:.. ;}.·:···.·;·1 Congenital Neutropenia

C HAP T E R 13 >;:.. ;}.·:···.·;·1 CONGENITAL NEUTROPENIA Jill M. Watanabe, MD, MPH, and David C. Dale, MD defined by a neutrophil count less than 1500 cellS/ilL; KEY POINTS beyond 10 years of age, neutropenia is defined by a neu trophil count less' than 1800 cells//1L in persons of white Congenital Neutropenia and Asian descent. 1 In persons of African descent, neu tropenia is defined by a count of 800--1000 cells//1L. 1 (& Congenital neutropenia encompasses a heterogeneous group of The severity and duration of neutropenia are also clin iuheri ted diseases. ically important. Mild neutropenia is usually defined by • The genetic mutations causing congenital neutropenia may neutrophil counts of 1000-1500 cells//1L, moderate neu have an isolated effect on the bone marrow but can also affect tropenia is 500-1000 cells//1L, and severe neutropenia one or more other organ systems. is less than 500 cells//1L. Acute neutropenia usually is present for only 5-10 days; neutropenia is chronic if its (& The genetic defects underlying the diseases that cause con duration is at least several weeks. Almost all congenital genital neutropenia have been rapidly identified over the past neutropenias are chronic neutropenia. decade. The characteristics and causes of congenital neu (& Granulocyte colony-stimulating factor has dramatically tropenia are shown in Tables 13-1 and 13-2, and an algo improved the prognosis for children with congenital rithm for their diagnosis is presented in Figure 13-1. neutropenia. SEVERE CONGENITAL NEUTROPENIA Patient'; with severe congenital neutropenia (SCN) typi cally present with recurrent bacterial infections and neutrophil count'> persistently less than 200 cells//1L. INTRODUCTION Kostmann described SCN as an autosomal recessive dis order in 1956 2 ; subsequently many sporadic cases and The congenital neutropenias are inherited hematologic families with an autosomal dominant inheritance were conditions that are usually recognized in infancy or early reported. The incidence of SCN is estimated at 2 per 1 childhood. Congenital neutropenia is often diagnosed million births. 3 when a young child has a differential white blood cell count performed for symptoms and signs of a severe infection. Congenital neutropenia may also be recognized Pathophysiology in evaluating a child with a complex congenital syn drome. The severity of the neutropenia and its clinical The genetics of SCN are heterogeneous. Up to 80o/i! of consequences vary considerably. patients have heterozygous mutations in exons 2, 3, 4, Neutropenia is defined as an absolute blood neu or 5 of the gene for neutrophil elastase (NE), also known trophil count more than 2 standard deviations below as e1astase-2 (EL42; locus 19p13.3) 4,5 (Fig. 13-2). ELA2 normaL The absolute count is percent neutrophils plus encodes a potent protease that is synthesized at the bands counted on a differential multiplied by the total promyelocytic stage in neutrophil development and white blood cell count Using this definition, the blood packaged in the neutrophil's primary granules. Genetic count to define neutropenia varies by age and race. In and cellular evidence is persuasive that mutations in children 1 month to 10 years of age, neutropenia is ELA2 cause sporadic and autosomal dominant SCN. The 2 SEC T I 0 N1 DISEASES OF HEMATOPOIETIC CELL PRODUCTION cause for the autosomal recessive cases is still unknown, immunoglobulins, 17,18 or granulocyte-macrophage In autosomal dominant SCN, the same colony stimulating factor 19 are of little benefit The role mutation is found in all affected family members but not of CCSF in the treatment of the congenital in normal relatives. 6 In a very informative case, the father is summarized in Table 13-3, The effectiveness of a patient with typical SCK showed mosaic phylactic G-CSF was established in a randomized, con of the same ELA2 mutation; half of his somatic trolled clinical trial. 20 In this study, the median G-CSF Wined the mutant gene, but the mutant was vir dose for SCN was approximately 5Jlg/kg/day; at tually absent in circulating neutrophils. In this natural this dose, G-CSF was increased by 5-10Jlg/kg/day every observation, neutrophils expressing the abnormal gene 14 days to achieve a neutrophil count greater than 1000 appeared to be destroyed in the marrow before cells/JlL. Currently, dosages higher than 50-100Jlg/ the circulation,7 fIuman promyelocytic leukemia kg/day are generally not recommended because of such as HL-60 cells, which express the neutrophil the low likelihood of benefit and the volume of drug 8 esterase mutants, exhibit accelerated apoptosis. Accel required, 3,21 Adverse effects are generally mild, primarily erated apoptosis may be mediated through altered of transient headache and bone pain. 20 expression of Bcl-2 proapoptotic factors, which appear Splenomegaly, osteoporosis, vasculitis, rashes, arthralgia, to be normalized with the administration of granulocyte and hematuria are infrequent adverse events. 22 Allogenic colony-stimulating factor CG-CSF). 