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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.

Background Cyclic neutropenia is a rare genetic disorder causing the arrest of neutrophil function and is characterized by periodic neutropenia and recurrent infections. Patients with cyclic neutropenia with autosomal dominant, sporadic, and X-linked may have mutations in the ELANE gene, and autosomal recessive cases have homozygous/compound heterozygous variants in the HAX1 gene primarily. Observation The authors describe a novel variant in the HAX1 gene, which was detected by next-generation sequencing in an 8-year-old male child who presented with recurrent infections and neutropenia. Conclusion The patient extends the clinical variability associated with HAX1 variants and highlights the importance of genetic investigations in patients with suspected cyclic neutropenia.

Background Cyclic neutropenia is a disease that causes a neutropenic decrease in peripheral blood in a cycle of about 21 days. It is a rare hereditary disorder with an estimated incidence of 0.5–1 cases per million population. The absolute neutrophil count can drop to zero, and neutropenic nadir may last for 3–5 days. This is a rare disease, and there are few reports of abdominal surgery in cyclic neutropenia patients; thus, we report this case of neutrophil count fluctuation and perioperative management. Case presentation A 31-year-old man with cyclic neutropenia was transferred to our hospital complaining of right season rib pain, but no rebound tenderness. His C-reactive protein was elevated (4.37 mg/L) and computed tomography revealed a large number of small stones in the gallbladder body and an incarceration in the gallbladder neck. He was diagnosed with acute cholecystitis. Ideally, surgical intervention should have been performed immediately, but because his neutrophil count was 300/μL, endoscopic naso-gallbladder drainage was performed and he was provided antibiotics until his neutrophil count increased to acceptable levels. Three days after admission, his neutrophil count had increased and laparoscopic cholecystectomy was performed. For one week after the operation, antibiotics were administered; he had an uneventful postoperative recovery. He was discharged on the seventh postoperative day and provided an oral antibiotic. Conclusions Infection can be serious in patients with cyclic neutropenia, and it is therefore, important to determine the timing of surgery and to apply appropriate perioperative management with drainage and antibiotic administration.

ELANE-related neutropenia includes severe congenital neutropenia and cyclic neutropenia. Both are clinically characterized by recurrent fever, skin and oropharyngeal inflammation. We report a novel mutation in ELANE in a 20-year-old man with a history of self-limiting febrile episodes and neutropenia with a cyclic pattern since 7 years of age. Direct sequencing analysis of ELANE revealed he was heterozygous for a novel missense mutation (p.Ala57Asp). The Ala57 residue is a mutation hotspot, and all previously reported missense mutations (Ala57Ser/Thr/Val) were observed in severe congenital neutropenia cases. Thus, the present case demonstrates a phenotypic variability in ELANE-related neutropenia from mutated Ala57.

International audience; Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease’s natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (3000/mm(3) ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

Mutations in the ELANE gene, which encodes the neutrophil elastase (NE) protein in neutrophils, result in ELANE-related neutropenia. ELANE-related neutropenia encompasses both cyclic neutropenia (CN) and severe congenital neutropenia (SCN), with ELANE mutations seen in a majority of SCN and almost all of CN patients. Clinical history in affected individuals typically reveals recurrent episodes of fever, oral ulcerations and bacterial as well as fungal infections, correlating with periodic oscillations or chronically low levels in the absolute neutrophil count (ANC). ELANE-related neutropenia is characterised by severely low neutrophil counts where ANCs may drop as low as zero. A two-year-old child presented at our hospital with a longstanding history of recurrent bacterial infections and previous admissions at another centre during some of these infectious episodes. Her full blood count demonstrated a markedly low ANC, which was chronic on assessment of her previous results. Decreased granulopoiesis with maturation arrest was seen on her bone marrow and genetic testing for the ELANE gene demonstrated a pathogenic variant of the mutation. Treatment with granulocyte colony-stimulating factor (G-CSF) was initiated.

