Recurrent, severe infections are the main cause of presentation. Such infections manifest shortly after birth and thus, coincidental diagnosis of CN after observation of neutropenia is rare. Affected individuals may present with varying infectious diseases triggered by bacterial and fungal pathogens, e.g., with pneumonia, hepatitis, cellulitis, furunculosis, and otitis media. Also, oral diseases like periodontitis and stomatitis, possibly resulting in tooth loss, are frequently observed. It is not uncommon to see CN patients suffering from multiple infectious diseases at a time. At any time, they may develop sepsis.

The aforedescribed susceptibility to bacterial or fungal infection is caused by severe neutropenia, and there are typically less than 500 neutrophils per microliter of blood sample. In case of cyclic neutropenia, neutrophil counts oscillate between physiological and severely reduced in cycles of 21 days. In contrast, neutropenia is permanent in patients suffering from SCN.

Additional, extrahematopoietic symptoms are often presented if CN is caused by mutations other than those of ELANE and CSF3R genes. It is beyond the scope of this article to discuss all forms of CN, and only a list of possible findings shall be given at this point. In this context, the interested reader is referred to an excellent review available elsewhere [5].

• G6PC3 mutations: atrial defects, uropathy, prominent veins
• HAX1 mutations: mental retardation, seizures
• SBDS mutations: mental retardation, metaphyseal dysplasia, cardiomyopathy, exocrine pancreatic insufficiency

• Hemophilia A

  Such diseases might include hemophilia, blood clots, other bleeding disorders and blood cancers such as leukemia, multiple myeloma, and lymphoma. [en.wikipedia.org]

  Bleeding Disorders von Willebrand disease (VWD) Hemophilia (factor VIII or factor IX deficiencies) Platelet function defects Clotting Disorders Rare factor deficiencies Protein C and S deficiencies Prothrombin gene mutation Thrombotic thrombocytopenia [versiti.org]

  Early eradication of factor VIII inhibitor in patients with congenital hemophilia A by immune tolerance induction with a high dose of immunoglobulin. Int J Hematol. 2016 Apr;103(4):473-7. 6: Ma CS et al. [home.hiroshima-u.ac.jp]

• Fever

  Antibiotics: If you have severe congenital neutropenia and develop a fever, you should seek immediate medical attention. Fever may be the only symptom of a serious infection. Blood work should be sent to identify a possible cause of infection. [verywellhealth.com]

  In severe neutropenia, the patient is likely to develop periodontal disease, oral and rectal ulcers, fever, and bacterial pneumonia. Fever recurring every 19-30 days suggests cyclical neutropenia. [medical-dictionary.thefreedictionary.com]

  What if the patient has a fever? For temperatures greater than 38.3°C, patients with an ANC less than 1,000/uL should be urgently evaluated by a physician. [cancertherapyadvisor.com]

  Approaches for treating neutropenia include: Antibiotics for fever. In neutropenic fever, the assumption is made that there is an infection causing the fever even when the source can't be found. [webmd.com]

• Recurrent Infection

  Fungal infections may lead to serious complications in immunodeficient patients. Recurrent and severe infections should alert physicians to possible immunodeficiency disease. [ncbi.nlm.nih.gov]

• Sepsis

  Early, empirical use of recombinant human granulocyte colony-stimulating factor in patients who are suspected of having a congenital neutropenia and who present with life-threatening sepsis is recommended. [ncbi.nlm.nih.gov]

  Mortality from sepsis has decreased considerably since the introduction of recombinant granulocyte colony… CONTINUE READING [semanticscholar.org]

  Early, empirical use of recombinant human granulocyte colony-stimulating factor in patients who are suspected of having a congenital neutropenia and who present with life-threatening sepsis is recommended. congenital neutropenia clostridium septicum rh-GCSF [pediatrics.aappublications.org]

  Sepsis mortality is reduced by an advent of granulocyte colony stimulating factor (G-CSF) therapy. More than 90% of patients respond to G-CSF therapy. [ajol.info]