9 Several other muta hematopoietic stem cell transplantation is the only estab tions have been associated with SCN, but their causal role lished alternative treatment for patients refractory to is uncertain. G-CSF receptor mutations, which have been G-CSF. reported in a few cases, were probably acquired muta SCN patients are at risk of developing myelodyspJas tions during evolution to acute myelogenous leukemia tic syndrome CMDS) and A\llL, a risk recognized before (AMi). 8,10 A mutation in CFII has been reported in one the of G-CSF. In a population of SCN patient child. d transformation to AML or MDS occurred in about 2% per year. 24 The risk appears to be higher for with more severe disease, as reflected by Clinical Features and Diagnosis of higher doses of G-CSF. 6 Monitoring clinical evaluations, blood counts, and an In addition to severe neutropenia, SCN patients usually have monocytOSis, thrombocytosis, and a mild normo marrow examination is recommended to normochromic, or hypochromic anemia. The bone changes and chromosomal abnormali ties, the acquisition of monosomy 7. Ras and marrow characteristically shows "arrest" of neutrophil G-CSF receptor mutations also have been linked to malig development at the promyelocyte and myelocyte stage, nant transformation. 22 Survival after hematopoietic stem although some samples show many maturing band and cell transplantation is more favorable if patients do not neutrophils, particularly in response to infec tions, The cellularity of the bone marrow is normal or have MDS/AML; transplantation should be considered in patients transformation in their bone with a reduced myeloid-to-erythroid ratiO, marrow. normal megakaryocytes, and occasional eosinophilia 3 Anemia and thrombocytOSiS are probably due to chronic inflammation; monocytosis may also reflect CYCLIC NEUTROPENIA growth factor stimulation of the neutrophil-monocyte lineage. At diagnosis, tests for anti neutrophil antibodies Cyclic neutropenia usually with recurring and chromosomal abnormalities are negative,3 Tests for episodes of fever, mouth ulcers, pharyngitis, and lym ELA2 mutations may be helpful but are still largely a phadenopathy every 3 which usually resolve research nr'..... r'~r1' spontaneously over about 5-7 days. In 1910, Leale Patients with SCK typically have recurrent fevers, reported the first case in a 19-month-old boy.25 CN and skin, respiratory, and perirec occurs sporadically or autosomal dominant inheri tissue abscesses in the liver and lungs tance; the estimated is 0.5-1 per 1 million with bacteremias are not uncommon, and these infec births, 26 tions may become life-threatening. Common pathogens include aureus, Escherichia and Pseudomonas Until recently, SCN was Pathophysiology often fatal as a result infections in early childhood, despite prompt and antibiotic therapy. Prior Mutations of ~he gene for NE were originally to the availability of the mortality by the age of implicated in autosomal dominant and sporadic forms of 2 years was estimated at 42%. Cl'\ prior to the discovery of the same associa tion with SCN, ELA2 mutations predominantly involve exon 4 at its junction with intron 4 27 In Treatment and Prognosis both SCN and CN, the neutrophil are sub~ jected to accelerated apoptosis) marrow produc The availability of G-CSF has markedly changed the tion of neutrophils ineffective, The loci of the mutations outlook for SCN Almost all patients respond to predicted that they affect function of the active site of the G-CSF with in their quality of life, lZ By enzyme binding to its substrates or to natural inhibitors, 4 contrast, corticosteroids, lithium, 15.16 intravenous 1 ) f () I', CHAPTER 13 CONGENITAL NEUTROPENIA 3 No abnormality of the gene for the GCSF receptor or MYELOKATHE.XIS AND WHIM SYNDROME other genes has been documented in well-characterized cases of CN. Myelokathexis term for retention of neutrophils in the bone marrow) is a rare congenital disorder characterized by severe neutropenia and lymphocytopenia, first Clinical Features and Diagnosis described by Zuezler and by Krill and colleagues in 1964,36,37 White blood cell counts are usually less than In most cases, neutrophil nadirs occur every 19~21 1000 cells!~L, and neutrophil counts less than 500 days, but some long and shorter cycles are reported, cellS/ilL. The neutrophils in the blood and marrow have ranging from 11 to 52 days. 29 Neutrophil counts typically very pyknotic nuclei, a distinctive if not entirely diag fall to zero at their nadir an.. d.... d.o.. n.. o...t.... i.n.. crease ~200 nostic feature of this disorder, Neutropenia associated cells/~L for 3~5 days; peaks are,gener,!-jJ,y les~OOO with wafts, hypogammagiobulinemia, infections, and cells/~L. The !Il0nocytecounts also cycle, rising as the myelokathexis constitute the WHIM syndrome. Both neutrophlIs . fall; platelets, eosinophils, lymphocytes, myelokathexis and WHIM syndrome have autosomal and reticulocytes can oscillate in a pattern of "cyclic dominant inheritance,38 although sporadic cases have hematopoeisis" 29 (Fig.

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