590 CHAPTER 12 Pediatric hematology Congenital red cell aplasia First described by Josephs in 1936 and subsequently by Diamond and Blackfan in 1938. Has come to be known as Diamond \200\223Blackfan anemia (DBA). Incide nce now estimated to be 4 \200\2237/million live births. Pathophysiology DBA is a heterogeneous disorder with evidence for at least 3 genetic subtyp es. Approximately 60% of DBA patients will have a heterozy- gous mutation in 1 of 10 riboso mal genes (RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPL5, RPL11, RPL26, RPL35A). These gene s encode com- ponents important in ribosome biogenesis. DBA therefore appears to be constit utional disorder arising from disruption of a key housekeeping pathway. This is associated with pleotropic eff ects in many systems but the maximal impact is on erythropoiesis result ing in a defi ciency of red cells. Clinical features \200 Usually presents in the 1st year of life: in 25% at birth and 90% <6 months of age. Rarely presents >1 year. Mildly aff ected individuals may rarely be detected as older children or adults during family studies. Associated physical anomalies in 50%; abnormal facies with abnormal eyes, webbed neck, malformed (including triphalangeal) thumbs, other skeletal abnormalities , short stature, congenital heart lesions, renal defects. Anemia usually severe and child commonly transfusion dependent. \200 Susceptibility to in fection is not i. \200 Hepatosplenomegaly absent. \200 Family history is +ve in only 10 \200\22320% cases; most are sporadic. \200 i risk of AML in long survivors; 75% in bigge st series reported to date. Laboratory diagnosis \200 d Hb, d reticulocytes, i MCV (> n for age), WBC and platelets n ot d. \200 Red cells \200\224n morphology to red cell anisocytosis/macrocytosis, have i i antigen positivity, i ADA activity. i HbF, i EPO, i serum Fe/ferritin. \200 BM fi ndings \200\224usually absent erythroid pre cursors; other cell lines n. \200 No evidence of parvovirus infection. \200 Radiologica l investigation to defi ne other congenital defects. \200 Genetic diagnosis possible in 6 0% of DBA patients (RPS19 gene). Diff erential diagnosis \200 TEC (E Transient erythroblastopenia of childhood, p.592; lat er presentation, transient, no other defects). Drugs, malnutrition, infection. \200 Haemolytic anaemias in hypoplastic phase, with parvo virus B19, delayed recovery in HDN. Megaloblastic anemia in aplastic phase. 591 CONGENITAL RED CELL APLASIA Treatment \200 Prednisolone 1mg/kg PO in divided doses, slowly d over weeks; 70% respond well. Titrate to lowest dose to maintain Hb >7g/dL. Many achieve this on almost homeopathic doses despite true dependence. Around 10% need high-dose maintenance and have trouble with side eff ects. 30% steroid resistant. Transfusion dependency usual in those who cannot be maintained on very low-dose steroids. N eed chelation to prevent Fe overload. Use CMV \210\222ve leucocyte-depleted packed RBC. Splenectomy not helpful (unless hypersplenism). \200 BM transplantation worth considering for transfusion dependents with suitable sibling donor; risk stratifi cation as for severe thalassaemia (Fe overload). Complicated decision due to chance of spontaneous remission even after years of transfusio n dependency. Natural history Spontaneous remission in 10 \200\22320% (even after several years). Median survival estimated at 30 \200\22350 years, though data patchy. Death due to haemosiderosis, complications of steroid therapy, or evolution of AML or aplastic anemia. BMT may off er b etter outlook. DBA Registries are now prospectively gathering new data. 592 CHAPTER 12 Pediatric hematology Acquired red cell aplasia Isolated failure of erythropoiesis. Most commonly transient \200 \224either due to parvovirus B19 infection or transient erythroblastopenia of child- hood ( TEC). Acquired pure red cell aplasia (PRCA) seen in adults with or without thymoma and prob ably autoimmune in nature (E Aplastic anemia, p.102) virtually unknown in childhood, though very