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Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by ELANE gene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects of ELANE mutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.

Congenital conditions caused by an absolute or functional deficiency of neutrophils are associated with considerable morbidity and mortality in children and adults. These disorders manifest with various phenotypes, but all contribute to an elevated risk of serious bacterial, fungal, and even viral infections. Quantitative neutrophil disorders include severe congenital neutropenia, cyclic neutropenia, and bone marrow failure syndromes, most notably Shwachman-Diamond syndrome. Phagocyte functional deficits result from myeloperoxidase deficiency; failed oxidative burst, e.g., chronic granulomatous disease; flawed migration as seen in the leukocyte adhesion disorders; and difficulty with intracellular granules as in Chediak-Higashi syndrome and neutrophil-specific granule deficiency. Early diagnosis is essential to minimizing the morbidity and mortality of these conditions with crucial diagnostic laboratory analyses including functional neutrophil studies to assess neutrophil migration and oxidative burst capabilities, flow cytometry, and direct pathologic evaluation of the bone marrow and peripheral blood. Supportive care often entails usage of antimicrobial prophylaxis, aggressive management of infectious complications, and regular administration of G-CSF. Frequently hematopoietic stem cell transplantation can be curative but is not without risks.

Neutropenic enterocolitis is a syndrome characterized by fever and abdominal pain in a neutropenic patient. It is often reported in children treated for leukemia and rarely reported in patients with other diseases. Herein, we report the case of a 9-year-old patient with a medical history of recurrent fever and mouth ulcers since the age of 4, who presented with neutropenic enterocolitis complicated with intestinal perforation which all leaded to disclose cyclic neutropenia. The patient was successfully treated by aggressive supportive care combined with surgical intervention. Neutropenic enterocolitis with possible complications should be considered and promptly managed in every neutropenic patient and may reveal a rare cause of neutropenia as cyclic neutropenia.

Cyclic neutropenia has been rarely associated with chronic inflammation and development of reactive AA amyloidosis. We report a family with cyclic neutropenia with associated renal and thyroid amyloid. A 12-year-old female presented with thyromegaly, recurrent aphthous ulcers, severe neutropenia, and renal failure. Renal and thyroid biopsies revealed abundant amyloid deposition. Presence of a heterozygous ELANE c.358 A>T gene mutation p.I120F variant with autosomal dominant inheritance confirmed the diagnosis of cyclic neutropenia. The patient's father also had neutropenia and amyloidosis with renal failure. We started filgrastim to attenuate neutropenia and thereby reduce chronic inflammation and minimize further amyloid deposition.

This paper summarizes the evidence supporting the classification of cyclic neutropenia as a dynamical disease and periodic chronic myelogenous leukemia is also considered. The unsatisfactory state of knowledge concerning the genesis of cyclic thrombocytopenia and periodic autoimmune hemolytic anemia is detailed.

Neutropenic enterocolitis is a syndrome characterized by fever and abdominal pain in a neutropenic patient. It is often reported in children treated for leukemia, rarely reported in patients with other diseases. Herein, we report the case of a 9-year-old patient with a medical history of recurrent fever and mouth ulcers since the age of 4, who presented with neutropenic enterocolitis complicated with intestinal perforation which all leaded to disclose cyclic neutropenia. The patient was successfully treated by aggressive supportive care combining to surgical intervention. Neutropenic enterocolitis with possible complications should be considered and promptly managed in every neutropenic patient and may reveal a rare cause of neutropenia as cyclic neutropenia

Human neutrophil elastase (HNE) is a major cause of the destruction of tissues in cases of several different chronic andinflammatory diseases. Overexpression of the elastase enzyme plays a significant role in the pathogenesis of various diseases including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, rheumatoid arthritis, the rare disease cyclic hematopoiesis (or cyclic neutropenia), infections, sepsis, cystic fibrosis, myocardial ischemia/reperfusion injury and asthma, inflammation, and atherosclerosis. Human neutrophil elastase is secreted by human neutrophils due to different stimuli. Medicine-based inhibition of the over-activation of neutrophils or production and activity of elastase have been suggested to mend inflammatory diseases. Although the development of new elastase inhibitors is an essential strategy for treating the different inflammatory diseases, it has been a challenge to specifically target the activity of elastase because of its overlapping functions with those of other serine proteases. This review article highlights the reported natural polypeptides as potential inhibitors of elastase enzyme. The mechanism of action, structural features, and activity of the polypeptides have also been correlated wherever they were available.

