Kostmann Disease 

Updated: Aug 24, 2017
Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

Kostmann disease was first described in 1956 as an autosomal recessive disorder characterized by severe neutropenia and onset of severe bacterial infections early in life.[1] In his pivotal doctoral thesis, Rolf Kostmann studied 14 affected children from an inbred family from the province of Norrbotten, Sweden. He reported that the neutropenia was accompanied by "a primary insufficiency of the bone marrow" and that the disease is determined by a "single recessive gene difference." Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 (HAX1) were found in affected descendants of the original Kostmann family.[2]

Today, the condition initially described by Kostmann is referred to as Kostmann disease. However, it is now apparent that congenital neutropenia is a genetically heterogeneous group of related disorders and, therefore, is designated as severe congenital neutropenia. Severe congenital neutropenia demonstrates several modes of inheritance, including autosomal recessive, autosomal dominant, sporadic, and X-linked forms.

Pathophysiology

Neutrophils are the most prevalent type of white blood cell and are an essential part of the innate immune system. They act as initial responders to inflammation and ingest, or phagocytize, microorganisms or particles. A phagosome is formed around the ingested microbes, and an oxidative burst is generated in the phagosome. They also release neutrophil granules that kill the invading microorganism. Neutrophils undergo apoptosis and are then cleared by macrophages or other phagocytic cells, which clear the toxic contents.[3, 4]

Neutropenia is a disorder characterized by an abnormally low absolute number of neutrophils in the blood. Mild neutropenia is classified as less than 1500 granulocytes/μL, moderate is less than 1000/μL, severe is less than 500/μL, and very severe is less than 200/μL. Severe congenital neutropenia usually presents in infancy with an absolute neutrophil count of less than 200/μL.[5, 6]

Several genetic causes of severe congenital neutropenia have been identified, but a common thread among the variants is excessive neutrophil apoptosis. A decrease in the production or shorter half-life of neutrophils results in fewer cells in the periphery.

The unfolded protein response (UPR) has been recently proposed as a potential explanation for increased apoptosis seen in severe congenital neutropenia. Increased endoplasmic reticulum stress leads to the activation of the UPR. When an accumulation of unfolded or misfolded proteins occurs in the lumen of the endoplasmic reticulum, the UPR works to protect the cell against the damage caused by these improperly folded proteins. The goals of the UPR are to maintain homeostasis in the cell by arresting protein translation and promoting signaling pathways that lead to increased production of molecular chaperones to help with protein folding. If this does not happen, the UPR initiates apoptosis.[7, 8, 9, 10]

Epidemiology

Frequency

International

Epidemiological data are limited given the overlapping case definitions of congenital neutropenia and few patient registries.

According to International Neutropenia Registry data from 2003 covering areas with a total population of 700 million in United States, Canada, Australia, and Europe (excluding France), 731 cases were reported, with a prevalence of about 1 case per million people.

A French registry reported an incidence as high as 6 cases per million people. Of the patients from the French survey, 30% had ELANE mutations (20% with severe congenital neutropenia and 10% with cyclic neutropenia), 30% had Shwachman-Diamond syndrome (SBDS), 5% had glycogen storage disease type 1b, and 35% had other disorders (1 or 2% each).[5]

In another study from the North American Severe Chronic Neutropenia Tissue Repository, mutations in ELANE genes were found in 90 (55.6%) of 162 patients. Of 72 patients with normal ELANE genes, 45 had sufficient DNA to undergo throughput sequencing to determine prevalence of other mutations(HAX1, -WASp, SBDS, GFI1, and G6PC3). Five of these patients were found to have mutations: G6PC3 in 2, GFI1 in 1, SBDS in 1, and WASp in 1. In 40% of patients, a genetic etiology for severe congenital neutropenia was unknown.[11]

Mortality/Morbidity

The mortality rate is 70% within the first year of life in the absence of medical intervention with granulocyte colony-stimulating factor (G-CSF), bone marrow transplantation, or peripheral blood stem cell transplantation.[12]

Patients with severe congenital neutropenia are at an increased risk of bacterial and fungal infections, with most frequent infections involving the skin, mucosa, ears, nose, throat, and lungs. Stomatitis starts after age 2 years with erosive hemorrhagic gingivitis and painful aphthouslike papules on the tongue and cheeks, contributing significantly to morbidity. Chronic periodontal disease has been attributed to deficiency in a defensin, the antimicrobial peptide LL-37.[13] Diffuse gastrointestinal lesions may cause abdominal pain and diarrhea, resembling bacterial enteritis. Bacterial infections involve Staphylococcus aureus and Staphylococcus epidermidis, streptococci, enterococci, pneumococci, Pseudomonas aeruginosa, gram-negative bacilli, and fungal infections with Candida or Aspergillus species.