occasion- ally seen in adolescents. Parvovirus B19 infection Clinical features \200 Causes transient reticulocytopenia and (o ccasionally) neutropenia and thrombocytopenia in otherwise healthy individuals. In children with i red cell turnover for any reason (compensated haemolysis, ineff ective e rythropoiesis) or those with reduced red cell production (marrow suppression or hypoplasia) can produce dramatic falls in Hb ( \200\230aplastic crisis \200\231). Can aff ect any age. \200 Self-limiting as infection subsides following antibody response , 7 \200\22310d. \200 In immunosuppressed children (e.g. chemotherapy, HIV) anemia can occasionally become chronic with persisting viraemia. Pathogenesis Parvovirus shows tropism for red cells through the P antigen, and is cyto- tox ic for erythroid progenitor cells at the colony forming stage (CFU-E) in vitro. Transient erythroblastopenia of childhood Pathogenesis Serum and cellular inhibitors of ery thropoiesis and defective BM response to stimulating cytokines have been demonstrated. The condi- tion may be idiopathic or associated with viral infection. It is uncommon but not ex cessively rare and there may be many subclinical cases where a blood count is not done. Clinical features \200 Boys and girls equally aff ected: age range 6 months \200\2235 yea rs; most commonly around 2 years. Typically a previously well young child presents with symptoms and signs of anemia, sometimes but not invariably following an infection. Onset is insidious an d the child becomes listless and pale \200\224or just pale. Associated infections are usually viral (EBV, mumps), preceding the onset of TEC by some weeks. Fever is rare. \200 Pallor may be striking. \200 No lymphadenopathy or hepatosplenomega ly. \200 No physical abnormalities. Laboratory diagnosis \200 Normocytic, normochromic anemia which may be severe (Hb <5g/dL). 593 ACQUIRED RED CELL APLASIA Reticulocytes absent unless in early recovery phase; WBC and platelets usually n. Blood fi lm shows no abnormality other than anemia. \200 Biochemical profi le n. \200 B M shows normocellular picture with absent erythroid precursors. n Fe content. No karyotypic abnormalities. \200 Exclude parvovirus infection (E Parvovirus B19 infectio n, p.592). \200 No other investigation is of diagnostic help. Diff erential diagnosis \200 Exclude acute blood loss and anemia of chronic disease. \200 Exclude common ALL. \200 Diamond \200\223Blackfan anemia (E Congenital red cell apl asia, p.590). Usually presents within the fi rst 6 months of life and other abnormalities (skeletal malfo rmation, short stature, abnormal facies) are commonly present. Parvovirus infection (E Parvovirus B19 infection, p.592) Treatment Blood transfusion should be avoided but may be necessary if sympto- matic. Natural history Spontaneously remits (if not then diagnosis probably wrong) commonly within 4 \200\2238 weeks but may be up to 6 months. Relapse is rare. There are no long-term seque lae or associations. 594 CHAPTER 12 Pediatric hematology Fanconi anemia First described by Fanconi in 1927, Fanconi anemia (FA) is a clinically hete rogeneous disorder usually presenting in childhood with the common feature being slowly pro gressive marrow failure aff ecting all 3 cell lines (RBC, WBC, and megakaryocytes) and mani fest by peripheral blood pancytopenia and eventual marrow aplasia. It is usually an autosomal recessive disorder with several diff erent germline genetic muta tions involving at least 16 genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG , FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, and FANCQ). One FA subtype (FAB) is X-li nked. The products of the FA genes are components of the \200\230FA-BRCA pathway \200\231 important in the maintenance of genomic stability of the cell. Pathophysiology of FA FA aff ects all cells of the body and the cellular phenotype is chara cter- ized by i chromosomal breakage, hypersensitivity to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC), hyper- sensitivity to oxygen, i apoptosis, and a ccelerated telomere shortening. The i chromosomal fragility is characteristic and used as a diagnostic test. Apart from progressive marrow failure, 70% of FA patients show somatic ab normalities, chiefl y involving the skeleton. 