Leukopoiesis is the process of forming and developing different types of leukocyte in the bone marrow of adults and hematopoietic organs of the fetus. The process of leukopoiesis starts from inactivated stem cells originating from hematopoietic. When the process of differentiation of blood cells occurs, the sub-process of leukocyte production becomes slow-down. This can lead to serious illnesses such as cyclic neutropenia. For this purpose, the mathematical model for leukocyte formation with two consecutive delays proposed using more general continuous function as feedback control functions. The apoptosis rate of the neutrophil precursor also being replaced by a nonconstant reduction function. The asymptotic stability of the equilibrium point is proved. The numerical simulation showed the illustration of solution behavior over time. We can conclude that the population of HSC daughter cells in the proliferation process tends to diverge in some critical cases.

Introduction: Severe congenital neutropenia (SCN) includes a group of genetic disorders which cause to arrest of neutrophil maturation. SCN can be associated with heterogenous group of genetic defects in ELANE, GFI1, HAX1, G6PC3, JAGN1, VPS45 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene. Aim: Here we report a patient who has a HAX1 mutation presented with cyclic manner. Case Report: A 6 year old female patients was admitted with recurrent apthous stomatitis. We followed the patient as cyclic neutropenia according to complete blood count results 2 times for 6 weeks. After persistant neutropenia developed during a severe varicella infection, we analysed HAX1 mutation, the result was interesting and incompatible with reported cyclic neutropenia patients. Conclusion: We suggest that HAX1 deficiency should be thought in patients who have normal neutrophil counts in the between of infections.

Key Clinical Message Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb‐Scargle periodogram).