• Falling

  If the count falls to 200/ μ L, the inflammatory response may be muted and the usual inflammatory findings of leukocytosis or WBCs in the urine or at the site of infection may not occur. [merckmanuals.com]

  Neutrophil counts fall from normal to low. A period of neutropenia may last a few days. Normal levels follow for the rest of the cycle. The cycle then resets and begins again. [healthline.com]

  Signs & Symptoms Symptoms and physical findings associated with severe chronic neutropenia vary greatly depending on how low the level of neutrophils in the blood falls. [rarediseases.org]

  Cf Neutrophilia. neu·tro·pe·ni·a ( nū'trō-pē'nē-ă ) Condition that occurs when neutrophil counts fall below the normal percentage in circulating blood. [ neutro phil + G. penia, poverty] neutropenia A reduction in the numbers of NEUTROPHIL POLYMORPHS [medical-dictionary.thefreedictionary.com]

  She responded to G-CSF (10 μ g/kg) administration with an increase in absolute neutrophil count up to 4900/ μ l, but after cessation of G-CSF, neutrophil percentage tended to fall to 1% in a short time. [nature.com]

• Trisomy 21

  Cytogenetics of cancer Cases complicated by the development of AML most commonly show monosomy 7or trisomy 21. Activating RAS mutations are seen in roughly 50% of secondary AML cases. [atlasgeneticsoncology.org]

  The fluid is then tested for chromosomal abnormalities such as Down syndrome (Trisomy 21) and Trisomy 18, which can result in neonatal or fetal death. Test results can be retrieved within 7–14 days after the test is done. [en.wikipedia.org]

  It is recommended that bone marrow examination and cytogenetic studies should be performed annually, or whenever a falling blood count is present, to detect morphological and clonal abnormalities (e.g. monosomy 7, trisomy 21) suggestive of malignant transformation [hkjpaed.org]

  Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended. [nature.com]

  Our findings also suggest, that HSC clones with acquired CSF3R mutations are not leukemic, but pre-leukemic clones with an increased susceptibility to secondary leukemogenic events (e.g., RUNX1 mutation, trisomy 21) and overt MDS or AML. [frontiersin.org]

• Pneumonia

  As the diagnosis of Chlamydia pneumonia was less likely than typical pneumonia given the full course of treatment her mother had received during pregnancy, she was started on intravenous cefotaxime and gentamicin. [ep.bmj.com]

  The patient is a 3-year-old boy, who was referred to our center because of pneumonia, oral and anal ulcers, and periodontitis. [ncbi.nlm.nih.gov]

  Affected individuals may present with varying infectious diseases triggered by bacterial and fungal pathogens, e.g., with pneumonia, hepatitis, cellulitis, furunculosis, and otitis media. [symptoma.com]

  These may cause inflammation of the umbilical cord stump, abscesses (or boils) on the skin, oral infections and pneumonia. [niaid.nih.gov]

• Failure to Thrive

  He had severe OSA, decreased oral intake, and failure to thrive (FTT) which all improved after undergoing a successful intracapsular T&A. [ncbi.nlm.nih.gov]

  This disorder is characterized by bone marrow failure with reduced neutrophils, presenting in infancy. Patients have multiple bacterial and fungal infections, failure to thrive, and enlarged livers and spleens. [sema4genomics.com]

  Patients present with an enlarged liver and spleen, failure to thrive, kidney problems, hypoglycaemia (low blood sugar) and recurrent infections. [neutropenia.ca]

• Nausea

  […] increased Blood uric acid increased Common Anorexia Nervous system disorders Common Headache Vascular disorders Rare Angiopathy Respiratory, thoracic and mediastinal disorders Common Cough Pharyngolary ngeal pain Very rare Lung infiltration Very common Nausea [nanopdf.com]

  Adverse reactions during apheresis were experienced in 20 percent of women and 8 percent of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.[49] Clinical observations[edit] A study involving 2,408 [en.wikipedia.org]