About 1 in 5 patients with severe congenital neutropenia develop secondary malignancies. The incidence of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in severe congenital neutropenia after 10 years of G-CSF treatment is 21%. Acquired mutations in G-CSF receptor CSF3R are a highly predictive marker for the progression of severe congenital neutropenia to leukemia.[14] Of patients with severe congenital neutropenia, 20-30% have acquired mutations in the CSF3R gene, which produce C-terminally truncated hyperresponsive forms of the G-CSFRhyper and a strong predisposition for MDS and AML.

Race

No major differences likely exist in prevalence across countries. However, certain mutations are linked to geographic origin, such as HAX1 in Kurdistan and Sweden and G6PC3 in Arameans.[5]

Sex

As the name implies, X-linked severe congenital neutropenia due to WASpmutations are only seen in boys. No sexual predilection is associated with the other causes of severe congenital neutropenia.

Age

Patients are diagnosed shortly after birth with recurrent bacterial infections within the first few months of life.

 

Presentation

History

Neutropenic patients are usually infected by organisms of their endogenous flora, the resident bacteria of the mouth and oropharynx, gastrointestinal tract, and skin. A cardinal feature of these infections is a lack of purulence. By age 2 years, oral ulcers and tooth decay are almost always present. The stomatologic disorders are distinguished by erosive, hemorrhagic, and painful gingivitis associated with papules on the tongue and the cheek mucosa, as well as perirectal inflammation or cellulitis. Abscesses, pneumonia, and septicemia may also occur.

The most common microbes seen are S aureus and gram-negative organisms. Patients with severe congenital neutropenia also are at risk for significant bacterial infections such as otitis media, bronchitis, pneumonia, osteomyelitis, or cellulitis. In addition, patients can also experience diffuse gastrointestinal lesions leading to abdominal pain and diarrhea that can mimic Crohn disease. They are not initially predisposed to other fungal, parasitic, or viral infections, but have a higher risk of fungal infection with prolonged neutropenia or extended antibiotic use.[5, 3]

Severe congenital neutropenia patients also may experience a variety of extrahematopoietic manifestations depending on their genetic abnormalities, such as neurologic involvement in HAX1 mutations, dermatologic manifestations in G6PC3 mutations, or monocytopenia in WASp mutations.

Before the introduction of granulocyte colony-stimulating factor (G-CSF), patients would often die during the first year of life. After the introduction of G-CSF, patients survive into adulthood but are at significant risk of leukemia or myelodysplasia.[15] On the basis of national averages of premature deliveries in the general population, an estimated 8% of patients with Kostmann disease are delivered prematurely and admitted to neonatal intensive care units. Although neutropenia is common in ill preterm infants and severe congenital neutropenia is relatively rare, severe congenital neutropenia should be considered if other etiologies for the neutropenia are not found. Therapy with G-CSF can save lives in this clinical setting because of the innate risks of infection in a preterm infant.

Physical

Signs and symptoms of Kostmann disease include the following:

  • Oral ulcers

  • Gingivitis, which may lead to early loss of permanent teeth

  • Pharyngitis

  • Sinusitis, otitis media

  • Lymphadenopathy, lymphadenitis

  • Bronchitis, pneumonia

  • Cellulitis

  • Cutaneous abscess, boils

  • Omphalitis

  • Perianal abscess

  • Lung abscess

  • Liver abscess

  • Peritonitis

  • Enteritis with chronic diarrhea and vomiting

  • Bacteremia and/or septicemia, most commonly caused by streptococci or staphylococci (Other commonly encountered organisms include Pseudomonas, fungi, and, in rare cases, Clostridium species.)

