of boys presented with a significantly lower height (–2.1 SD, p < 0.0001) and BMI (–1.0 SD, p < 0.00001). The group of girls also showed significantly lower height (–2.6 SD, p < 0.00001) and BMI (–0.7 SD, p < 0.0001). All patients had significantly lower height than their mid-parental height. Delayed bone age was found in 15 patients (84%) and osteopaenia in 12 of 15 patients (80%). Conclusions: Endocrine dysfunctions are common in SDS, especially growth hormone (GH) deficiency. Children with poor growth can benefit from an endocrinological evaluation and tests for GH deficiency. Bone mineral density measurements should be a part of a routine screening. Longitudinal studies are needed to better understand the aetiology and true prevalence of these disorders.

Background Shwachman-Diamond syndrome (SDS) is a rare genetic, multi-systemic disease characterized by exocrine pancreatic insufficiency, immune deficiency, bone marrow failure and skeletal abnormalities. Most patients present with failure in somatic development and short stature, but systematic data concerning those features are limited. The aim of the study was to assess the prevalence of failure in somatic development in the children with SDS. Methods An analysis of anthropometric measurements of 21 patients (14 girls and 7 boys),aged 2 to 17 years (mean age 6.3 years) with SDS diagnosed in The Children’s Memorial Health Institute in Warsaw, Poland was performed. The patients were measured using a Holtain Limited stadiometer, an electronic scale, a Harpenden anthropometer, a metric tape and a spreading caliper. The assessed anthropometric parameters were expressed as standard deviation scores in relation to the reference values in Poland, suitable for sex as well as calendar and growth age. Results A total of 66 measurements was collected and analyzed with a median number of 3 observations per patient. The group of boys presented with a significantly lower height (− 3.0 SD, p p p p p p p Conclusions Patients with SDS have abnormal somatic development. Both boys and girls are characterized by short stature, decreased weight, BMI, leg length, chest width as well as circumference and width of head. Anthropometric measurements provide important data on the process of growth and body proportions in children with SDS.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

Summary Two unrelated infants were diagnosed with and initially treated for hemophagocytic lymphohistiocytosis (HLH), but progressed to cholestasis and liver failure. Early onset lysosomal acid lipase deficiency (EO-LAL-D) was suspected due to lymphocytes with cytoplasmic vacuolation and/or adrenal calcifications and confirmed by enzymatic and genetic analysis. Enzyme replacement therapy with sebelipase alfa was implemented, but both children died, despite initial improvement. Since this inborn error of metabolism progresses rapidly in infants, early diagnosis is crucial, and appropriate treatment should be started as soon as possible. The authors suggest that the diagnosis of EO-LAL-D should be considered in infants with symptoms of HLH.

Primary immunodeficiencies (PID) lead to recurrent and/or severe infections in children and adults. They may play a unique role of ‘indicating’ disease, as they do not affect immuno-competent people. Patients who underwent such an infection have an urgent indication to be examined towards PID. In case of detecting any abnormalities, suggesting congenital disease of immune system, they need further advanced diagnostics and treatment to protect them against other infectious complications.

Rodzinna limfohistiocytoza (FHL)/rodzinny zespol hemofagocytarny to rzadka, zagrazająca zyciu choroba, bedąca skutkiem wrodzonego upośledzenia aktywności cytotoksycznej komorek NK i limfocytow T cytotoksycznych, ktora zwykle ujawnia sie pod wplywem zakazenia wirusowego. Glownymi objawami tego dziedziczonego w sposob autosomalnie recesywny zespolu są: trwająca ponad 7 dni gorączka, powiekszenie wątroby i/lub śledziony oraz bi- lub pancytopenia we krwi obwodowej. Do typowych objawow laboratoryjnych nalezą: hipofibrynogenemia, hipertrojglicerydemia, hiperferrytynemia, hipertransaminazemia, hiperbilirubinemia oraz limfocytarna pleocytoza w plynie mozgowo-rdzeniowym. W przebiegu choroby czesto obserwowane są zaburzenia funkcji wątroby i ośrodkowego ukladu nerwowego, spowodowane hipercytokinemią i naciekami z hiperaktywowanych makrofagow i limfocytow cytotoksycznych. Hemofagocytoza – charakterystyczny objaw morfologiczny, bywa nieobecna we wcześnie pobranej biopsji szpiku lub wezla chlonnego. Jeśli kryteria diagnostyczne są spelnione, to przed wykonaniem badan genetycznych nalezy oznaczyc wewnątrzkomorkową ekspresje perforyny w komorkach NK i limfocytach T cytotoksycznych, np. za pomocą cytometrii przeplywowej. Badanie to wykonywane jest w Pracowni Zgodności Tkankowej IP-CZD w Warszawie. Wynik mozna uzyskac w ciągu dwoch godzin. Chorzy pozbawieni wewnątrzkomorkowej ekspresji perforyny wymagają przeprowadzenia diagnostyki genetycznej w poszukiwaniu mutacji w genie PRF1, odpowiadającej za okolo 40% FHL na świecie. Pelne wyleczenie mozna osiągnąc jedynie po udanym przeszczepieniu macierzystych komorek krwiotworczych.