  ● Side effects Side effects from filgrastim are common and include: bone pain weakness muscle aches nausea vomiting stomach pain Tell your doctor if the following symptom is severe or lasts for several hours: redness, pain, and burning at the injection [medmk.com]

• Periodontitis

  One bone marrow-transplanted patient had no periodontal disease. [ncbi.nlm.nih.gov]

• Oral Ulcers

  Both patients suffered from oral ulcers, candidiasis, respiratory tract infections, and diarrhea. [ncbi.nlm.nih.gov]

  She was suffering with the history of recurrent oral ulcerations, genital ulcerations, and fever every month from the age of 3 years. The symptoms had cyclical pattern of every 28 days and persisted for about a week. [ijabmr.org]

  Local symptoms (e.g., oral ulcers) may appear, but in most cases they are minimal. The mechanism and cause of neutropenia must be determined. Family history or the presence of other concomitant diseases may help in suspecting a genetic origin. [gsdinternational.com]

  Symptoms may include: Otitis media (ear infections) Cellulitis (skin infection) Oral ulcers Gingivitis (gum inflammation) Diagnosis It is likely that during one of these infections, your doctor will obtain a complete blood count (CBC). [verywellhealth.com]

  Otitis media (ear infections) Cellulitis (skin infection) Oral ulcers Gingivitis (gum inflammation) How Is It Diagnosed? It is likely that during one of these infections, your doctor will obtain a complete blood count (CBC). [verywell.com]

• Tooth Loss

  Oral manifestations include ulcerations, gingival desquamation, gingival inflammation, attachment loss, and alveolar bone loss which may result in tooth loss. [ncbi.nlm.nih.gov]

  Symptoms - Severe congenital neutropenia * Premature tooth loss * Gum infections * Frequent bacterial infections * Fever * Mouth ulcers * Diarrhea * Sore throat * Chills * Shortness of breath * Redness around a wound * Increased risk of acute myelogenous [checkorphan.org]

  Also, oral diseases like periodontitis and stomatitis, possibly resulting in tooth loss, are frequently observed. It is not uncommon to see CN patients suffering from multiple infectious diseases at a time. At any time, they may develop sepsis. [symptoma.com]

  The ultimate consequence of such recurrent stomatitis and parodontal infections is tooth loss early in life. [onlinelibrary.wiley.com]

  However, chronic stomatologic infection remains very difficult to manage, even with G-CSF and neutrophil recovery, leading to tooth loss [190]. [ojrd.biomedcentral.com]

• Aphthous Ulceration

  It lasts for approximately 10 days; during this time, gingival inflammation and aphthous ulcer occur. Cyclic neutropenia. neutropenia a diminished number of neutrophils in the blood. cyclic neutropenia periodic neutropenia. [medical-dictionary.thefreedictionary.com]

• Furunculosis

  The infections that most frequently occur in patients with profound neutropenia are: cellulitis, furunculosis, pneumonia, and septicemia. Fever is often the sole indication of the infectious state. [gsdinternational.com]

  Affected individuals may present with varying infectious diseases triggered by bacterial and fungal pathogens, e.g., with pneumonia, hepatitis, cellulitis, furunculosis, and otitis media. [symptoma.com]

  Such patients frequently demonstrate mucosal inflammation, particularly of the gingival and perirectal areas and often manifest cellulitis, abscesses, furunculosis, pneumonia or septicemia. [neutropenia.ca]

  Reccurent furunculosis in an infant showing an unusual blood picture. JAMA 23, 1845–1855 (1910). 137. Reimann, H. A. [nature.com]

While neutropenia is a frequent finding, CN is a rare disorder. Differentiation between transient, cyclic and chronic neutropenia is important to distinguish between possible causes: Transient neutropenia may be induced by cytotoxic drugs, or may occur if neutrophils are consumed in excess due to an infection. The latter situation is clinically very similar to that encountered in CN patients, i.e., the affected individual presents with pneumonia and/or other infectious diseases and laboratory analyses of blood reveal reduced neutrophil counts. Thus, CN is usually not suspected until recurrent, severe infections are claimed that are associated with repeated diagnoses of neutropenia. Of note, chronic neutropenia may not only be provoked by genetic disorders, but also by nutrient deficiencies like vitamin B12 deficiency or folic acid deficiency.