  • Urinary tract infection

  • Fractures or bone pain

  • Splenomegaly

  • Neurological symptoms, including epilepsy and neuropsychological deficits[16]

Causes

Although the first description of severe congenital neutropenia was reported in 1956 by Rolf Kostmann, the underlying genetic defect was not elucidated until 50 years later.[1, 17] Today, the condition initially described by Kostmann is referred to as Kostmann disease. However, it is now apparent that severe congenital neutropenia is a genetically heterogeneous group of related disorders. Our evolving understanding of severe congenital neutropenia parallels the explosion of new genetic discoveries. Below in chronological order based on date of discovery, some of the mutations responsible for severe congenital neutropenia and recent advances are highlighted. The underlying genetic cause remains elusive in about 40% of patients with severe congenital neutropenia, and future discoveries will certainly yield new insights.

Excess neutrophil apoptosis is a central mechanism in the pathogenesis of severe congenital neutropenia. Several of the mutations associated with severe congenital neutropenia result in increased apoptosis, including those involving neutrophil elastase (ELANE), WASp, HAX1, and, potentially, GFI1. This suggests that errors in trafficking and the unfolded protein response (UPR) may be triggers for premature neutrophil cell death.

CSF3R mutation (1999) (acquired)

The most critical myeloid cytokine for neutrophil production, differentiation, and survival is G-CSF. Since 1987, G-CSF has been used for the treatment of severe congenital neutropenia. Therefore, mutations in the G-CSF receptor (CSF3R gene) were initially suggested to be the cause of severe congenital neutropenia.[18] It was subsequently realized that these mutations were acquired during the lifetime of severe congenital neutropenia patients.

Two classes of CSF3R mutations have been recognized, resulting in hyporesponsive and hyperresponsive forms of the G-CSF receptor.[8] Of patients with severe congenital neutropenia, 20-30% have acquired mutations in the CSF3R gene, which produce C-terminally truncated hyperresponsive forms of the G-CSFRhyper. Patients with this mutation have a strong predisposition for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). G-CSFRhyper enhances stat-5 activation, which seems to provide a selective advantage to hematopoietic stem cells with this mutation. Hence, this mutation may be an early step in leukemogenesis. Acquired G-CSFR mutations have been detected in approximately 80% of severe congenital neutropenia patients who develop AML/MDS.

The second mutation class is a hyporesponsive form of the receptor, G-CSFRhypo, which is seen in severe congenital neutropenia patients who are unresponsive to G-CSF therapy. These mutations act in a dominant fashion over wild-type receptors and prevent normal ligand binding. Although 10% of severe congenital neutropenia patients are refractory to G-CSF, it is not known what percentage of patients harbor the G-CSFRhypo mutation. As G-CSF receptor mutations (CSF3R) are not present at birth, they do not represent the underlying defect for severe congenital neutropenia.

Neutrophil elastase mutations (ELA2) (2000) (autosomal dominant)

ELANE (previously ELA2) mutations account for about 50-60% of patients with severe congenital neutropenia. Gene expression is autosomal dominant. The mutation is in the gene for neutrophil elastase, which is a serine protease made primarily at the promyelocytic stage of neutrophil production. The ELANE gene has been implicated as a cause of severe congenital neutropenia, as well as cyclic neutropenia. More than 40 mutations have been identified.

It is not understood why the same ELANE mutations can result in either cyclic neutropenia or severe congenital neutropenia. Some experts consider cyclic neutropenia and severe congenital neutropenia due to ELANE mutations along the same spectrum of disease. The molecular mechanisms whereby neutrophil elastase mutations disrupt neutrophil production are not entirely understood. One hypothesis is that neutrophil elastase mutations may lead to disruptions in intracellular trafficking. This, in turn, may lead to activation of the UPR and, ultimately, apoptosis of granulocytic precursors.[19, 5]

WASp gain-of-function mutation (2001) (X-linked recessive)

The Wiskott-Aldrich syndrome protein (WASp) regulates actin polymerization in hematopoietic cells. Actin polymerization is required for cell signaling, cell-to-cell interactions, and cell motility. Wiskott-Aldrich syndrome is an X-linked immunodeficiency associated with congenital microthrombocytopenia and eczema. There are almost 150 different WASp mutations leading to Wiskott-Aldrich syndrome, including missense and splice mutations, short deletions, and nonsense mutations, all of which result in loss of protein function.