Severe congenital neutropenia (SCN) is characterized by persistent neutropenia and risk of invasive, life-threatening infection as well as transformation to hematopoietic malignancy. The closely related syndrome cyclic neutropenia is characterized by recurrent episodic neutropenia accompanied by symptoms including infection. Understanding the genetic etiology of congenital neutropenia can help to direct therapy, guide surveillance and health maintenance strategies, and contribute to our understanding of basic neutrophil biology. Although mutations in ELANE are the most frequent cause of congenital neutropenia, there is a wide and ever-growing list of additional causative variants. Additionally, there appears to be regional genetic variability. For example, mutations in HAX1 are rarely if ever observed in North America while they are more common in Europe. We undertook exome sequencing of a large cohort from the Severe Chronic Neutropenia International Registry (SCNIR) of North America in an effort to define the genetic spectrum of congenital neutropenia and aid in the discovery of new pathogenic variants. We expanded our previously reported study of whole exome sequencing to include 152 cases of chronic neutropenia, comprised of 94 cases of SCN and 58 cases of cyclic neutropenia. We selected cases in which ELANE testing was negative, or in a small minority of cases, where ELANE testing had not yet been performed. Indeed, exome sequencing only identified 7 cases (5 SCN and 2 cyclic) carrying pathogenic ELANE mutations in this cohort. In the remaining 145 cases, we analyzed exomes for the presence of variants in genes previously associated with congenital neutropenia including AK2, AP3B1, CD40LG, CLPB, CSF3R, CXCR2, CXCR4, DNAJC21, DNM2, DOCK2, EFL1, EIF2AK3, ELANE, G6PC3, GATA1, GATA2, GFI1, GINS1, HAX1, IRAK4, JAGN1, KAT6A, KRAS, LAMTOR2, LYST, MYD88, PGM3, PSTPIP1, RAB27A, RAC2, SBDS, SEC61A1, SLC37A4, SMARCD2, SRP54, STK4, TAZ, TCIRG1, TCN2, TLR8, USB1, VPS13B, VPS45, WAS, WDR1 and WIPF1. Pathogenic heterozygous mutations of CLPB that localize to the ATP-binding pocket were identified in 7 cases, making it the second most common cause of congenital neutropenia in North America. We additionally identified 4 cases with G6PC3 pathogenic variants, and one case each with pathogenic variants in JAGN1, CXCR4 (the cause of WHIM syndrome), germline homozygous CSF3R, and GFI1. Interestingly, we identify 2 unrelated individuals (one with SCN and one with cyclic) and 2 siblings with SCN all of whom possess a recently described heterozygous variant in SRP54 (p.T117del). We collected genomic DNA from the affected mother of the 2 siblings, an additional unaffected sibling, and the unaffected grandparents. Through this kinship, we can confirm the de novo appearance of this variant in the second generation and demonstrate that it tracks with disease status (Figure 1). We also identified 2 unrelated individuals with SRP54 variants affecting residue 175 also located within the GTPase domain (p.G175E or p.G175del). Both variants are absent from the gnomAD database, and studies are underway to demonstrate de novo acquisition. In summary, we have defined the spectrum of mutations present in ELANE-wildtype chronic neutropenia cases in North America. Pathogenic or likely pathogenic variants were identified in 26 out of 145 (18%) cases. The most frequently mutated genes were of CLPB, SRP54, and G6PC3, while mutations in HAX1 were not seen. Importantly, some of these mutations are associated with genetic syndromes with extra-hematopoietic findings (for example, CLPB and SRP54) that would warrant additional evaluations and targeted health maintenance. These findings emphasize the importance of sending large panels for genotyping, rather than targeted ELANE testing. Figure 1 Figure 1. Disclosures Bolyard: X4 Pharmaceuticals: Research Funding. Makaryan: Emendo Biotherapeutic: Research Funding. Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Background: Cyclic neutropenia is a rare hematologic disorder affecting neutrophils. It is classified by recurrent neutropenia (typically every three weeks) with associated symptoms including fever, malaise, and recurrent mucosal and skin infections. Pathogenic variants of ELANE, the gene that encodes neutrophil elastase, are thought to cause these findings, however, other pathogenic variants of different genes have also been noted. The estimated frequency of cyclic neutropenia is 1/10 6 in the general population. It is most commonly diagnosed in children but may rarely be diagnosed in adulthood. There is no known increased prevalence in women as compared to men. Whole Exome Sequencing can be used for diagnosis when genetic concerns are present. Objective: This case report aims to describe a novel pathogenic variant in a pediatric patient with cyclic neutropenia. Design/Method: Single subject case report Results: This is a single case report of a 7-year-old female with past medical history of cyclic neutropenia, anemia, recurrent skin and buccal infections, speech delay, and behavioral problems. The patient initially presented at age 1 with high fevers and skin infections and was found to have decreased neutrophil counts. Work up at that time was consistent with cyclic neutropenia. Bone marrow aspirate and biopsy performed at 1 and 7 years of age showed decreased neutrophil count with normal maturation without any evidence of MDS. Her peripheral blood for bone marrow failure evaluation was non-contributory. Due to persistent neutropenia, normal bone marrow findings, and being on weekly chronic G-CSF administration Whole Exome Sequencing was evaluated. Results of which showed a novel compound heterozygous pattern for two variant copies of the G6PC3 gene, with our patient inheriting a copy from each parent. Discussion: The G6PC3 gene encodes the expressed glucose-6-phosphate enzyme which catalyzes the final step in glycogenolysis. It is hypothesized that this deficiency causes unregulated levels of glucose, resulting in increased stress of the endoplasmic reticulum leading to apoptosis of neutrophils. Pathogenic variants of G6PC3 cause autosomal recessive G6PC3 deficiency and this can be clinically characterized as severe congenital neutropenia. Classic G6PC3 deficiency includes severe congenital neutropenia as well as cardiovascular abnormalities, urogenital abnormalities, and pulmonary hypertension. This novel pathogenic variant is likely responsible for the cyclic neutropenia observed in our patient. G6PC3 variants are an important differential diagnosis in the work-up of other causes of neutropenia. Whole Exome Sequencing is a cost-effective method for diagnosis and a valuable tool in evaluation and management of complex hematologic disorders. Disclosures No relevant conflicts of interest to declare.

Mutations in ELANE, the gene for neutrophil elastase (NE), a protease expressed early in neutrophil development, are the most frequent cause of cyclic (CyN) and severe congenital neutropenia (SCN). We hypothesized that inhibitors of NE, acting either by directly inhibiting enzymatic activity or as chaperones for the mutant protein, might be effective as therapy for CyN and SCN. We investigated β-lactam–based inhibitors of human NE (Merck Research Laboratories, Kenilworth, NJ, USA), focusing on 1 inhibitor called MK0339, a potent, orally absorbed agent that had been tested in clinical trials and shown to have a favorable safety profile. Because fresh, primary bone marrow cells are rarely available in sufficient quantities for research studies, we used 3 cellular models: patient-derived, induced pluripotent stem cells (iPSCs); HL60 cells transiently expressing mutant NE; and HL60 cells with regulated expression of the mutant enzyme. In all 3 models, the cells expressing the mutant enzyme had reduced survival as measured with annexin V and FACS. Coincubation with the inhibitors, particularly MK0339, promoted cell survival and increased formation of mature neutrophils. These studies suggest that cell-permeable inhibitors of neutrophil elastase show promise as novel therapies for ELANE-associated neutropenia.