Confirmation of a tentative diagnosis of CN usually requires an analysis of bone marrow specimens. If a maturation arrest accounts for the impairment of granulopoiesis - which is typical for patients presenting with mutations of genes ELANE, G6PC3, HAX1, SBDS, WAS, and CSF3R, but which may be missing in case of GFI1 mutations [5] - hypereosinophilia and monocytosis usually dominate the histopathological picture. Genetic screens should also be conducted; they are very specific, but little sensitive because only part of the gene defects causing CN have been described so far. In order to rule out differential diagnoses, levels of antibodies against neutrophil plasma membrane antigens and of serum immunoglobulins should be measured.

• Staphylococcus Aureus

  We report a 2-month-old boy with severe congenital neutropenia (SCN), who developed acute necrotizing otitis media and coalescent mastoiditis due to methicillin-sensitive Staphylococcus aureus. [ncbi.nlm.nih.gov]

  aureus, but other gram-positive and gram-negative infections also occur. [merckmanuals.com]

  Bacterial infections involve Staphylococcus aureus and Staphylococcus epidermidis, streptococci, enterococci, pneumococci, Pseudomonas aeruginosa, gram-negative bacilli, and fungal infections with Candida or Aspergillus species. [emedicine.medscape.com]

  Staphylococcus aureus is a common gram positive infection in phagocytic defects. Patients of CGD (Chronic Granulomatous disease) are prone to Organisms with catalase positivity. [sites.google.com]

• Pseudomonas

  She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. [ncbi.nlm.nih.gov]

  Cyclic forms are slightly more common in females.SCN patients develop frequent fevers, skin infections and stomatitis with organisms such as E. coli, S. aureus, and Pseudomonas species. 90% of patients are diagnosed by 6 months of age. [atlasgeneticsoncology.org]

  Bacterial infections involve Staphylococcus aureus and Staphylococcus epidermidis, streptococci, enterococci, pneumococci, Pseudomonas aeruginosa, gram-negative bacilli, and fungal infections with Candida or Aspergillus species. [emedicine.medscape.com]

  Defects in phagocytes make on prone to infections with gram negative organisms like E coli, Klebsiella, Pseudomonas aeruginosa, Serratia maecescens. They are also prone to fungal infections like candida and aspergillosis. [sites.google.com]

  Enteric organisms such as Escherichia coli, Klebsiella and Pseudomonas may be implicated as well. In developing countries, tetanus may be a causative organism when the cord is contaminated with soil. [hkjpaed.org]

There is no causal therapy for CN, but there are therapeutic options that allow to reinforce the patient's host defense mechanisms. In this context, long-term administration of G-CSF is the treatment of choice; it aims at reestablishing a pool of mature, functional neutrophil granulocytes. Recombinant human G-CSF is generally applied in a daily dose of up to 5 µg/kg, and although it has been suggested that high doses of G-CSF increase the individual risk of myeloproliferative disorders, recent studies argue against that hypothesis [3]. If at all possible, neutrophil counts should be maintained above 1000 cells/µl, and adjustments of the individual treatment regime should be based on regular measurements of this parameter. Corticosteroids have been shown to improve the survival of neutrophils and may thus be applied in combination with G-CSF [15].

In case the patient responds poorly to G-CSF treatment, the possibility of an allogeneic hematopoietic stem cell transplantation should be considered. If successful, this procedure is curative. However, considerable risks are associated with hematopoietic stem cell transplantation and transplant-related mortality has been reported to be approximately 17% [16]. Furthermore, graft failure and graft-versus-host disease may occur. A favorable outcome is more likely if patient and donor are HLA-matched and if the transplantation is carried out in patients aged less than 10 years.