In contrast, X-linked severe congenital neutropenia has been linked to gain-of-function WASp mutations. These mutations lead to constitutional-active protein forms and consequently unregulated actin polymerization. The 3 mutations seen (L270P, 1294T and S27OP) are thought to disrupt the autoinhibitory domain of this protein.[11] These patients have defective mitosis and cytokinesis, which leads to decreased proliferation and increased apoptosis in myeloid progenitors.[8]

GFI1 mutation (2003) (autosomal dominant)

In 2003, Person et al screened GFI1 as a candidate gene for patients affected with severe congenital neutropenia.[20] GFI1 is a proto-oncogene that encodes a zinc finger transcription factor. Dominant negative zinc finger mutations result in disabled transcriptional repressor activity. It is hypothesized that GFI1 mutations cause overexpression of neutrophil elastase. The up-regulation of neutrophil elastase activates the UPR and induces neutrophil apoptosis.

Bcl-2 expression (2004)

Carlsson et al noted that the Kostmann disease patients they studied had elevated apoptosis in the bone marrow.[21] They also found an abnormally low number of B-cell lymphoma-2 (Bcl-2) in biopsies from patients with severe congenital neutropenia prior to initiation of G-CSF therapy. The primary function of Bcl-2 is prevention of mitochondrial release of cytochrome c, which initiates apoptosis, into the cells. After G-CSF administration, Bcl-2 levels appeared normalized and apoptosis of the cells decreased.

HAX1 mutations (2006) (autosomal recessive)

Although Kostmann disease was first described in 1956, the underlying genetic mutation was not elucidated until recently. HAX-1 deficiency is now known to be responsible for Kostmann disease, an autosomal recessive type of severe congenital neutropenia. Members of the original Swedish “Kostmann” family members were found to have mutations in HAX1 gene.[17] This gene is on chromosome 1 and encodes HAX-1 or HCLS-1–associated protein X, which is a mitochondria-targeted protein member of the Bcl-2 family of apoptosis-regulating proteins.[21]

Increased apoptosis is seen in HAX-1–deficient neutrophils. There is also increased release of cytochrome c from mitochondria in myeloid progenitor cells, suggesting HAX-1 helps in stabilizing the mitochondrial membrane potential. Mitochondrial control of apoptosis seems to be a mechanism in humans of regulating myeloid cell homeostasis.

Homozygous HAX1 mutations have been found in autosomal-recessive severe congenital neutropenia, and compound heterozygous HAX1 mutations have also been identified. All mutations described inactivate the HAX-1 protein. A mutation affecting transcript variant 1 of HAX-1 is associated with congenital neutropenia alone, but mutations affecting both transcripts caused congenital and neurological symptoms.[16] Isoform B also may affect neuronal function.[10]

G6PC3 mutation (2009) (autosomal recessive)

In 2009, Boztug et al described a congenital neutropenia syndrome with biallelic mutations in G6PC3, a gene encoding glucose-6-phosphatase, catalytic subunit 3.[22] Like patients with mutations in ELA2 or HAX1, peripheral-blood neutrophils had increased rates of spontaneous apoptosis in the absence of G6PC3. Therefore, G6PC3 is required to maintain neutrophil viability. It is hypothesized that increased neutrophil apoptosis in G6PC3 deficiency involves increased endoplasmic reticulum stress, which is seen in deficient protein folding in the endoplasmic reticulum.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

An absolute neutrophil count (ANC) of less than 200/μL is seen in classic cases of severe congenital neutropenia (see the Absolute Neutrophil Count calculator).

Monocytosis and eosinophilia may be evident. Total leukocyte counts are frequently normal because of the monocytosis. Mild anemia may be present from chronic inflammation, and thrombocytosis may be present.

Quantitative immunoglobulins may show hypergammaglobulinemia. Patients have a normal response to vaccinations.

Complement levels typically are normal.

Antineutrophil antibodies are absent but should be checked to exclude an autoimmune etiology when the diagnosis is entertained in the first few months of life.

Electrolyte levels and renal and liver function test results are within the normal range.

Imaging Studies

Imaging studies are performed only as clinically indicated to evaluate for infection. Bone density (duel-energy x-ray absorptiometry [DEXA] scanning) is performed to evaluate for osteopenia or osteoporosis.

Other Tests

Genetic testing can be considered to differentiate between the variants of severe congenital neutropenia depending on the clinical findings.