Purpose: To present a 1-year-old boy with cyclic neutropenia who presented with multiple episodes of periorbital cellulitis (POC). Methods: The child presented with three episodes of POC. In the second episode, the cellulitis was associated with nasolacrimal duct obstruction, and in the third episode, a pansinusitis was noted. He underwent a thorough systemic evaluation. Results: Patient's evaluation revealed the diagnosis of cyclic neutropenia. Conclusion: This report emphasizes the possibility of an underlying immunodeficiency with recurrent POC, even in an apparently healthy child.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a sweeping pandemic. Its major manifestation is in the respiratory tract, and the general extent of organ involvement and the microscopic changes in the lungs remain insufficiently characterised. Autopsies are essential to elucidate COVID-19-associated organ alterations.This article reports the autopsy findings of 21 COVID-19 patients hospitalised at the University Hospital Basel and at the Cantonal Hospital Baselland, Switzerland. An in-corpore technique was performed to ensure optimal staff safety. The primary cause of death was respiratory failure with exudative diffuse alveolar damage and massive capillary congestion, often accompanied by microthrombi despite anticoagulation. Ten cases showed superimposed bronchopneumonia. Further findings included pulmonary embolism (n = 4), alveolar haemorrhage (n = 3), and vasculitis (n = 1). Pathologies in other organ systems were predominantly attributable to shock; three patients showed signs of generalised and five of pulmonary thrombotic microangiopathy. Six patients were diagnosed with senile cardiac amyloidosis upon autopsy. Most patients suffered from one or more comorbidities (hypertension, obesity, cardiovascular diseases, and diabetes mellitus). Additionally, there was an overall predominance of males and individuals with blood group A (81% and 65%, respectively). All relevant histological slides are linked as open-source scans in supplementary files.This study provides an overview of postmortem findings in COVID-19 cases, implying that hypertensive, elderly, obese, male individuals with severe cardiovascular comorbidities as well as those with blood group A may have a lower threshold of tolerance for COVID-19. This provides a pathophysiological explanation for higher mortality rates among these patients.

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.

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.

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.

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.

The use of granulocyte colony-stimulating factor in patients with cyclic neutropenia is associated with long-term survival and a decreased risk of serious infections and sepsis.

Cyclic neutropenia occurs due to the fluctuation of cellular production levels of bone marrow stem cells. This is to say, they change during the cycle, and although numbers are recurrently low, function is normal. Cyclic neutropenia was first described by Leale in 1910 with dominant autosomal character. It manifests approximately every 21 days, with range of 14 to 36 days, lasting 3-6 days per episode. During the time when there are few circulating neutrophils, the patient is susceptible to infections. The clinical picture of this process includes: susceptibility to infection, feverish conditions, oral ulcers, impetigo, increased lymph nodes, periodontitis and stomatitis. It is important to stomatologically handle these patients; after inter-consultation with treating physician, prevent infection in a prophylactic scheme based on amoxicillin 50mg/per kg weight or clindamycin 20mg/per kg weight, review recent blood count results (maximum ten days before treatment). In emergency treatments pain and infection will be handled conservatively, with use of 0.12% chlorhexidine mouthwashes and Philadelphia solution when necessary.

ResumenLa neutropenia cíclica ocurre debido a que los niveles de producción celular por parte de las células madre de la médula ósea fluctúan, es decir, cambian durante el ciclo; aunque el número es recurrentemente bajo, su función es normal. Fue descrita por primera vez por Leale en 1910, con carácter autosómico dominante. Se presenta aproximadamente cada 21 días con un rango de 14 a 36 días durando un total de 3 a 6. Durante el periodo en el que existen pocos neutrófilos circulantes, el paciente es susceptible a las infecciones. Dentro del cuadro clínico se presentan: susceptibilidad a infecciones, cuadros febriles, fatiga, úlceras orales, impétigo, aumento de ganglios linfáticos, periodontitis, estomatitis. Es importante manejar estomatológicamente a estos pacientes, previa interconsulta con médico tratante, prevenir cuadros infecciosos bajo un esquema profiláctico a base de amoxicilina 50mg/kg peso o clindamicina 20mg/kg peso, revisar biometría hemática reciente (máximo 10 días previos al tratamiento); en tratamientos de urgencia se manejará de forma conservadora el dolor e infección; uso de enjuagues con clorhexidina al 0.12% y solución Philadelphia en caso de ser necesario.AbstractCyclic neutropenia occurs due to the fluctuation of cellular production levels of bone marrow stem cells. This is to say, they change during the cycle, and although numbers are recurrently low, function is normal. Cyclic neutropenia was first described by Leale in 1910 with dominant autosomal character. It manifests approximately every 21 days, with range of 14 to 36 days, lasting 3-6 days per episode. During the time when there are few circulating neutrophils, the patient is susceptible to infections. The clinical picture of this process includes: susceptibility to infection, feverish conditions, oral ulcers, impetigo, increased lymph nodes, periodontitis and stomatitis. It is important to stomatologically handle these patients; after inter-consultation with treating physician, prevent infection in a prophylactic scheme based on amoxicillin 50mg/per kg weight or clindamycin 20mg/per kg weight, review recent blood count results (maximum ten days before treatment). In emergency treatments pain and infection will be handled conservatively, with use of 0.12% chlorhexidine mouthwashes and Philadelphia solution when necessary.

