Epidemiologic investigations of congenital neutropenia aim to determine several important indicators related to the disease, such as incidence at birth, prevalence, and outcome in the population, including the rate of severe infections, leukemia, and survival. Genetic diagnosis is an important criterion for classifying patients and reliably determining the epidemiologic indicators. Patient registries were developed in the 1990s. The prevalence today is probably more than 10 cases per million inhabitants. The rate of infection and leukemia risk can now be calculated. Risk factors for leukemia seem to depend on both the genetic background and cumulative dose of granulocyte colony stimulating factor.
Key points
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Congenital neutropenia is a large family of diseases, and genetic diagnosis is an important criterion for classifying patients and reliably determining the epidemiologic indicators.
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Globally, patient registries were developed in the early 1990s to assess the safety of granulocyte colony-stimulating factor (GCSF) and concentrate expertise on the diseases.
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Approximately 20 years after starting the registries, incidence at birth was determined in 2 countries, roughly between 10 and 15 cases per million births, and the prevalence is probably more than 10 cases per million inhabitants.
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The rate leukemia risk can now be calculated reliably. Risk factors for leukemia seem to depend on both the genetic background and cumulative dose of GCSF.
Introduction
Congenital neutropenia is characterized by chronic neutropenia caused by a constitutional genetic defect. Epidemiologic investigations of congenital neutropenia aim to define the incidence at birth, prevalence, and several complications that occur in the course of the disease, such as lethal infections or leukemia. The management of congenital neutropenia has changed since granulocyte colony-stimulating factor (GCSF) became available for commercial use in 1993. Before this date, the literature was composed exclusively of case reports. The largest survey before 1990 involved 16 cases. However, during this period, several entities have been described, including Kostmann disease, Shwachman disease, cyclic neutropenia, glycogen storage disease type Ib, and WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome). With its potential risk of leukemia, the availability of GCSF stimulated the development of patient registries. In 1993, such registries were organized in the United States, Canada, France, and Germany, and with the support of Amgen, an International Severe Chronic Neutropenia Registry (ISCNR) encompassing North America and Germany via independent association with public support in France. The establishment of registries allows better definition of diseases and their outcomes. Since the early 1990s, particularly during the last decade, the molecular bases of several entities have been discovered, leading to changes in disease classification. Kostmann syndrome is often considered to be part of the paradigm of congenital neutropenia; it was first described in a Swedish publication in 1950, and subsequently in English in 1956. The syndrome has 3 main characteristics: profound neutropenia (<0.2 G/L) occurring during the first weeks of life, maturation arrest of granulopoiesis at the promyelocyte stage, and death due to bacterial infections. Eleven of the 14 patients in the first report of the disease died in their first year of life from bacterial infections. Nearly 50 years later, a patient’s life expectancy routinely exceeds 20 years and the molecular basis of this entity has been identified. Kostmann syndrome is now known to be accompanied by mutation of HAX1 protein (Kostmann pedigree) and neurologic involvement (mental retardation and epilepsy) if mutation involved 1 of the 2 isoforms of the HAX1 protein. Thus, the paradigm of congenital neutropenia is early hematologic expression and later neurologic involvement.
Knowledge of the molecular basis of other forms of congenital neutropenia has also modified the disease classification. Until the late 1990s, the literature distinguished between permanent neutropenia (severe congenital neutropenia or Kostmann syndrome) and cyclic neutropenia, which is associated with a regular pattern of change in the neutrophil count, typically every 21 days, with autosomal dominant transmission. This distinction was made based on the International Registry of Chronic Neutropenia, in which cyclic neutropenia was not included among the congenital neutropenias. In 1999, Horwitz and colleagues identified mutations in the neutrophil elastase gene ( ELANE ) among 13 pedigrees of patients with cyclic neutropenia. The same team later found that many patients with severe congenital neutropenia also have mutations in ELANE. This finding pointed to a continuum between severe congenital neutropenia and cyclic neutropenia, and showed that both can be considered congenital.