Allogeneic hematopoietic stem cell transplantation is also indicated in CN patients who developed myelodsyplastic syndrome and acute myeloid leukemia.

If adequate medical care is provided, more than 90% of infants diagnosed with CN survive into adulthood. In developed countries, the vast majority of those people live beyond 20 years of age, but their life expectancy is still significantly reduced when compared with the general population [14]. CN patients most frequently die from complicated infections and sepsis and from myeloproliferative disorders like myelodsyplastic syndrome and acute myeloid leukemia. Additionally, extrahematopoietic failure is a common cause of death of patients suffering from determined subtypes of CN [5].

There are two main forms of CN, namely severe congenital neutropenia (SCN) and cyclic neutropenia (CycN) [4]. When revising literature published more than twenty years ago, the reader may encounter a more narrow definition of CN, since CycN has not been considered a form of CN until then [5].

Both the most common form of SCN as well as CycN are genetic diseases inherited with an autosomal dominant trait. Corresponding mutations are located on chromosome 19 and affect the ELANE gene, which is encoding for neutrophil elastase. More than a hundred mutations of the ELANE gene have been described so far, but they are only partially related to a determined phenotype [4] [6].

SCN may also be provoked by a mutation of the GFI1 gene, which encodes for a growth factor independent transcription repressor that affects the expression of ELANE and further DNA segments involved in granulopoiesis. Also, SCN-associated mutations may be inherited with an autosomal recessive trait. Patients suffering from those forms of SCN may present with mutations of genes G6PC3 (encodes for glucose-6-phosphatase 3, involved in glucose metabolism, mutations associated with reduced differentiation and survival of neutrophils) [7]., HAX1 (encodes for HCLS1 associated protein X-1, involved in hematopoiesis) [2]., SBDS (encodes for a ribosomal protein of unknown function), and VPS45 (encodes for vacuolar protein sorting 45 homolog, affects endosomal trafficking and triggers premature apoptosis) [8]., to name a few [5].

Furthermore, mutations of the WAS gene, which is located on the X chromosome, may interfere with the synthesis of the Wiskott-Aldrich syndrome protein and thus cause neutropenia.

Presumably, this list is not complete, and almost half of all CN patients present neither of the aforedescribed gene defects [9]. Additional genetic (and possibly environmental) factors are most likely involved in CN pathogenesis, and a more complex etiology could also explain why different mutations of the ELANE gene are related to distinct types of CN. In fact, it has been reported that a considerable share of SCN patients shows an acquired mutation of the CSF3R gene [4]. This gene encodes for the G-CSF receptor.

Two studies realized in order to assess the incidence of the disease yielded similar results and it has been estimated that CN occurs in about 1 to 1.5 per 100,000 live births. Prevalence rates are somewhat lower. Clinical symptoms manifest shortly after birth in form of recurrent, severe infections. The respective studies have been conducted by Canadian and Swedish researchers [10] [11].

No epidemiological data are available that would support a hypothesis of racial predilection.

Despite the use of the common term CN, determined forms of SCN as well as CycN differ largely with regards to their pathogenesis. In general, CN is the result of disturbances of granulopoiesis, whereby the latter is a complex process comprising distinct developmental stages, e.g., hematopoietic stem cells, myeloblasts, promyelocytes, myelocytes, band cells and mature granulocytes. In patients with ELANE mutations, differentiation of promyelocytes into myelocytes is impaired. This condition is often referred to as promyelocytic arrest, but depending on the severity of the disease, minor shares of precursor cells still reach the stage of mature granulocytes. Accordingly, individuals affected by mild to moderate disease respond to therapy with G-CSF. In contrast, the promyelocytic arrest may not be overcome by administration of G-CSF in case of severe neutropenia [4]. Similarly, loss-of-function mutations of the G-CSF receptor render the patient refractory to G-CSF therapy [12].