Barth syndrome (BTHS) is a rare X-linked disease characterized by dilated cardiomyopathy, proximal skeletal myopathy and cyclic neutropenia. It is caused by various mutations in the tafazzin (TAZ) gene located on Xq28 that results in remodeling of cardiolipin and abnormalities in mitochondria stability and energy production. Here we report on a novel c.285-1G>C splice site mutation in intron 3 of the TAZ gene that was detected prenatally.

PFAPA syndrome—Periodic fever with aphthous stomatitis, pharyngitis, and adenitis—is the most common auto inflammatory condition amongst children worldwide—with the caveat that excludes specific geographic regions with a high prevalence of Familial Mediterranean Fever. A cardinal feature in addition to the described clinical signs is the clockwork like regular periodicity of the fevers. In contrast to most of the other auto inflammatory conditions and cyclic neutropenia the course is usually benign, the condition is self-limiting and the long-term outlook is very favourable, with most children outgrowing the condition by 10 years of age. The precise aetiology remains unknown and to date no specific genetic mutation has been identified although familial cases have been described.

CyN is a rare hematopoietic disorder characterized by an oscillating count of neutrophils ranging from less than 200 neutrophils per µl at the cycle nadir to a maximum of 2000 neutrophils per µl at the cycle peak in an average 21-day rhythm. At the nadir of the ANC cycle, the patients consequently suffer from multiple bacterial and fungal infections. As a subtype of SCN, which shows a constant low ANC, both phenotypes are known to be associated with mutations in ELANE. However, the pathomechanism leading to the typical ANC cycling in CyN is unclear. This work focuses on the probable influences and regulatory mechanisms that could contribute to this cycling phenomenon. A microarray run performed with an index CyN patient represented the starting point of experiments. This microarray showed cycling patterns of granule protein genes and NAMPT expressions inverse to the ANC course. To confirm these findings, the index patient’s data were verified by using qPCR. Additionally, four further CyN patients and six healthy donors served as comparison groups. While the cycling character in nine out of ten examined genes was confirmed in the index CyN patient, only three genes were cycling only slightly in the other CyN patients, among them ELANE. This inversely cycling ELANE expression, as compared to the ANC oscillations in all examined CyN patients, contributed to the hypothesis of a negative feedback regulation of neutrophil maturation. Moreover, as a reason for the difference in expression of the index patient to the others, the index patient’s additionally inherited C/EBPe mutation was discussed. This mutation could lead to the inhibition of secondary granule proteins, thus contributing, besides other variables, to the unique protein expression and the neutropenic situation in this patient. As another differentiating criterion to SCN, CyN was always described as benign and not to be associated with MDS/AML. However, in 2016, the author’s research group identified the first two CyN patients harboring the preleukemic CSF3R mutation by deep, ultradeep, and exome sequencing. One of these patients additionally acquired the RUNX1 mutation and was diagnosed with AML. With this knowledge, a prophylactic screening of CyN patients becomes particularly important.

Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.

A hypocellular bone marrow with isolated decrease in myeloid precursors, and early onset low neutrophil count below 500/μL, are suggestive of congenital neutropenia Congenital neutropenia often refers to severe congenital neutropenia (SCN), subsuming a constellation of other syndromes including Kostmann syndrome (with HAX1 mutation), cyclic neutropenia (with ELANE gene mutation), Shwachman-Diamond syndrome (with SBDS mutation), etc. The recurring pattern of neutropenia and fever lasting between 3 and 7 days and a rise in ANC above 500/μL few days after neutropenic fever attacks, can guide to a diagnosis of cyclic neutropenia Decreased bone marrow cellularity with early myeloid “arrest” at the promyelocyte/myelocyte stage is diagnostic for SCN These are at highest risk for development of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)