A 14-year-old girl presented with recurrent episodes of pharyngitis, aphthous ulcers, diarrhea and fever for the past four years. The episodes lasted a week each time. The patient was admitted and blood studies revealed neutropenia. On further investigations, it was found that her neutrophil count dropped to less than 0.5 x 10⁹/L after every three weeks. Bone marrow study was normal. She was diagnosed as cyclic neutropenia.Journal of Patan Academy of Health Sciences. 2014 Dec;1(2):46-48

Background Loss of the primary dentition is a physiological process. However, changes in pattern of tooth loss may herald systemic disease. Dental trauma and non-accidental injury should also be considered. A number of cases of premature exfoliation with subsequent investigation and diagnosis are presented. Case presentations A four year old girl presented with painful, bleeding gingivae and oral ulceration. Haematological investigations revealed a raised B12 and neutrophil count of 0.16 and a diagnosis of cyclic neutropenia was confirmed. A complicating factor was dental caries which required dental extractions under general anaesthesia. Although this case didn’t present with premature exfoliation there was significant recession and mobility of the primary teeth which if left untreated could lead to exfoliation. A 2 year old female patient presented with a history of pyrexial illness, swollen gingivae and difficulty eating. On examination severely hyperplastic, atrophic erythematous gingivitis affecting the upper and lower anterior gingiva was noted. The severity of the presentation prompted a review of her recent hospitalisation investigations. A discharge summary obtained from her GP showed a neutrophil count of 0.07 × 109/L. An urgent referral to Paediatric Haematology was required for same day hospital admission. A bone marrow aspirate showed the presence of antigranulocyte antibodies in her serum leading to a diagnosis of primary autoimmune neutropenia. Siblings presented with premature exfoliation of anterior primary teeth with generalised bone loss and mobility in the remaining dentition. Blood tests revealed low vitamin D levels which were remedied with vitamin supplementation. They also showed decreased alkaline phosphatase levels and increased CRP levels. Both were diagnosed with odonto-hypophosphatasia. A 3 year old presented with premature loss of upper left central primary incisor. History revealed the child was upset, with oral bleeding and the tooth was found on a coffee table. The contralateral incisor showed signs of trauma. Clinical diagnosis is trauma however the tooth was sent to histopathology to rule out any other cause. Conclusion Premature loss of primary teeth should alert clinicians to the possibility of dental trauma, safeguarding issues or systemic involvement. Therefore, prompt referral to a Consultant in Paediatric Dentistry is indicated.

Objective and Importance.Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection.Case.A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation.Intervention.Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN.Conclusion.BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual’s symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.

