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Congenital Neutropenias

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Congenital Neutropenias Hematology, 2005; 10 Supplement 1: 306Á/311 CONGENITAL CYTOPENIAS Congenital neutropenias CORNELIA ZEIDLER Introduction course of the disease indicate an underlying genetic instability leading to an increased risk of malignant The term congenital neutropenia (CN) has been used transformation. If and how rHuG-CSF treatment for a group of hematological disorders characterized impacts on these adverse events remains unclear since by severe neutropenia with absolute neutrophil counts 9 1 there are no historical controls for comparison. (ANC) below 0.5/10 L associated with increased Hematopoietic stem cell transplantation is still the susceptibility to bacterial infections. This group of only available treatment for patients refractory to diseases includes primary bone marrow failure syn- rHuG-CSF treatment. dromes with isolated neutropenias like Kostmann syndrome and cyclic neutropenia, and neutropenias associated with metabolic or immunological disor- Severe congenital neutropenia ders, like glycogen storage disease type 1b and Hyper IgM-syndrome, and neutropenias being one feature of Pathophysiology a complex syndrome, like Shwachman-Diamond The underlying genetic defect of this group of syndrome or Barth syndrome. To avoid confusion, disorders, including Kostmann syndrome is still only we prefer using the term CN only for the most severe partially identified. The original hypothesis for disorder among this group. Severe neutropenia char- Kostmann syndrome included a genetic predisposi- acterized by an early stage maturation arrest of tion resulting in defective production of G-CSF or myelopoiesis leading to bacterial infections from early defective response of the neutrophilic precursors to infancy. This disease has originally been described as G-CSF or other hematopoietic growth factors. How- Kostmann syndrome [14,15] with an autosomal ever, serum from CN patients contains normal or recessive inheritance. Recent pathogenetic investiga- increased levels of G-CSF [18] and in vitro assays tions have demonstrated that this clinical phenotype demonstrate a normal biological activity of the includes different disorders, with a heterogenous endogenous G-CSF. pattern of inheritance including autosomal recessive, Myeloid cells from CN patients express slightly autosomal dominant and sporadic cases. Different increased numbers of G-CSF receptors [16] with a point mutations in the neutrophil elastase gene have normal binding constant for G-CSF to its receptor. been detected in a subgroup of patients. Data on over With the recent detection of various mutations 400 patients with CN collected by the Severe Chronic within the neutrophil elastase gene as the cause of Neutropenia International Registry demonstrate that cyclic neutropenia [13], genetic screening for muta- independent from the CN-subtype more than 90% of tions of the neutrophil elastase was also started in these patients respond to recombinant human gran- patients diagnosed with congenital neutropenia ulocyte-colony stimulating factor (rHuG-CSF) with [7,11]. Inspite of phenotypical uniformity, character- 9 1 ANCs that can be maintained around 1.0/10 L . ized by severe chronic neutropenia and a maturation Adverse events include mild splenomegaly, moderate arrest of myelopoiesis in the bone marrow at the thrombocytopenia, osteoporosis and malignant trans- promyelocyte/myelocyte stage, in congenital neutro- formation into MDS/leukemia. Development of addi- penia patients neutrophil elastase mutations were tional genetic aberrations, e.g., G-CSF-receptor gene present only in a major subgroup. All mutations mutations, monosomy 7 or ras mutations during the identified so far are present in one allele only. Analysis Correspondence: Dr. Cornelia Zeidler, MD, Department for Pediatric Hematology/Oncology, Kinderklinik, Medizinische Hochschule Hannover, Carl- Neuberg-Str. 1, 30625 Hannover. Tel: /49-511-532-6710 or /49-511-557105. Fax: /49-511-557106. E-mail: [email protected] ISSN 1024-5332 print/ISSN 1607-8454 online # 2005 Taylor & Francis DOI: 10.1080/10245330512331389944 Congenital neutropenias 307 of CN families also discovered that only one parent Blood values carried the mutated elastase gene indicating an To confirm the diagnosis repeated differential blood autosomal dominant inheritance. counts are required indicating persistent absolute In CN patients who developed leukemia, acquired neutrophil counts (ANC) within a range of 0Á/0.2/ G-CSF receptor mutations affecting the cytoplasmic 109 L1. Blood counts often indicate additionally domain were present in most patients tested so far mild anemia and thrombocytosis. There may also [1,9,23,24], suggestive of an important role of these be increases in blood