The phagocytic system is an indispensable part of the immune defense mechanism and innate immune system. Pulmonary manifestations could be either ambiguous or misleading. The most common involved organ in chronic granulomatous deficiency (CGD) is the lung, which manifests with infectious and non-infectious (granuloma and fibrosis) complications. Myeloperoxidase (MPO)-deficient individuals are mostly asymptomatic; however, invasive Candida (IC) may present as candidemia, disseminated infection, and pneumonia. Neutrophil-specific granule deficiency pulmonary manifestations are recurrent pneumonias and lung abscess mostly due to Staphylococcus aureus and Pseudomonas aeruginosa. In leukocyte adhesion deficiency (LAD), involvement of the skin and mucus membranes is a predominant clinical feature and then recurrent pulmonary infections. In RAC-2 deficiency, pulmonary involvement although uncommon includes recurrent sinopulmonary infections, pneumonia, and bronchiectasis. In congenital neutropenia (CN), the child might begin to have fevers associated with respiratory symptoms of pneumonia. ELANE (neutrophil elastase) mutations are the most frequent known cause of congenital neutropenia which is characterized by oropharyngeal inflammation. G6PC3 deficiency and its severe form called Dursun syndrome are characterized by a triad of familial primary pulmonary hypertension (PPH), leukopenia, and atrial septal defects. Cyclic neutropenia is characterized by oscillating numbers of blood neutrophils. Pulmonary manifestations are upper respiratory infections (sinusitis and otitis media), pneumonia, and bronchitis. In Shwachman-Diamond syndrome (SDS), pulmonary manifestations are recurrent bronchopulmonary bacterial, viral, and fungal opportunistic infections and recurrent otitis media. Cohen syndrome is associated with laryngeal dysfunction and laryngomalacia to stenosis and vocal cord paralysis. Poikiloderma often accompanies severe neutropenia and bronchiectasis, lung abscesses, and lung granulomas. In other phagocytic deficiencies, including b-actin, aggressive periodontitis, Papillon-Lefevre syndrome, Barth syndrome, and glycogen storage disease Ib, no pulmonary manifestations have been reported.

A 78-year-old woman diagnosed with cyclic neutropenia 5 years previously had been treated with recombinant granulocyte-colony stimulating factor (G-CSF). She developed fever, tenderness and distension of temporal arteries after the treatment with G-CSF. Magnetic resonance imaging and ultrasonography revealed wall thickening of the temporal arteries. She was therefore diagnosed with giant cell arteritis (GCA). Small vessel vasculitis has been reported as a complication of G-CSF. However, the development of large vessel vasculitis after G-CSF treatment is quite rare. To our knowledge, the present case is the first report of GCA suspected to be associated with coexisting cyclic neutropenia and G-CSF treatment., Internal Medicine, 55(16), pp.2291-2294; 2016

To the editor: Congenital neutropenia (CN) and cyclic neutropenia (CyN) are rare genetic disorders of hematopoiesis predominantly caused by ELANE mutations.[1][1][⇓][2]-[3][3] Due to overlaps in their genetic profiles, CyN can be distinguished from CN by cycling neutrophil counts, usually at 21

Acquired mutations in the intracellular part of CSF3R (colony stimulating factor 3 receptor, granulocyte) have been detected with a frequency of more than 30% in severe congenital neutropenia (CN) patients. CN is a preleukemic syndrome with a risk of approximately 20% to develop leukemia. More than 80% of CN patients who develop acute myeloid leukemia or myelodysplastic syndrome reveal CSF3R mutations, suggesting that they are involved in leukemogenesis. Using deep-sequencing technology, we were able to analyze large cohorts of CN patients for the entire CSF3R sequence as well as to identify cell clones carrying mutations in the intracellular part of CSF3R with very high sensitivity. Acquisition of CSF3R mutations is a CN-specific phenomenon and is associated with inherited mutations causing CN or cyclic neutropenia, such as ELANE mutations. In the group of CN patients negative for known germ-line mutations, biallelic CSF3R mutations were identified. In addition, CSF3R mutant clones are highly dynamic and may disappear and reappear during continuous granulocyte colony-stimulating factor (G-CSF) therapy. The time between the first detection of CSF3R mutations and overt leukemia is highly variable.

Mucormycosis is an uncommon opportunistic fungal infection mostly affecting immunocompromised patients and gastrointestinal mucormycosis is a rare and life-threatening. We describe a 31-year-old man with a history of idiopathic cyclic neutropenia who developed perforations of the stomach and intestine and intra-abdominal bleeding due to disseminated gastrointestinal mucormycosis after the initial operation.

