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Neutrophil Disorders and Their Management J Clin Pathol: First Published As 10.1136/Jcp.54.1.7 on 1 January 2001

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J Clin Pathol 2001;54:7–19 7 Neutrophil disorders and their management J Clin Pathol: first published as 10.1136/jcp.54.1.7 on 1 January 2001. Downloaded from R Lakshman, A Finn Abstract degranulation and respiratory burst activity Neutrophil disorders are an uncommon and this leads to killing of the target as well as yet important cause of morbidity and inflammatory changes in the tissues. The mortality in infants and children. This respiratory burst is an important pathway for article is an overview of these conditions, microbial killing and involves the generation of with emphasis on clinical recognition, superoxide, hydrogen peroxide, hydroxyl radi- rational investigation, and treatment. A cal, and subsequently hypochlorous acid and comprehensive list of references is pro- chloramines. Degranulation involves release of vided for further reading. the contents of the cell granules and contrib- (J Clin Pathol 2001;54:7–19) utes to “oxygen independent bactericidal activity”. If granulocyte activation persists, Keywords: neutrophil disorders; chronic granulomatous disease; neutrophil chemotaxis; phagocytosis neutrophils release substances such as monocytic chemotactic protein that attract monocytes to the area. These in turn release Neutrophils are phagocytic granulocytes that monokines that enhance lymphocytic infiltra- constitute an important component of the tion and also present antigens to T cells to pro- rapid “non-specific” immune defences. They, duce cell mediated immune responses and like other leucocytes, are derived from pluripo- promote T dependent humoral (B cell) re- tent stem cell progenitors in the bone marrow. sponses. Upon stimulation by colony stimulating fac- Neutrophils have a short circulating life span tors, including stem cell factor, granulocyte– (about eight hours) after leaving the bone mar- monocyte colony stimulating factor (GM- row and then undergo apoptosis.4 Anti- CSF), and granulocyte colony stimulating apoptotic signals generated by growth factors factor (G-CSF), phagocyte precursors prolifer- and cytokines can aVect neutrophil survival ate and develop in the bone marrow to form and increase neutrophil numbers.5 mature segmented neutrophils. The first three Neutrophil disorders can result from a stages of neutrophil maturation—myeloblast, reduced number of cells or defective function. promyelocyte, and myelocyte—involve young Neutropenias are a result of one or more actively dividing cells. After the myelocyte defects in the diVerentiation or proliferation in stage, the cells lose their ability to divide and the bone marrow, or increased peripheral http://jcp.bmj.com/ form metamyelocytes, band cells, and finally destruction. Functional disorders include dis- segmented polymorphonuclear neutrophils. In orders of chemotaxis, adhesion, phagocytosis, times of stress, corticosteroids, complement and the respiratory burst. The extent to which fragments, and catecholamines accelerate the such disorders are recognised and diagnosed, release of mature neutrophils, as well as meta- understood at the cellular and molecular level, myelocytes and band cells, into the circulation. and amenable to corrective or compensatory Chemotactic substances such as C5a, inter- medical treatment is very variable. In consider- on September 29, 2021 by guest. Protected copyright. leukin 8 (IL-8), monocyte chemotactic factor, ing disorders of neutrophils, it is worth bearing leukotrienes, and bacterial peptides induce the in mind that humans can survive quite migration of circulating neutrophils to sites of prolonged periods without medical interven- infection and inflammation. This extravasation tion with profound deficiency of specific (lym- involves selectin mediated rolling along the phocytic) immunity, but all would perish of vascular endothelium, integrin mediated firm infection within days of onset of absolute neu- adhesion to the endothelium, and transend- tropenia. othelial migration through intercellular junc- tions to extravascular sites. Migrating neu- trophils have a profoundly diVerent shape and Disorders of neutrophil number: form from those seen in the circulation; neutropenia progress through the tissues is thought to be Neutropenia is an absolute reduction in the SheYeld Institute for mediated principally by the integrin CD11b/ number of circulating neutrophils. Interpret- Vaccine Studies, CD18 on the cell surface,1 ation of peripheral blood neutrophil counts is Division of Child and might be regu- Health, University of lated by soluble gradients (chemotaxis) or fixed rendered more diYcult by the fact that these 2 3 SheYeld Children’s gradients (haptotaxis) of chemoattractants. can change rapidly within an individual in Hospital, SheYeld Neutrophils have an array of surface recep- response to non-specific changes such as exer- S10 2TH, UK tors that enable them to bind to and ingest for- cise and heart rate. Reference ranges6 vary R Lakshman eign particles and microbes by a process known with age and race; infants have lower neutro- A Finn as phagocytosis. This mechanism is greatly phil counts than older individuals, as do Afri- 7 Correspondence to: facilitated if microbes are coated with opsonic cans compared with whites. Neutrophil Dr Lakshman proteins such as immunoglobulins, comple- counts obtained by analysis of blood many [email