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

BACKGROUND AND OBJECTIVE Giant cell hepatitis (GCH) with autoimmune hemolytic anemia (AIHA) is a rare, progressive disorder in infants and young children. The disease is aggressive and may lead to liver or multiorgan failure with fatal prognosis. Therapy with anti-CD20 monoclonal antibody, rituximab (Rtx), proved effective. The primary objective of the study was to evaluate therapy for severe GCH with AIHA. METHODS We report on 5 cases of severe GCH with AIHA treated in our department between 2006 and 2011. RESULTS The median age of the children was 7 months (2-12 months), follow-up lasted 44 months (12-78 months), median (min-max), and the main observed symptoms were jaundice and hepatosplenomegaly. All of the children had positive direct Coombs test and biopsy-proven giant cell transformation of hepatocytes. Liver failure was observed in 3 children. First-line therapy (prednisone, azathioprine) proved ineffective in all but 1 of the patients, who initially responded to the treatment but relapsed after 4 months. The child subsequently developed hemophagocytic lymphohistiocytosis and died 2 months after hemopoietic stem cell transplantation. Four remaining patients finally achieved complete remission after 4 to 6 doses of Rtx. CONCLUSIONS We propose Rtx as the treatment of choice for severe GCH with AIHA in the early stages of the disease, provided steroids and azathioprine are ineffective.

Two unrelated children with HSE carry distinct heterozygous mutations in the gene encoding TANK-binding kinase 1., Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-α/β or IFN-λ is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid–induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-α2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients’ peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect of phagocyte NADPH-oxidase and characterized by severe, recurrent bacterial and fungal infections. Invasive aspergillosis (IA) is the leading cause of mortality in patients with CGD. We report the case of a 3-year-old boy with CGD, who developed IA despite antifungal prophylaxis. His treatment consisted of a 10-month-long multi-drug antifungal therapy, together with surgery, but these did not cause any substantial clinical improvement. BMT in high-risk patients with CGD remains a challenge due to both, higher risk of graft rejection and inflammatory flare in the course of immune recovery. Our patient rejected the first matched unrelated donor (MUD) allograft after RIC regimen recommended by the EBMT Inborn Errors Working Party for high-risk patients. After treosulfan-based conditioning and second MUD peripheral blood stem cell transplantation both, full reconstitution of the granulocytic series and complete recovery from IA, were achieved.