Introduction: Few studies have evaluated the quality of life (QOL) in those with chronic neutropenia. We present the largest such study to date with an additional extensive evaluation of patient reported outcomes (PROs) within this patient population. Methods: Adult & pediatric patients (or their caregivers) aged 5 years or greater electively completed the adult or pediatric PedsQL version 4.0 questionnaire and PROMIS short forms via an online survey tool following solicitation from the National Neutropenia Network. Survey measures were scored according to their respective scoring manuals. PROMIS scoring used item-level calibrations and patient raw scores were translated into standardized T-scores compared to healthy controls (mean 50, standard deviation 10) with higher scores representing more of the concept being measured. For PROMIS interpretations a minimally important difference (MID) between T-scores was considered ½ of one standard deviation. Demographic and health history questionnaires were also provided to participants. Calculated z-scores used means and standard deviations from previously published age-matched healthy controls. Data comparisons used t-test and Wilcoxon rank-sum test analyses. Results: Eighty adults & 14 children were assessed (Table 1). Chronic autoimmune neutropenia & cyclic neutropenia were the most common diagnoses in adults (45% & 25% respectively); while 43% of children had severe congenital neutropenia (SCN). The majority of adults (57%) receive G-CSF or GM-CSF (15% scheduled daily); 93% felt bone pain from the medication. A greater percentage of children receive G-CSF or GM-CSF (79% overall, 43% scheduled daily) but less (60%) felt bone pain. Bone pain from G-CSF or GM-CSF was rated as moderate or severe in 68% of adults & 40% of children (Table 1). Compared to healthy individuals (assuming mean of zero), patients surveyed had lower overall total QOL scores with a median z-score of -1.77 and interquartile range (IQR) of -3.48 to -0.23. Based on median (IQR) total PedsQL scores, there was a significant difference in the QOL between adults & children, as adults had a lower overall QOL (-2.12 (-3.54, -0.52) vs -0.17 (-1.71, 0.14); p=0.014). Adults showed no difference in mean total overall PedsQL scores for those with congenital neutropenia conditions (SCN & cyclic neutropenia) (mean 56.47, SEM 4.649) compared to those with acquired neutropenia (chronic autoimmune & idiopathic neutropenia) (mean 59.52, SEM 3.209) (p=0.5931). Pediatric patients with congenital neutropenia conditions (mean 68.37, SEM 5.959) showed a significantly lower QOL than children with acquired neutropenias (mean 85.7, SEM 4.304) (p=0.0428). Children & adults were noted to have higher overall scores of anxiety & anger compared to healthy controls (did not reach MID). Both groups also had reduced cognitive function scores compared to controls, with adults only meeting MID criteria (Table 2a). While adults had a MID decrease in physical function versus healthy controls, children with neutropenia were noted to have a MID increase in mobility. Adults described having significantly worse fatigue & pain than healthy controls. Interestingly, children with neutropenia had significantly less depression and stronger peer relationships than controls (Table 2a). Comparable PROMIS analyses between adult & pediatric patients showed a significant difference in fatigue (p=0.001) & depression (p=0.001) with adults noting elevated levels of the parameters. There was nearly a significant difference in pain between the two groups (p=0.081) but no difference in cognitive function, anxiety or anger scores (Table 2a). In-general proxy-reported pediatric PROMIS scores trended towards a negative impact of neutropenia on a child's mental health, mobility, pain, cognition and peer relationships. A significant difference (p=0.005) was noted in PROMIS mobility scores with patients self-reporting improved mobility versus controls and proxies describing reduced mobility (Table 2b). Conclusions: Chronic neutropenia undoubtedly complexly affects QOL and PROs. Assessments of these parameters by adult patients show a negative impact of the condition most prominently on QOL, physical function, fatigue, & pain. Children with neutropenia had comparable QOL scores to healthy controls but were reported to have fewer depressive symptoms, improved mobility and stronger peer relationships. Disclosures No relevant conflicts of interest to declare.