protected] ment fragment C3b, and mannan binding lec- hours after collection may show falsely low Accepted for publication tin, for which the neutrophil expresses multiple values. After infancy, absolute neutrophil 20 July 2000 specific receptors. Phagocytosis is followed by counts (ANC) < 1.5 × 109/litre are considered www.jclinpath.com 8 Lakshman, Finn Table 1 Causes of neutropenia reduced bone marrow reserve of neutrophils and neutrophil precursors (such as Kost- J Clin Pathol: first published as 10.1136/jcp.54.1.7 on 1 January 2001. Downloaded from Transient mann’s syndrome) pose a greater risk for severe Chronic (1) Congenital neutropenias infections compared with those associated with Failure of production (bone marrow) normal reserve and increased peripheral de- Severe chronic neutropenia Cyclic neutropenia struction (such as autoimmune neutropenia of Reticular dysgenesis infancy). Although there is good correlation (2) Associated with syndromes between the severity of neutropenia and occur- Primary immunodefeciencies: XLA, hyper-IgM Glycogen storage disease (1b) rence of infections, there is considerable varia- Shwachman diamond syndrome tion in infective symptoms for any given Cardioskeletal myopathy neutrophil range, within a patient population Onychotrichodysplasia Antibody mediated neutropenias and also in a single individual, owing presum- Autoimmune neutropenia of infancy ably to other compensatory immunological Alloimmune neonatal neutropenia factors and to chance. Neonatal neutropenia owing to autoimmune disease in mother Autoimmune neutropenia seen in association with primary specific immunodeficiencies In our experience, children with neutropenia Idiopathic commonly present with malaise and lethargy Chronic benign neutropenia (parents often describe their children as totally XLA, X linked agammaglobulinaemia. unwilling to get up and walk around), skin infections (cellulitis and subcutaneous ab- to be abnormally low and severe infections scesses), mucosal and respiratory infections 9 occur at values below 0.5 × 10 /litre. (gingivitis, stomatitis, apthous ulcers, peri- Transient states of neutropenia, often only odontitis, perirectal abscess, pneumonia, and noted on a single measurement, and not lasting otitis media), and septicaemia. In one series, six for more than two weeks, are common in chil- of 23 girls with chronic neutropenia had a his- dren and not usually associated with clinical tory of abscess or cellulitis aVecting the labia problems. They are usually associated with majora.9 The paucity of neutrophils may viral infections and may therefore be the result dampen the inflammatory response, reducing of transient dysregulation of myelopoeisis or the ability to localise the infection and permit- accelerated consumption. By contrast, neutro- ting rapid dissemination. Classic radiological penia in neonates might be caused by exhaus- features of pneumonia may be absent and there tion of bone marrow reserves and can be an might be little or no abdominal tenderness important sign of severe generalised infection, even in the presence of ruptured viscus. such as septicaemia. Other causes of transient The most common causes of infections in neutropenia include drugs such as cytotoxic individuals with chronic neutropenia are agents and nonsteroidal anti-inflammatory mainly endogenous flora: Staphylococcus spp, agents. Neutropenia can also occur in babies Serratia marcescens, Klebsiella spp, other Gram born to mothers with pregnancy induced negative organisms and Aspergillus spp. They hypertension. The term chronic neutropenia is are not noted to have an increased susceptibil- http://jcp.bmj.com/ usually reserved for abnormally low absolute ity to viral or parasitic infections. neutrophil counts lasting more than six 8 months. Children with severe chronic neutro- SEVERE CONGENITAL NEUTROPENIA (SCN) penia (SCN) can be registered with the Severe Children with SCN are characterised by the Chronic Neutropenia International Registry.* early onset of life threatening infections, severe Chronic states of neutropenia (table 1) may in persistent neutropenia, and maturation arrest some cases have definable underlying genetic at the myelocyte/promyelocyte stage. causes and are
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  • Severe Congenital Neutropenia with Monocytosis and Non-Syndromic Sensorineural Hear

    Severe Congenital Neutropenia with Monocytosis and Non-Syndromic Sensorineural Hear

    Venugopal et al. BMC Medical Genetics (2020) 21:35 https://doi.org/10.1186/s12881-020-0971-z RESEARCH ARTICLE Open Access Two monogenic disorders masquerading as one: severe congenital neutropenia with monocytosis and non-syndromic sensorineural hearing loss Parvathy Venugopal1,2†, Lucia Gagliardi1,2,3,4,5†, Cecily Forsyth6†, Jinghua Feng7,8, Kerry Phillips9, Milena Babic1,2, Nicola K. Poplawski9, Hugh Young Rienhoff Jr10, Andreas W. Schreiber2,7,8,11, Christopher N. Hahn1,2,3,8†, Anna L. Brown1,2,8† and Hamish S. Scott1,2,3,7,8*† Abstract Background: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. Methods: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. Results: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. Conclusions: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants. Keywords: Neutropenia, Congenital neutropenia, Leukemia predisposition, Polygenic inheritance, Hearing loss Background cases [2]. It may also occur as a part of a syndrome with Severe congenital neutropenia (SCN) was first described other developmental defects (e.g.