We have identified a novel point mutation in the ELANE gene of a 5.5-month-old boy with severe cyclic neutropenia, and we are reporting for the first time, to our knowledge, the presence of hematogones in the peripheral blood of an infant. The novel point mutation occurred at base number 290 in codon 97, where adenine was replaced with cytosine. The mutation caused the replacement of amino acid glutamine with amino acid proline in the activation domain of the elastase 2 enzyme. The heterozygous mutation generated severe cyclic neutropenia, granulocytic maturation arrest, an increased number of hematogones (26% of marrow cells) in the bone marrow, an absence of neutrophils, and the presence of stage 3 (mature) hematogones in the peripheral blood. The percentage of hematogones in the peripheral blood was inversely proportional to the absolute number of neutrophils. Leukemic number of blast-like cells (hematogones) in the bone marrow, blast-like cells in the peripheral blood, marked neutropenia, and the arrest of granulopoiesis might suggest an acute leukemia. However, the finding of characteristic flow cytometric features of hematogones should help to avoid a wrong diagnosis.

Immunodeficiencies reduce the functional activity of the immune system resulting in a disorder of the defensive mechanisms and increased incidents of different pathologies. A congenital immunodeficiency occurs because of genetically determined inability to control effective immune function. The congenital immunodeficiencies appear shortly after birth and are inherited mostly on the autosomal recessive type. Depending on the disorder extent and localization, the immunodeficiencies are classified as the defects of B-cells, the prevalent defects of T-cells, and a combined deficiency on the cell and humoral factors. In the review the classification, as well as clinical, immunological and immunogenetic characteristics of the congenital immunodeficiencies in different animal species are summarized with respect to diagnostics and correction. There are considered the combined immunodeficiency in Arabian and American horses due to absence of mature Tand B-lymphocytes; the selective IgM deficiency in the Arabian horses; the combines immunodeficiency in Duchshund dogs linked to X-chromosome; a combined immunodeficiency in mice С.В-17 of the BALB/c line; a combined immunodeficiency in Angus calves; the selective IgG 2 deficiency in Danish Red cattle; the inherited parakeratosis (Т-cell deficit) in Black-and-White Danish, Friesian and Holstein cattle; the Chediak-Higashi syndrome; bovine leukocyte adhesion deficiency (BLAD); the selective IgA deficiency in dogs; a transitory hypogammaglobulinemia in Pomeranian puppies; lethal acrodermatitis in Bull Terriers; Т-cell immunodeficiency in dwarf Weimaraner dogs; cyclic hematopoesis (silver collies syndrome, or cyclic neutropenia); the deficiency of neutrophyl bactericidal activity in Doberman-Pincher; the Реlger-Нuet anomalia; leukocyte adhesion deficiency (granulocytopathy syndrome) in Irish setters; autosomal recessive deficiency on the third component of complement in British spaniels. Diagnostics of immonodeficienсies is aimed to estimation of different parameters and regulatory mechanisms, responcible for maturation, differentiation and cooperation of Т-, В-lymphocytes, NK-cells, immunoglobulins and complement. For further development of clinical immunology and diagnostics of immunodeficiency, more data must be obtained to found out the integral parameters for healthy animals and those under different immunodeficiencies.

Persistent Neutropenia in a child presents a wide differential diagnosis, spanning the spectrum of benign disorders (such as congenital neutropenia, cyclic neutropenia, etc.) to malignant processes (such as myelodysplasia or acute leukemia). The morphologic findings in the bone marrow of a patient with neutropenia may show considerable overlap with those seen in hematopoietic malignancies. We present herein a case that demonstrates this overlap and discuss features that can help in avoiding diagnostic pitfalls.

The clinical presentation of oral lesions in immunosuppressed children is highly variable. In some cases, it is the oral manifestations that results in the discovery an underlying disease that is causing the immunosuppression. Immunosuppression/deficiency can either be primary or acquired. The World Health Organization recognizes more than 100 primary immune deficiency diseases. Examples include DiGeorge syndrome, complement deficiencies, gammaglobulinemia X-linked (Bruton's) disease, immunoglobulin heavy chain deficiency, selective IgA deficiency, transient hypo-gammaglobulinemia of infancy, phagocytic disorders, severe congenital neutropenia (Kostmann syndrome), cyclic neutropenia, leukocyte adhesion defects, Chediak–Higashi syndrome, etc. Examples of acquired immunosuppression include HIV/AIDs and medication-induced immunosuppression seen in transplant patients as well as children undergoing chemotherapy.