Neutropenic syndrome is quite common in pediatric practice. Its nature is diverse, and every case of neutropenia needs thorough differential diagnosis to determine the patient’s management. Only a differentiated approach to patients with neutropenia can prevent the development of severe complications of infectious processes. To illustratу this point, we present a clinical case of severe chronic bronchopulmonary disease in a 4-year-old child, who was examined and treated in children’s city pulmonology center. The child was admitted to the hospital with the complaints of persistent non-productive cough, episodic distal rales, loss of hearing. From the history of the disease it was found that from one month of age, the child had repeated otitis, relapsing bronchitis with bronchial obstructive syndrome, repeated pneumonia of different localization. A comprehensive examination including, in addition to standard laboratory tests, diagnostic and diagnostic bronchoscopy, computed tomography of the thoracic organs, revealed a bilateral diffuse catarrhal-purulent endobronchitis, computed tomography signs of diffuse interstitial changes in the lungs and bronchomalacia. A thorough dynamic analysis of hemograms from the outpatient card made it possible to suspect a congenital neutropenia in the patient. Multiple occurrence of neutropenic crises with a decrease in the number of neutrophils to 1,000 cells/μl and lower during the first year of the child’s life and their periodicity of 3–4 weeks confirmed the cyclical nature of neutropenia. The sternal puncture performed with the evaluation of the myelogram revealed no significant changes in the granulocyte number that was probably due to the period of remission of cyclic neutropenia at the time of examination. Thus, severe chronic respiratory disease in this child was clinical mask of cyclic neutropenia, which required a thorough diagnosis. Neutropenia in children should be considered by the practicing physician as a laboratory symptom, which requires understanding, comparison with clinical manifestations and obligatory dynamic analysis., Нейтропенический синдром довольно часто встречается в практике педиатра. Природа его разнообразна, и каждый случай нейтропении нуждается в проведении тщательной дифференциальной диагностики для определения тактики ведения больного. Только при дифференцированном подходе к пациентам с нейтропениями можно предупредить развитие серьезных осложнений инфекционных процессов. Для иллюстрации приводим клинический случай собственного наблюдения ребенка 4 лет с тяжелым хроническим бронхолегочным заболеванием, который находился на стационарном обследовании и лечении в детском городском пульмонологическом центре. Ребенок поступил с жалобами на постоянный влажный малопродуктивный кашель, эпизодические дистанционные хрипы, снижение слуха. Из анамнеза заболевания было установлено, что с месячного возраста у ребенка наблюдались повторные отиты, рецидивирующие бронхиты с бронхообструктивным синдромом, неоднократные пневмонии различной локализации. Комплексное обследование, включающее, помимо стандартных лабораторных исследований, лечебно-диагностическую бронхоскопию, компьютерную томографию органов грудной клетки, выявило у ребенка двусторонний диффузный катарально-гнойный эндобронхит, КТ-признаки диффузных интерстициальных изменений в легких и бронхомаляции. Тщательный динамический анализ имеющихся в амбулаторной карте гемограмм позволил заподозрить у пациента врожденную нейтропению. Многократное возникновение нейтропенических кризов со снижением числа нейтрофилов до 1000 кл/мкл и ниже на первом году жизни ребенка и периодичностью в 3–4 недели подтвердило циклический характер нейтропении. Проведенная стернальная пункция с оценкой миелограммы не выявила выраженных изменений гранулоцитарного ряда, что, вероятно, было обусловлено периодом ремиссии циклической нейтропении на момент обследования. Таким образом, тяжелое хроническое бронхолегочное заболевание у ребенка явилось клинической маской циклической нейтропении, которая требовала проведения тщательной диагностики. Нейтропения у детей должна рассматриваться практикующим врачом как лабораторный симптом, который требует осмысления, сопоставления с клиническими проявлениями и обязательного динамического анализа., Нейтропенічний синдром досить часто зустрічається в практиці педіатра. Природа його різноманітна, і кожен випадок нейтропенії потребує проведення ретельної диференціальної діагностики для визначення тактики ведення хворого. Тільки за диференційованого підходу до пацієнтів із нейтропенією можливо попередити розвиток серйозних ускладнень інфекційних процесів. Для ілюстрації наводимо клінічний випадок власного спостереження дитини 4 років із важким хронічним бронхолегеневим захворюванням, яка знаходилася на стаціонарному обстеженні та лікуванні в дитячому міському пульмонологічному центрі. Дитина поступила зі скаргами на постійний вологий малопродуктивний кашель, епізодичні дистанційні хрипи, зниження слуху. З анамнезу захворювання було встановлено, що з місячного віку у дитини спостерігалися повторні отити, рецидивуючі бронхіти з бронхообструктивним синдромом, неодноразові пневмонії різноманітної локалізації. Комплексне обстеження, що включало, окрім стандартних лабораторних досліджень, лікувально-діагностичну бронхоскопію, комп’ютерну томографію органів грудної клітини, виявило у дитини двосторонній дифузний катарально-гнійний ендобронхіт, КТ-ознаки дифузних інтерстиціальних змін у легенях і бронхомаляції. Ретельний динамічний аналіз наявних в амбулаторній картці гемограм дозволив запідозрити в пацієнта вроджену нейтропенію. Багаторазове виникнення нейтропенічних кризів зі зниженням числа нейтрофілів до 1000 кл/мкл і нижче на першому році життя дитини та їх періодичністю в 3–4 тижні підтвердило циклічний характер нейтропенії. Проведена стернальна пункція з оцінкою мієлограми не виявила виражених змін гранулоцитарного ряду, що, ймовірно, було обумовлено періодом ремісії циклічної нейтропенії на момент обстеження. Таким чином, важке хронічне захворювання бронхолегеневої системи у дитини стало клінічною маскою циклічної нейтропенії, що вимагала проведення ретельної діагностики. Нейтропенія у дітей повинна розглядатися практикуючим лікарем як лабораторний симптом, що потребує осмислення, зіставлення з клінічними проявами та обов’язкового динамічного аналізу.