monocytes and eosinophils. mutations in the leukemogenesis. None of the G-CSF Immunoglobulin levels for IgG are elevated in the receptor mutations was detectable from birth, indi- majority of patients independent of their infectious cating that these mutations are not causative for the status (unpublished data). The specific immunologic neutropenia. A small subgroup of patients develops competence after vaccination is normal. Blood chem- these mutations during the course of life, most likely istry is within the normal, age-dependent range for caused by genetic instability. G-CSF receptor analyses electrolytes, kidney and liver function. cannot be used to discriminate between the different diseases causing severe neutropenia, but might be helpful in screening for risk of leukemia. The time Bone marrow between acquisition of a G-CSF receptor mutation The bone marrow usually shows a maturation arrest and development of leukemia varies considerably of neutrophil precursors at an early stage (promyelo- [24]. In few patients a G-CSF receptor is only present cyte/myelocyte level) with few cells of the neutrophilic in the leukemic cells whereas other patients show series beyond the promyelocyte stage. Promyelocytes single or multiple mutations of the G-CSF receptor often reveal morphological atypical nuclei and vacuo- gene several years prior to leukemic transformation lization of the cytoplasma. The number of promyelo- already [24]. Like the elastase mutations, also the cytes is slightly increased [27] with a median G-CSF receptor mutations affect one allele only in the percentage of promyelocytes of 8% prior to G-CSF majority of patients. There is no evidence that a treatment. While on G-CSF treatment, the percen- G-CSF receptor mutation leads to a change in the tage of promyelocytes decreases to 3%, whereas clinical response to G-CSF treatment irrespective of myelocyte and neutrophil counts increase. Marrow any increase or decrease in G-CSF dose. eosinophilia and monocytosis is common, and mono- cyte counts may change during treatment. Cellularity Clinical features is usually normal or slightly decreased. Megakaryo- All patients suffer from severe chronic neutropenia cytes are normal in number and morphology. The in- with absolute neutrophil counts continuously below vitro growth of granulocyte colonies in CFU-GM 200 m1L1, and in many patients peripheral blood assays is often defective with a maturation arrest that neutrophils are completely absent. The estimated mimics the disease. frequency of CN is approximately 1 to 2 cases per million with equal distribution for gender. If the Cytogenetic evaluation and molecular testing disease is diagnosed during the first months of life, anti-neutrophil antibodies should be excluded. Normal bone marrow cytogenetics at diagnosis may In patients with CN severe bacterial infections change during the course of the disease with monos- frequently occur during the first year of life. Post- omy 7 being the most frequent aberration in about natal an omphalitis may be the first symptom, but 50% of abnormal cytogenetic results. Abnormal later also otitis media, pneumonitis and infections of cytogenetics are often associated with morphological the upper respiratory tract, abscesses of skin or liver changes of the bone marrow indicating the onset of are common infections, which often lead to the myelodysplasia or leukemia (see below). diagnosis of CN. Blood cultures are mainly positive Studies of the G-CSF receptor gene have shown for Staphylococci or Streptococci, but also other that mutations occur mainly within a critical region bacteria, e.g., Pseudomonas, Peptostreptococcus, (nucleotide position 2300 to 2500) of the intracel- and fungi were reported. In addition, rare infections lular part of the receptor. These mutations are like a clostridial gas gangrene infection may occur in acquired mutation by a subgroup of patients. In- these patients. The outcome of these fulminant dividual patients may develop single or multiple infections is often lethal due to lack of neutrophil mutations within this critical region. Analysis of the defense. Most patients suffer from frequent aphthous G-CSF receptor gene in order to detect acquired stomatitis and gingivahyperplasia leading to an early mutations can be performed from blood and bone loss of permanent teeth. marrow. 308 C. Zeidler Table I. Differential Diagnosis of Congenital Neutropenia 9 1 their absolute neutrophil counts to 1.0/10 L and 1. Other congenital neutropenias: above. Most CN patients respond to a dose between 3 Cyclic neutropenia and 10 mcg kg1 per day with a few individuals that Myelokathexis require doses higher than 80 mcg kg1 per day to Che´diak-Higashi syndrome respond. Non-responders to rHuG-CSF are defined Inborn errors of metabolism: as patients failing to respond to
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