The term congenital neutropenia is not used homogeneously in the literature. One restrictive definition reserves the term congenital neutropenia for severe forms of the disease that are not associated with immunologic or extrahematopoietic abnormalities, whereas a broader definition includes all diseases that comprise chronic neutropenia, with or without immunologic or extrahematopoietic abnormalities. Thus, only some investigators include glycogen storage disease Ib, Shwachman disease, WHIM syndrome, and Barth disease in the definition of congenital neutropenia.
Introduction
Congenital neutropenia is characterized by chronic neutropenia caused by a constitutional genetic defect. Epidemiologic investigations of congenital neutropenia aim to define the incidence at birth, prevalence, and several complications that occur in the course of the disease, such as lethal infections or leukemia. The management of congenital neutropenia has changed since granulocyte colony-stimulating factor (GCSF) became available for commercial use in 1993. Before this date, the literature was composed exclusively of case reports. The largest survey before 1990 involved 16 cases. However, during this period, several entities have been described, including Kostmann disease, Shwachman disease, cyclic neutropenia, glycogen storage disease type Ib, and WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome). With its potential risk of leukemia, the availability of GCSF stimulated the development of patient registries. In 1993, such registries were organized in the United States, Canada, France, and Germany, and with the support of Amgen, an International Severe Chronic Neutropenia Registry (ISCNR) encompassing North America and Germany via independent association with public support in France. The establishment of registries allows better definition of diseases and their outcomes. Since the early 1990s, particularly during the last decade, the molecular bases of several entities have been discovered, leading to changes in disease classification. Kostmann syndrome is often considered to be part of the paradigm of congenital neutropenia; it was first described in a Swedish publication in 1950, and subsequently in English in 1956. The syndrome has 3 main characteristics: profound neutropenia (<0.2 G/L) occurring during the first weeks of life, maturation arrest of granulopoiesis at the promyelocyte stage, and death due to bacterial infections. Eleven of the 14 patients in the first report of the disease died in their first year of life from bacterial infections. Nearly 50 years later, a patient’s life expectancy routinely exceeds 20 years and the molecular basis of this entity has been identified. Kostmann syndrome is now known to be accompanied by mutation of HAX1 protein (Kostmann pedigree) and neurologic involvement (mental retardation and epilepsy) if mutation involved 1 of the 2 isoforms of the HAX1 protein. Thus, the paradigm of congenital neutropenia is early hematologic expression and later neurologic involvement.
Knowledge of the molecular basis of other forms of congenital neutropenia has also modified the disease classification. Until the late 1990s, the literature distinguished between permanent neutropenia (severe congenital neutropenia or Kostmann syndrome) and cyclic neutropenia, which is associated with a regular pattern of change in the neutrophil count, typically every 21 days, with autosomal dominant transmission. This distinction was made based on the International Registry of Chronic Neutropenia, in which cyclic neutropenia was not included among the congenital neutropenias. In 1999, Horwitz and colleagues identified mutations in the neutrophil elastase gene ( ELANE ) among 13 pedigrees of patients with cyclic neutropenia. The same team later found that many patients with severe congenital neutropenia also have mutations in ELANE. This finding pointed to a continuum between severe congenital neutropenia and cyclic neutropenia, and showed that both can be considered congenital.
The term congenital neutropenia is not used homogeneously in the literature. One restrictive definition reserves the term congenital neutropenia for severe forms of the disease that are not associated with immunologic or extrahematopoietic abnormalities, whereas a broader definition includes all diseases that comprise chronic neutropenia, with or without immunologic or extrahematopoietic abnormalities. Thus, only some investigators include glycogen storage disease Ib, Shwachman disease, WHIM syndrome, and Barth disease in the definition of congenital neutropenia.