To the Editor: Disseminated bacillus Calmette-Guerin (BCG) infection has been noted in patients with primary immunodeficiency. Incidence rates have ranged from 0.06 to 1.56 cases per million vaccinated, and mortality rates have remained at ≈60% (1–7). Of 946 patients with primary immunodeficiency, including 29 with severe combined immunodeficiencies, diagnosed from 1980 through 2006 at the Children’s Memorial Health Institute in Warsaw, adverse events after BCG vaccination were observed in 16 (8,9). All 16 were children who had been vaccinated at birth with BCG, Brazilian strain (BioMed, Lublin, Poland). Four patients with severe combined immunodeficiency showed adverse reactions to BCG. Patient M.K. had mild inflammation at the site of the BCG injection and was successfully treated with rifampin. The patient subsequently received a bone marrow transplant, and 2 months later poor appetite, failure to thrive, and subfebrile condition were noted. Disseminated skin changes (with pus formation in the subcutaneous layer), osteomyelitis, and multiple lesions in the liver were found. A skin biopsy showed tuberculoma formations, which were PCR-positive for Mycobacterium tuberculosis complex (Amplified Mycobacterium Tuberculosis Direct [MTD] Test, Gen-Probe, Inc., San Diego, CA, USA) but had negative culture results. Complete recovery, including full immunologic reconstitution, was reached after 12 months of treatment with triple antituberculosis (TB) therapy (rifampin, isoniazid, and ciprofloxacin). Patient M.C., a 6-month-old boy, was admitted to an intensive care unit because of respiratory insufficiency. An unhealed BCG vaccination site was noted. Bronchopulmonary lavage samples were tested for M. bovis; positive PCR and culture results led to the diagnosis of disseminated BCG infection. Despite intensive anti-TB therapy, the child died of multiple organ failure. Autopsy showed typical granuloma formations and a hypoplastic thymus, typical for severe combined immunodeficiency. Male patients S.D. and C.G. were admitted to intensive care units at 6 and 8 months of age, respectively, with lymphadenopathy and multiple organ insufficiency. Each boy died of multiple organ failure; postmortem examination found granuloma formation and a hypoplastic thymus in each (8). Eight patients with severe combined immunodeficiency had local adverse events after vaccination with BCG. Inflammation 200 cases of disseminated BCG infection in patients with primary immunodeficiency (1–7). The diagnostic difficulties described for 8 of our patients with primary immunodeficiency have been noted by others (1–6,8–10). In only 2 cases was the Mycobacterium species successfully isolated and identified as M. tuberculosis complex, and in 1 case it was the M. bovis BCG strain. We propose novel criteria for the diagnosis of disseminated BCG infection in persons with primary immunodeficiency (Table). These criteria have recently been submitted to the European Society for Immunodeficiencies. Table Suggested diagnostic criteria for disseminated bacillus Calmette-Guerin (BCG) infection in persons with primary immunodeficiency* We believe that patients with severe combined immunodeficiency and any form of mild local changes at the BCG injection site should be given anti-TB therapy, which should be continued until complete immunologic reconstitution occurs after bone marrow transplant. Disseminated BCG infection with regional lymph node involvement needs at least triple anti-TB therapy followed by long-term prophylaxis. Disseminated BCG infection needs anti-TB therapy, including ≥4 anti-TB drugs, until the patient fully recovers.

Chronic neutropenia (CN) is defined by an absolute neutrophil count (ANC) below 1500/ul, lasting at least 6 months.clinical course and treatment of children afflicted with CN was analysed.we present 60 children treated in our department due to CN. The diagnosis was based on: bone marrow smears, ANC, immunologic investigation.we established the diagnosis of: Kostmann disease (KD), cyclic neutropenia (CyN), hyperIgM syndrome (HIGM), Shwachman-Diamond syndrome (SDS), severe chronic neutropenia (SCN) and chronic benign neutropenia (CBN) in: 4, 2, 2, 1, 21 and 20 children respectively. Due to positive results of tests: MAIGA, GIFT or GAT autoimmune neutropenia of infancy (AIN) was confirmed in 7 children. In 3 infants neutropenia was connected with HCMV- infection and Gancyclovir therapy. RHuG-CSF treatment was implemented in 14 and effective in 13 patients. A girl, suffering from KD, during rHuG-CSF therapy, developed chronic myeloblasts leucaemia and died. A boy, with the same diagnosis, underwent bone marrow transplantation from related donor but died from invasive pulmonary aspergillosis. Antibacterial prophylaxis was necessary in 29 children. We used Amoxicillin or Trimethoprim/Sulfametoxazole, obtaining decrease of frequency and severity of infections. During observation period all children suffered from upper respiratory tract infections, 19 had chronic gingivitis. Severe infections- bacterial pneumonia, sepsis, severe varicella and measles were observed in 30, 5, 2 and 1 patient respectively. A teenager, affected with SCN, died due to fulminant Clostridium perfringens infection.1. RHuG-CSF therapy is essential in children with KD and SCN (when accompanied by severe infections). 2. AIN proved to be a mild condition, although ANC decreased below 500. In this entity rHuG-CSF is recommended during severe infections and before surgery. 3. Antibiotic prophylaxis is recommended for children with: KD, CyN, GSD1b, CN in 1st year of life, HIGM; in other cases it is considered individually.

Combined vaccines are urgently needed because of the increasing number of recommended vaccines for children. Combined vaccines could be considered as having the same priming effect as monovalent vaccines. They demonstrated a good reactogenicity and tolerability profile. Combined vaccines are more comfortable option for the infant vaccination providing immunity against four or more important childhood diseases with a single injection at each visit.

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naive B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.