Procedures

Bone marrow biopsy can be very helpful in the diagnosis of severe congenital neutropenia. Bone marrow is also necessary to rule out malignant conditions, evaluate myeloid maturation, determine cellularity, and elucidate an etiology.[15]

When leukemic or myelodysplastic transformation occurs, bone marrow cytogenetics exhibit monosomy 7 in 50% of cases. Granulocyte colony-stimulating factor (G-CSF) receptor mutations occur within an intracellular part of the receptor and can be identified from either blood or bone marrow samples. As G-CSF receptor mutations (CSF3R) are not present at birth, they do not represent the underlying defect for the disease.

Histologic Findings

The bone marrow findings of severe congenital neutropenia typically demonstrate normal or decreased cellularity with an arrest of neutrophil precursor maturation at the promyelocyte or myelocyte level. This is typically seen in the severe congenital neutropenia due to ELANE, HAX1, WASp, G6PC3, and CSF3R mutations. Maturation arrest in the promyelocyte phase is often associated with bone marrow hypereosinophilia and monocytosis.[15]

 

Treatment

Medical Care

Antimicrobial prophylaxis

Antimicrobial prophylaxis may be useful in preventing recurrent infections. Oral sulfamethoxazole/trimethoprim sulfate (Bactrim) as a once daily, 50 mg/kg/d dose has been used. This only partially prevents the gingivostomatitis associated with severe congenital neutropenia. Concurrent therapy with metronidazole, which covers oral saprophytic flora, especially anaerobes, also may be added.

Hematopoietic growth factors

Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte macrophage colony-stimulating factor [GM-CSF]) are used to correct neutropenia. G-CSF has been used since the late 1980s and has shown a greater than 90% response rate. G-CSF is more efficacious and tolerable than GM-CSF, with less flu-like syndrome and less marked eosinophilia. There are 2 forms of G-CSF available: filgrastim (Neupogen in 480- or 330-µg vials) and lenograstim (Granocyte in 340- or 130-µg vials). Lenograstim is the glycosylated form of G-CSF.

Pegfilgrastim (Neulasta)

Pegfilgrastim is the pegylated, covalent conjugate of G-CSF, a combination of filgrastim and polyethylene glycol, with a half-life of 15-80 hours, which decreases the number of injections needed from daily to once weekly. Pegfilgrastim has been shown to be clinically efficacious and improve compliance and quality of life in various case reports.[23, 24, 25] However, in an observational study of 17 patients from the French Severe Chronic Neutropenia Registry who received pegfilgrastim, only half the patients prescribed were able to continue this medication long term because of adverse events and lack of efficacy.[26] Further studies evaluating long-term outcomes are required.

Filgrastim/lenograstim (G-CSF)

There is an induction phase with G-CSF to evaluate the response of individuals, with an increase in absolute neutrophil count (ANC) (>1500/μL) and clinical improvement after 10-15 days. The initial daily dose is 5 μg/kg subcutaneously. If there is no response after 15 days, the daily dose is increased by 5 μg/kg. If the response is rapid or excessive (ANC >5000 /μL), the dose is halved. Once the minimal daily dose is determined, the maintenance phase can begin, with monitoring of neutrophil counts every 3-6 months. Almost two thirds of patients respond to a daily dose of 2-10 µg/kg, while 20% respond to 10-20 μg/kg. A small percentage of patients require higher doses, up to 100 μg/kg. Around 10% of patients are unresponsive to G-CSF therapy.[8]

Short-term tolerability

G-CSF has good short-term tolerability with occasional immediate and local reactions (< 1 per 100). Flu-like reactions are another infrequent adverse effect. Bone pain occurs in 2-5% of patients, which resolves within 24 hours and does not recur with lower doses.[5]

Long-term tolerability

G-CSF acts principally on granulocytes, but various blood cell abnormalities can be seen transiently during treatment. Monocytosis (above 1500/μL) is frequent and eosinophilia can be amplified by G-CSF, but lymphocytosis and hemoglobin levels are usually not affected. Occasionally, reticulocytosis and elevated hemoglobin levels can be seen if there is an initial inflammatory anemia at the start of treatment.

Thrombocytopenia is the most common hematologic adverse effect and is usually moderate and resolves when the G-CSF dose is reduced. Thrombocytopenia can also be from hypersplenism. The spleen is usually enlarged at the start of treatment. Spleen rupture requiring splenectomy can sometimes occur.

Uricemia can arise from long-term treatment but has no clinical consequences. Gout exacerbations have been seen in short-course therapy, however.