Epidemiology
Definition of Congenital Neutropenia
Definition of the morbid phenomenon is critical in epidemiology. In this review, the term congenital neutropenia is not restricted to disorders in which neutropenia is the only phenotypic manifestation but encompasses all congenital disorders comprising neutropenia. The authors also consider neutropenia as a continuum, ranging from intermittent forms with various periods of neutrophil deficiency to permanent circulating neutrophil deficiency. Table 1 provides the list of genetic diseases that we consider congenital neutropenia and for which there is information available in the literature. All of these forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked, autosomal, recessive, or dominant. In addition to congenital neutropenia with a documented genetic defect, several patients present with chronic neutropenia of probable genetic origin that is presumably considered congenital neutropenia. This category represents 30% to 50% of patients, depending on the survey, and cannot be considered as marginal. Increased knowledge regarding genetic neutropenia will help to classify the forms of this disease. A category termed idiopathic neutropenia is frequently reported. Patients in this category have chronic neutropenia with no detectable cause. Whether idiopathic neutropenia and congenital neutropenia with no known genetic defect are the same cannot yet be determined, but they are likely the same and the difference just a matter of terminology. In addition to this group of patients, ethnic neutropenia should be considered because it is a congenital neutropenia. Epidemiologic studies have shown that the prevalence of neutropenia (<1.5 g/L) is approximately 4.5% in blacks and 0.8% in whites. Few data are available on other populations, but a high frequency has been noted in the Arabian peninsula, and the frequent mild neutropenia reported in Crete likely corresponds to the same entity. Ethnic neutropenia is not associated with increased susceptibility to infection, and no symptoms have ever been reported. Three simple, but poorly specific, classic features are present: moderate neutropenia (0.5–1.5 g/L), no infection attributable to neutropenia, and no identifiable cause. The few available studies of ethnic neutropenia have yielded strictly normal findings; in particular, the bone marrow is qualitatively and quantitatively normal. A particular polymorphism of the Duffy antigen receptor for cytokines (DARC) is associated with ethnic neutropenia in blacks. Because ethnic neutropenia is not a morbid situation, it is not discussed further, but many ethnic neutropenia cases may be considered idiopathic neutropenia, which causes some misclassification. The ultimate difficulty in defining congenital neutropenia is caused by a genetic defect involving B or T lymphocytes, such as Bruton disease, severe combined immune deficiency (SCID) including peculiar reticular dysgenesis, and several forms of familial hemophagocytic lymphohistiocytosis such as Chediak-Higashi syndrome or Griscelli syndrome type 2. We have excluded these diseases from congenital neutropenia, even though some may actually present neutropenia in the course of the disease or be diagnosed as neutropenia. In addition, we have excluded all types of neutropenia secondary to drugs, viral infection, or autoimmune processes.
| Subgroup of Neutropenia | Disease Name/Reference | OMIM Code | Main Hematologic Features | Other Features | Inheritance | Gene Localization | Gene | Normal Function of the Gene |
|---|---|---|---|---|---|---|---|---|
| Congenital neutropenia without extrahematopoietic manifestations | Severe congenital neutropenia/cyclic neutropenia | 202700 162800 | Severe permanent Maturation arrest Intermittent/cyclic with variable bone marrow features | No | Dominant | 19q13.3 | ELANE | Protease activity Antagonism with α1 antitrypsin |
| Severe congenital neutropenia, somatic mutation of CSF3R | 202700 | Permanent Maturation arrest Unresponsive to GCSF | No | No genetic inheritance | 1p35-p34.3 | CSF3R | Transmembrane GCSF receptor/intracellular signaling | |
