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

• Recurrent Infection

  We describe an SCN patient with a history of recurrent infections. The clinical course was complicated by necrosis of the nasal cartilage due to mucormycosis. Molecular studies revealed a homozygous germline HAX1 mutation. [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]

• Pediatric Disease

  Disease Working Parties of the European Society for Blood and Bone Marrow Transplantation (EBMT) and Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE). [ncbi.nlm.nih.gov]

• Recurrent Sinusitis

  sinusitis and recurrent gingivitis. [gps.wustl.edu]

• Recurrent Otitis Media

  Other features include anemia, thrombocytopenia, developmental and mental retardation, diarrhea, failure to thrive, and recurrent otitis media and pneumonia. The chromosomal mutation is located at locus 7qll. [clinicaladvisor.com]

• Pneumonia

  His elder sister died from pneumonia at 2 years. Direct sequencing of ELANE in the proband identified a heterozygous novel frameshift mutation: c.658delC (p.Arg220Glyfs20*). [ncbi.nlm.nih.gov]

  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]

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

  Affected infants may have fever, pneumonia, septicemia, and other infections that can be fatal. [medical-dictionary.thefreedictionary.com]

• Perianal Ulcer

  One particular aspect is ecthyma gangrenosum (infectious perianal ulceration). [onlinelibrary.wiley.com]

• Periodontitis

  CONCLUSION: This study demonstrates an association between ELANE mutations in SCN and the development of periodontitis with skewed subgingival microbiota, indicating a potential role of ELANE mutations in the pathogenesis of periodontitis. [ncbi.nlm.nih.gov]

• 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]

• Furunculosis

  with pneumonia, hepatitis, cellulitis, furunculosis, and otitis media. Also, oral diseases like periodontitis and stomatitis, possibly resulting in tooth loss, are frequently observed. [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]

• Neurologic Manifestation

  This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. [ncbi.nlm.nih.gov]

  Faiyaz-Ul-Haque M, Al-Jefri A, Al-Dayel F, Bhuiyan JA, Abalkhail HA, Al-Nounou R, Al-Abdullatif A, Pulicat MS, Gaafar A, Alaiya AA: A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations. [ojrd.biomedcentral.com]

• Atonic Seizures

  This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. [ncbi.nlm.nih.gov]

• Neonate-Onset

  Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. [ncbi.nlm.nih.gov]

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.

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.

1. Carlsson G, Andersson M, Putsep K, et al. Kostmann syndrome or infantile genetic agranulocytosis, part one: celebrating 50 years of clinical and basic research on severe congenital neutropenia. Acta Paediatr. 2006; 95(12):1526-1532.
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.
3. Rosenberg PS, Alter BP, Bolyard AA, et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood. 2006; 107(12):4628-4635.
4. Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013; 27(1):19-41, vii.
5. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011; 6:26.
6. Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat. 2013; 34(6):905-914.
7. Gautam S, Kirschnek S, Gentle IE, et al. Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-beta (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation. Cell Death Differ. 2013; 20(8):1068-1079.
8. Bonora M, Wieckowski MR, Chinopoulos C, et al. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene. 2015; 34(12):1475-1486.
9. Xia J, Bolyard AA, Rodger E, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009; 147(4):535-542.
10. Tsangaris E, Klaassen R, Fernandez CV, et al. Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. J Med Genet. 2011; 48(9):618-628.
11. Carlsson G, Fasth A, Berglof E, et al. Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia. Br J Haematol. 2012; 158(3):363-369.
12. Druhan LJ, Ai J, Massullo P, Kindwall-Keller T, Ranalli MA, Avalos BR. Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. Blood. 2005; 105(2):584-591.
13. Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood. 2007; 109(1):93-99.
14. Donadieu J, Beaupain B, Mahlaoui N, Bellanne-Chantelot C. Epidemiology of congenital neutropenia. Hematol Oncol Clin North Am. 2013; 27(1):1-17, vii.
15. Dror Y, Ward AC, Touw IP, Freedman MH. Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF: Activated glucocorticoid receptors synergize with G-CSF signals. Exp Hematol. 2000; 28(12):1381-1389.
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.