The first cases of leukocytoclastic vasculitis were seen after short-term G-CSF treatment and seem to be due to the increase in neutrophil adhesion molecule expression.

Two cases of mesangioproliferative glomerulonephritis have been seen with long-term treatment, but they resolved after dose reduction or stoppage of treatment.

Osteoporosis occurs in up to one fourth of patients with severe congenital neutropenia who receive G-CSF therapy, and 2 cases of pathological fractures have been reported. However, severe congenital neutropenia alone seems to be associated with osteopenia, which is usually present before treatment starts.

Surgical Care

Surgical drainage of abscesses may be required for infections refractory to intravenous antibiotics.

Hematopoietic stem cell transplantation (HSCT) can be curative for severe congenital neutropenia and is the only option when patients continue to have severe infections despite G-CSF therapy. HSCT is indicated when there is G-CSF resistance (>50 μg/kg/day) and myelodysplasia/leukemic transformation.

Patients chronically dependent on high doses of G-CSF (at least 20 μg/kg per injection at least 3 months a year) should be considered for bone marrow grafting on a case-by-case basis since there is a high risk of leukemic transformation, taking into account whether related donors are available. Survival with HSCT is now is over 70%, even with malignant transformation in most cases.

Consultations

A pediatric immunologist, pediatric hematologist, and pediatric dentist are helpful consultations.

Diet

Historically for oncology patients, the neutropenic diet has reduced the introduction of bacteria into the host's gastrointestinal tract, thus minimizing the patient's exposures to potential pathogens. This diet excludes foods considered at high risk for bacterial colonization, especially raw fruits and vegetables. The Neutropenic Diet Guideline includes the following recommendations:

  • Avoid raw vegetables and fruit (Oranges and bananas are acceptable.)

  • Avoid take-out foods, fast foods, and fountain drinks

  • Avoid aged cheese (bleu, Roquefort, brie)

  • Cook all produce to well done; eggs must be hard-boiled

  • Avoid deli meats

  • No raw nuts, nuts roasted in shell, or freshly ground nut butters from a health food store

  • No well water

  • No yogurt

No dietary restrictions are necessary in patients with severe congenital neutropenia, so long as they are on adequate doses of G-CSF and their ANCs are maintained above 1000/μL.

 

Medication

Medication Summary

History and physical examination is important in assessing the severity of acute infections and determining treatment. Fevers higher than 39°C and low monocyte count (< 100/μL) are associated with more serious infections. Oral antibiotic therapy can be used for superficial or ear/nose/throat infection in moderate neutropenia with close monitoring if inflammatory markers are low (C-reactive protein, < 15 mg/L).

Patients with severe congenital neutropenia and sepsis require hospitalization. Blood, urine, and infectious-site cultures, as well as chest radiography, should be performed as clinically indicated. Aggressive intravenous parenteral antibiosis with a combination of a third-generation cephalosporin and an aminoglycoside should be considered. If fevers persist beyond 48 hours, the addition of antifungal agents is recommended.

In patients with severe infections that are worrisome, G-CSF should be started at the known dose that patient responds to, or standard dose of 5 μg/kg/d. There is an induction phase with G-CSF to evaluate the response of individual, with an increase in absolute neutrophil count (ANC) (>1500/μL) and clinical improvement after 10-15 days. The initial daily dose is 5 μg/kg subcutaneously. If there is no response after 15 days, the daily dose is increased by 5 μg/kg. If the response is rapid or excessive (ANC >5000/μL), the dose is halved.

Colony-stimulating factors

Class Summary

These agents are used to stimulate neutrophil production and act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia. Glycosylated G-CSF is not FDA approved in the United States but is available in England.

Filgrastim (G-CSF, Neupogen, tbo-filgrastim, Granix, filgrastim-sndz, Zarxio)

Filgrastim is a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF) consisting of a 175-amino acid protein with a molecular weight of 18,800 d. It is produced by Escherichia coli bacteria into which the human G-CSF gene is inserted. This protein has an amino acid sequence identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Because it is produced in E coli, the product is nonglycosylated and thus differs from G-CSF isolated from human cells.

Pegfilgrastim (Neulasta)

Recombinant pegylated-conjugated human G-CSF. Acts on hematopoietic cells to stimulate production, maturation, and activation of neutrophilsl. Increases migration and cytotoxicity of neutrophils.