| Congenital neutropenia with innate or adaptive deficiency but no extrahematopoietic features | Severe congenital neutropenia | 202700 | Permanent/severe or mild Sometimes maturation arrest | Internal ear (in mouse model) Lymphopenia | Dominant | 1p22 | GFI1 | Transcription factor Regulation of oncoprotein |
| Severe congenital neutropenia | 301000 | Severe, permanent maturation arrest | Monocytopenia | X-Linked | Xp11.4-p11.21 | WAS | Cytoskeleton homeostasis | |
| WHIM | 193670 | Severe, permanent No maturation arrest Myelokathexis | Lymphopenia Monocytopenia Warts | Dominant | 2q21 | CXCR4 | Chemokine receptor | |
| STK4/MTS1 | Mild neutropenia, inconstant | Lymphopenia Monocytopenia Warts | Dominant | 20q13.12 | STK4/MTS1 | Serine/threonine kinase | ||
| GATA2 | 614172 614038 | Mild neutropenia No maturation arrest | Monocytopenia Warts | Dominant | 3q21.3 | GATA2 | Transcription factors/zinc finger | |
| Congenital neutropenia with extrahematopoietic manifestations | Kostmann disease | 614038 | Maturation arrest | Mental retardation/seizures | Recessive | 1q21.3 | HAX1 | Anti-apoptotic protein located in mitochondria and in the cytosol |
| Shwachman-Bodian-Diamond disease | 601626 | Mild neutropenia Dysgranulopoiesis mild dysmegakaryopoeisis | Exocrine pancreatic deficiency Metaphyseal dysplasia Mental retardation Cardiomyopathy | Recessive | 7q11.22 | SDBS | Ribosomal protein regulation | |
| Severe congenital neutropenia | 614286 | Maturation arrest | Prominent superficial venous network Atrial defect Uropathy | Recessive | 17q21 | G6PC3 | Glucose-6-phosphatase complex: catalytic unit | |
| Barth disease | 302060 | No maturation arrest | Hypertrophy Cardiomyopathy | X-Linked | Xq28 | TAZ (G4.5) | Tafazzin: phospholipid membrane homeostasis | |
| Hermansky-Pudlak syndrome type 2 | 608233 | No maturation arrest | Albinism | Recessive | 5q14.1 | AP3B1 | Cargo protein/ER trafficking with ELANE interaction | |
| Neutropenia with LAMTOR2 mutation | No maturation arrest | Albinism | Recessive | 1q21 | LAMTOR2 | Lysosome packaging | ||
| Poikiloderma type Clericuzio | 604173 | No maturation arrest Minor dysgranulopoietic features | Poikiloderma | Recessive | 16q13 | 16ORF57 | Not known | |
| Glycogen storage type Ib | 232220 | No maturation arrest | Hypoglycemia Fasting hyperlactacidemia Glycogen overload of the liver | Recessive | 11q23.3 | SLC37A4 | Glucose-6-phosphatase complex: trans ER transporter | |
| Cohen syndrome | 216550 | No maturation arrest | Psychomotor retardation Clumsiness Microcephaly Characteristic facial features Hypotonia Joint laxity Progressive retinochoroidal dystrophy Myopia | Recessive | 8q22-q23 | VPS13B | Sorting and transporting proteins in the ER |
What Health Indicators are Useful for Describing Congenital Neutropenia?
Health indicators are not original in congenital neutropenia; they encompass standard indicators such as incidence at birth, prevalence in the overall population, and some well-defined indicators of morbidity, including mortality rate, age at death, and quality of life. More specific to congenital neutropenia is the rate of severe infections, the proportion of patients receiving GCSF, the dose of GCSF used, the number of hematopoietic stem cell transplantations, the rate of severe comorbidity, and the rate of leukemia.
How to Determine Health Indicators and the Role of Registries
Congenital neutropenia is poorly recognized by the public health system. The International Classification of Diseases (ICD) versions 9 and 10 offer some possibilities for coding chronic neutropenia, including codes 284.0, 288.0, 288.2, and 288.5 in ICD9 and D70 and P61.5 in ICD10, but in practice, large databases, including hospital discharge records and national death records, are not appropriate for identifying patients with congenital neutropenia because congenital neutropenia is not separated from chemotherapy-induced neutropenia, a far more common condition.
Patient registries have been in place for several decades for cancer, birth defects, and cardiovascular diseases, and have been recognized as appropriate tools for improving knowledge about rare diseases in both the European Union (EU) and North America.