CN patients are at high risks of developing myelodsyplastic syndrome and acute myeloid leukemia, and since most patients receive long-term G-CSF treatment, a correlation between those myeloproliferative disorders and G-CSF administration has repeatedly been assumed. The hypothesis has been tested by Rosenberg and colleagues, and they found the incidence of myelodsyplastic syndrome and acute myeloid leukemia to be related to the dose of G-CSF but not to the duration of treatment [3]. Interestingly, mutations of the CSF3R gene may not only cause refractoriness to G-CSF treatment, as indicated above, but may also uncouple negative feedback mechanisms, which leads to constitutive activity of the receptor and possibly malignant transformation [13].

Due to CN being a hereditary disorder, affected families may benefit from genetic counseling. Infants that may have inherited a defective gene from their parents should be tested for CN as early as possible in order to initiate an adequate treatment in a timely manner. Administration of G-CSF largely contributes to avoiding the manifestation of symptoms, i.e., if neutrophil counts can be maintained above 1000 cells/µl, patients are less susceptible to bacterial and fungal infections. Consequently, it becomes less likely they develop severe complications such as sepsis and multi organ failure. Present infections should be treated with antibiotics since the patient's immune system is generally unable to eliminate the causative pathogens. Regular follow-ups are required throughout life, and patients should be examined for myeloproliferative disorders.

Congenital neutropenia (CN) refers to a severe depletion of neutrophil granulocytes that is detected shortly after birth.

This condition has first been described by Rolf Kostmann, a Swedish physician, in the middle of the last century, and has then been named infantile genetic agranulocytosis [1]. In order to honor this physician, the term Kostmann syndrome has also been used to refer to CN. Considerable research efforts have allowed to shed more light on the disease' heterogenous etiology and by now, it is accepted that CN is not an own entity, but rather the main symptom of a variety of genetic disorders. Today, only individuals suffering from one particular type of CN are diagnosed with Kostmann syndrome [2].

Patients affected by any of those genetic diseases underlying CN present clinically similarly, with the following signs:

• Cyclic or chronic neutropenia (less than 500 neutrophils/µl)
• Disturbed granulopoiesis, mostly with promyelocytes unable to differentiate into myelocytes
• Recurrent, life-threatening infections, e.g., pneumonia, hepatitis and cellulitis

Patients are generally treated with granulocyte colony-stimulating factor (G-CSF) in order to compensate for neutropenia. Nevertheless, CN patients are severely immunodeficient and they remain at high risks of developing lethal complications of infections and myeloproliferative disorders like myelodsyplastic syndrome and acute myeloid leukemia [3]. Still, G-CSF therapy allows for a considerable increase of life expectancy of CN patients, which is now greater than 20 years, while decades ago, affected children died from bacterial infections shortly after birth.

CN is a rare disorder and occurs in about 1 in 100,000 live births.

If someone talks about "immune cells", they refer to many different cell types that fulfill a myriad of functions, that interact and regulate the immune response. One of those cell types is the neutrophil granulocyte, and neutrophils are mainly required to prevent bacterial and fungal infections. If neutrophil counts are below their physiological reference range, the affected individual suffers from neutropenia. This condition may be congenital, i.e., present at birth, or acquired, and congenital neutropenia may be provoked by distinct gene defects.

Congenital neutropenia renders the patient very susceptible to infectious diseases, which manifests in form of recurrent, severe pneumonia, dermatitis, stomatitis and periodontitis, among others. Depending on the precise genetic disorder underlying congenital neutropenia, additional symptoms may be experienced. These range from mental retardation to cardiomyopathy and pancreatic insufficiency.

Treatment aims at rebuilding the patient's immune system by stimulating the production of mature, functional neutrophils. This is usually achieved by means of long-term administration of granulocyte colony-stimulating factor (G-CSF). If a patient doesn't respond to G-CSF treatment, they may require an allogeneic hematopoietic stem cell transplantation.

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2. Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007; 39(1):86-92.
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16. Fioredda F, Iacobelli S, van Biezen A, et al. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation. Blood. 2015; 126(16):1885-1892; quiz 1970.