Periodontal diseases are infections, and many forms of the disease are associated with specific pathogenic bacteria which colonize the subgingival area. At least two of these microorganisms, Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, also invade the periodontal tissue and are virulent organisms. Initiation and progression of periodontal infections are clearly modified by local and systemic conditions called risk factors. The local factors include pre-existing disease as evidenced by deep probing depths and plaque retention areas associated with defective restorations. Systemic risk factors recently have been identified by large epidemiologic studies using multifactorial statistical analyses to correct for confounding or associated co-risk factors. Risk factors which we know today as important include diabetes mellitus, especially in individuals in whom metabolic control is poor, and cigarette smoking. These two risk factors markedly affect the initiation and progression of periodontitis, and attempts to manage these factors are now an important component of prevention and treatment of adult periodontitis. Systemic conditions associated with reduced neutrophil numbers or function are also important risk factors in children, juveniles, and young adults. Diseases in which neutrophil dysfunction occurs include the lazy leukocyte syndrome associated with localized juvenile periodontitis, cyclic neutropenia, and congenital neutropenia. Recent studies also point to several potentially important periodontal risk indicators. These include stress and coping behaviors, and osteopenia associated with estrogen deficiency. There are also background determinants associated with periodontal disease including gender (with males having more disease), age (with more disease seen in the elderly), and hereditary factors. The study of risk in periodontal disease is a rapidly emerging field and much is yet to be learned. However, there are at least two significant risk factors-smoking and diabetes-which demand attention in current management of periodontal disease. J Periodontol 1996;67:1041-1049.

Background: Cyclic neutropenia (CyN) is a rare hematological disease. Herein, a CyN girl, aged 3 years and 2 months, with recurrent fever and oral mucosal ulcer caused by neutrophil elastase (ELANE) gene mutation is reported. Case presentation: A 3 years and 2 months old girl presented with recurrent fever and oral mucosal ulcer for 1 year. Routine blood test revealed that her absolute neutrophil count repeatedly decreased (minimum 0. 04 × 109/L) every 21 days on an average. Gene testing showed that the patient suffered from ELANE gene heterozygous mutation (c.197T>G) (exon2) (p.M66R). She was finally diagnosed as CyN. The patient's symptoms were relieved after infection prevention and treatment as well as granulocyte-colony stimulating factor (G-CSF) therapy. Her condition continues to remain stable. Conclusion: Active prevention and treatment of infection as well as G-CSF therapy can successfully control CyN.

Isolated neutropenia may be either congenital or acquired. Congenital neutropenias result from single gene mutations, where the genes encode a diverse range of proteins involved in granulocytic progenitor expansion, survival, differentiation, cytoskeletal organization, and metabolism. Congenital neutropenias may be associated with non-hematologic abnormalities. While recombinant human granulocyte colony-stimulating factor can improve neutrophil counts, its usage may be associated with mutations in its cognate receptor and herald the transformation to myelodysplastic syndrome or acute myeloid leukemia. Besides serving as a model for understanding bone marrow failure and transformation to myeloid malignancy, these monogenic disorders provide insight into normal cellular and developmental biology of neutrophils and granulopoiesis.