Patient registries are the only instruments able to provide epidemiologic knowledge on congenital neutropenia, but a registry is a complex medical organization and its development requires several steps. First, these structures must meet sufficient ethical and administrative criteria according to their national health system. A registry must have technical expertise and computer technology to manage information flow and produce relevant health indicators. Case recruitment and monitoring is also a crucial step, which implies centralization of information and simultaneous contacts with physicians following patients, who are necessarily scattered and not experts in these diseases. The identification of cases is also made difficult by the evolution of the classifications of these diseases, both for the referring physicians and the patients. Thus, development of a registry is a dynamic process that occurs over many years. In each country, these registries have a specific history, usually starting from the commitment of 1 institution and extending to national multisite recruitment. According to the national context, congenital neutropenia can undergo either specific organization or be included in registries built for all types of immunodeficiencies or bone marrow failure. In addition to a large registry aiming to collect all subtypes of congenital neutropenia, some structures are dedicated to a single disease, such as Barth disease or Shwachman-Diamond disease.
The quality of information produced by registries can be classified according to the grading of evidence-based medicine. Here, evidence is ranked on 4 levels: A, meta-analyses, high-quality systematic reviews, randomized controlled trials with a low risk of bias; B, systematic reviews of case-control or cohort studies; C, nonanalytical studies, including case reports, case series, and retrospective small studies; D, expert opinion.
Organization of registries for congenital neutropenia
So far, no homogeneous approach exists for a congenital neutropenia registry. In Israel and Canada, patients are included in the registry of bone marrow failure syndrome, but some cases in these countries may be enrolled in the ISCNR. In Sweden and France, a specific structure is dedicated to recording congenital neutropenia cases, but in France the Severe Chronic Neutropenia Registry also participates in the French National Registry of Primary Immune Deficiency Diseases (CEREDIH) and the European Society for ImmunoDeficiencies (ESID) database. In Iran, congenital neutropenia cases are recorded in a general immunodeficiency registry. The ISCNR was funded in 1993 and is dedicated to chronic neutropenia, which includes patients from Australia, North America, and many EU countries, except France. The enrollment by countries remains heterogeneous, with many discrepancies in prevalence by country. According to the standard of evidence-based medicine, the quality of the information produced by registries is still low. Almost all collections of data have to be considered to be grade C with regard to evidence-based medicine criteria, but it is clearly progress from the previous period when no data were collected. A critical issue for all registries is the completeness of cases in a given population.
Incidence at Birth
The incidence at birth is a relevant indicator for a genetic condition. To date, only 2 studies have investigated incidence at birth by establishing a ratio between the number of new cases observed during a specified period and the number of births during the same interval. These 2 studies have considered virtually the same diagnostic categories, although the Swedish study considered the diagnostic categories of Pearson syndrome and Griscelli disease among congenital neutropenia. In the Canadian study, a rate of 15.9 cases of congenital neutropenia per million births were reported, whereas the Swedish study reported an incidence rate of 10 cases per million births. The magnitude of these incidence rates seem to be similar at birth, but significant differences emerge for some pathologies, such as Shwachman syndrome, which has an incidence rate of 8.5 cases per million births in Canada and 2.5 cases per million births in Sweden. Thus far, it is difficult to establish if such a difference reflects the genetic background of the studied population rather than some bias interfering in the evaluation.
Prevalence
The prevalence is the number of living patients in a defined geographic area. This indicator is extremely difficult to evaluate because it supposes that all living patients in a given territory can be counted. Another method is to know the exact birth incidence and mean life expectancy for each disease, because it is simply the incidence multiplied by the duration of the disease. It is too early in the development of knowledge about congenital neutropenia to expect reliable information with regard to the prevalence in a population. The evidence does not go above grade B. However, the most recent information from the various patient registries is compared in Table 2 . Some registries combine congenital neutropenia and idiopathic neutropenia, or even autoimmune neutropenia. Nevertheless, the prevalence rates are heterogeneous and reflect the efficacy of the registry to detect cases in their respective countries. Among the different countries, the highest observed prevalence rate was 9 cases per million inhabitants (France). Such a high rate is probably a minimal value because the coverage of all registries, including the French registry, is less efficient for adult patients, who may have congenital neutropenia. Progress in enrollment into the registry has to occur in all countries to obtain better indicators.
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