 

Follow-up

Further Outpatient Care

Obtain a CBC count with differential twice per week during the first 4 weeks after the initiation of granulocyte-colony stimulating factor (G-CSF) or for 2 weeks following any dosage adjustments. Thereafter, obtain a CBC count with differential monthly for 6 months. When the minimum daily dose is found, the maintenance phase can be started, with monitoring of absolute neutrophil counts every 3-6 months.

Routine clinical follow-up every 3 months for patients who are stable is recommended.

Enroll patients in the Severe Chronic Neutropenia International Registry (SCNIR).

Further Inpatient Care

Patients admitted for inpatient care related to infection warrant blood, urine, and infectious-site cultures, as well as chest radiography, as clinically indicated. Aggressive intravenous antibiotic therapy and appropriate supportive therapies should be initiated. Consultation with pediatric immunologist, pediatric hematologist, and infectious diseases specialist is recommended.

Transfer

Once severe congenital neutropenia is suspected, patient should be referred to a specialized treatment center regarding genetic testing and treatment.

Deterrence/Prevention

Provide genetic counseling to parents of infants because Kostmann disease has an autosomal recessive form of inheritance. Other disorders of severe congenital neutropenia demonstrate several modes of inheritance, including autosomal recessive, autosomal dominant, sporadic, and X-linked forms.

Maintaining an adequate absolute neutrophil count (≥1000/μL) with G-CSF is central to preventing infections.

Annual bone marrow examination for morphology and cytogenetic testing should be performed in order to identify any changes indicating malignant transformation and to allow for early intervention with bone marrow transplantation.

Regular G-CSF receptor analysis should be performed to identify mutations. This can be done on either peripheral blood or bone marrow samples by laboratories headed by the SCNIR.

Regular dental and periodontal evaluation and care should be performed in order to minimize dental complications. The characteristic gingivitis and periodontal disease persist even after G-CSF.

Isolating patients within their homes or away from crowds has shown little practical value.

Complications

Most complications relate to infections.[27]

Bone demineralization occurs in approximately 50% of patients, which may result in bone pain and unusual fractures, either as a part of the pathophysiology of the disease or potentially from either endogenous or exogenous G-CSFs by increased bone resorption.

About 1 in 5 patients with severe congenital neutropenia develop secondary malignancies. The incidence of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in severe congenital neutropenia after 10 years of G-CSF treatment is 21%. Acquired mutations in G-CSF receptor CSF3R are a highly predictive marker for the progression of severe congenital neutropenia to leukemia.[14] Of patients with severe congenital neutropenia, 20-30% have acquired mutations in the CSF3R gene, which produce C-terminally truncated hyperresponsive forms of the G-CSFRhyper and a strong predisposition for MDS and AML.

Prognosis

In the 1950s, almost all patients would die of sepsis, cellulitis, or pneumonia within the first 2 years of life. In the 1960s and 1970s, more antibiotic therapy was used and lethal infections were less frequent.

In the 1970s, survival with severe congenital neutropenia started to improve owing to antibiotic prophylaxis and to curative parenteral antimicrobial chemotherapy.

Since 1987, the use of G-CSF has resulted in fewer infections of shorter duration. This has dramatically improved patient's quality of life and prolongs survival. However, G-CSF and neutrophil recovery does not improve chronic stomatitis or gingivitis, and tooth loss can occur.

Patient Education

Educate patients and their families on the signs and symptoms of infections to ensure appropriate and prompt therapy.

Inform patients and their families of the risk for developing leukemia.

The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. The telephone number is 1-800-296-4433. The Web site is www.primaryimmune.org. The foundation's mailing address is 40 W Chesapeake Ave, Suite 308, Towson, MD 21204; some states have local chapters.

The Jeffrey Modell Foundation, at 747 3rd Avenue, New York, NY 10017, also provides educational support. The telephone number is 1-866-INFO-4-PI. The Web site is www.jmfworld.org.

The SCNIR was established in March 1994, in the United States, Australia, Canada, and the European Community. The SCNIR is directed by a scientific advisory board of physicians from around the world who care for severe congenital neutropenia patients. Their mission is to establish a worldwide database of treatment and disease-related outcomes for persons diagnosed with severe chronic neutropenia. Collection of this information will lead to improved medical care and is used for research to determine the causes of neutropenia. The Web site is www.depts.washington.edu/registry.