90% develop marrow failure and survivors show an i risk of developing leukemia, chiefl y AML. Rarely, FA can present as AML. There is al so an i risk of liver tumors and squamous cell carcinomas. Clinical features \200 Autosomal recessive inheritance usually, rarely X-linked: in 10 \200\22320% the parents are related. Phenotypic expression of the disease varies widely, though often similar in any given kindr ed. Most commonly presents as insidious evolution of pancytopenia, presenting in mid-childh ood with a median age of presentation of 9 years. Cell lines aff ected asynchronously; isol ated thrombocytopenia may be fi rst manifestation, lasting 2 \200\2233 years before other c ytopenias occur. 10% present in adolescence or adult life, 4% present in early infancy (<1 year). Disorders of skin pigmentation common (60%) \200\224caf -au-lait spots, hypo- and hyperpigmentation. Short stature in 60%, microcephaly, and delayed development in >20%. \200 Congenital abno rmalities can aff ect almost any system \200\224skeletal defects common, >50% in the upper limb especially thumb, spine, ribs. \200 Characteristic facies described \200\224elfi n-like, with tapering jaw line. Diagnosis Laboratory \201 ndings \200 Pancytopenia and hypoplastic marrow \200\224patch y cellularity. \200 BM may also show dyserythropoietic morphology. \200 Anemia varies i n its severity and may be macrocytic (MCV 100 \200\223120fL). 595 FANCONI anemia Excessive chromosomal breaks/rearrangements in culture of peripheral blood lymphocytes stressed with clastogens (DEB or MMC) is the defi ning abnorma lity, and can be used on fetal cell culture for antenatal diagnosis. Direct probing for mutations in the FA genes that have been identifi ed and characterized p ermits molecular diagnosis in >95% of patients, but is complex, slow, and is not routinely available. Further investigation for systemic congenital abnormalities is indicated. Diff erential diagnosis \200 Acquired aplastic anemia (E Aplastic anemia, p.102). \200 Other congenital or inherited childhood marrow failure syndromes \200\224 E see Rare congenital marrow failure syndromes, p.596. Bloom syndrome \200\224clinically like FA with similar congenital defects, spontaneous chromosomal breaks, and a predisposition to leukemia but without pancytopenia, or BM hypoplasia. Autosomal recessive. Characteristically have photosensitivity and telangi ectatic facial erythema. Due to genetic mutations in the RECQL3 helicase gene. Treatment General \200 Supportive \200\224blood transfusion with Fe chelation as required . \200 Treatment of associated congenital anomalies where necessary. Speci \201 c \200 Androgens (oxymetholone 0.5 \200\2235mg/kg/d). Most patients respond to treatment but may eventually become refractory. Haemopoietic growth factors may off er temporary relief from neutropenia and anemia. BMT is potentially curative, but FA patients hypersensitive to conditioning agents cyclophosphamide and radiation. Using low doses, matched sibling grafts give 80% actuarial survival at 2 years; unrelated donor results less good but improving us ing fl udarabine based protocols. Early survivors showed i risk of tumors, especially head and neck. Much interest in gene therapy. Early trials have occurred, but no major therapeutic success . Theoretically should be possible to transduce patient stem cells from those with known mu tations with the appropriate wild type FA gene, and for these stem cells to have a natural growth advantage over FA cells. So far responses have been disappointing and short-lived. Outcome Median survival of conventional treatment responders who do not undergo BMT is 725 years. Non-responders have a median survival of 712 years. Death most commonly due to marro w failure, but 10 \200\22320% will develop MDS or AML after a median period of observation of 13 years. 596 CHAPTER 12 Pediatric hematology Rare congenital marrow failure syndromes Amegakaryocytic thrombocytopenia (congenital amegakaryocytic thrombocytopenia \200\224CAMT) Presents in infancy (usually at birth or within 2 months) with profoundly d platelets and associated physical signs (petechiae and bruising). Around 40% of aff ected children also h ave other congenital abnormali- ties \200\224chiefl y neurological or cardiac. Developmenta l delay is common. The marrow completely lacks megakaryocytes and the disorder evolves to s evere aplastic anemia in around 50% of suff erers, usually in the 1st few years of life. Ha s none of the unstable DNA features of Fanconi anemia (E see Fanconi anemia, p.594). Also q uite distinct from the syndrome of thrombocytopenia with absent radius (TAR syndrome) since it is a trilineage problem with a much greater mortality. Usually sporadic, but familial c ases occur and disorder thought to be inherited. In a subgroup of CAMT patients mutations i n the gene encoding for the thrombopoietin receptor (MPL) have been identifi ed. Outlook Without BMT, mortality from bleeding, infection or (occasionally) pro- gression to leukemia near 100%. Amegakaryocytic thrombocytopenia with absent radii (TAR syndrome) \200 Usually diagnosed at birth because of lower arm deformity due to bilateral radial aplasia. \200 No hyperpigmentation. \200 Isolated thrombocytopenia wit h other cell lines n. \200 BM lacks megakaryocytes; has adequate WBC/RBC precursors. \200 No chromosomal breaks in cell culture. \200 Autosomal recessive; the gene mutated i s RBM8A. \200 Thrombopoietin i; platelets gradually increase as child grows. \200 Bleed ing problems greatest in infancy. \200 Supportive therapy only needed. Outlook Usually good, with problems receding as childhood proceeds. Occasional patients con tinue to have problems with d platelets. No i malignancy. Dyskeratosis congenita (DC) \200 Inherited multi-system disorder including mucocutaneous and haematopoietic and other abnormalities. Clinical triad of abnormal skin pigmentation, leucoplakia of the mucous membranes, dystroph ic nails and in 80% patients BM failure develops, usually in the 2nd decade. X-linked recessive, autosomal dominant and autosomal recessive subtypes recognized. 10 DC genes (DKC1, TERC, TERT, TINF2, NHP2, NOP10, C16orf57, TCAB1, CT C1, and RTEL1) identifi ed. The DC genes have an important role in the maintenance of telom eres. 597 RARE CONGENITAL MARROW FAILURE SYNDROMES Some patients with AA and MDS have TERC and TERT mutations. \200 Chromosome fragility on challenge with DEB or mitomycin C normal \200\224important to distinguish DC from FA (E see Fanconi anemia, p.594). Despite this DC is a chromosome instability disorder due to defective telomere maintenance. Results of BMT for aplastic anemia in DC patients poor, perhaps because of this. Anecdotal reports of good response to haemopoietic growth factors. Majority of patients also have a trilineage haemopoietic response to oxymetholone. Outlook 10% develop cancers before the age of 40 years \200\224mostly epithelial, but also MDS/AML. Life expectancy depends on development of aplasia or malignancy. 30% survive to mi ddle age. Results of BMT improving with low-intensity fl udarabine-based protocols. Kostmann syndrome (congenital neutropenia) \200 Autosomal recessive, due to biallelic mut ations in HAX1. \200 Severe Kostmann syndrome with neutrophils <0.2 \227 109/L. \200 M arrow shows maturation arrest at promyelocyte/myelocyte stage. \200 High risk of severe i nfection in untreated state. \200 Not due to germline mutation in G-CSF receptor gene, th ough abnormal receptor may be present in myeloid precursors. Some cases attributed to mutations in neutrophil elastase (ELA2). 90% will respond to pharmacological doses of G-CSF and continue to do so for years. Up to 10% develop AML/MDS \200\224role of G-CSF not clear, but probably complication of dis ease revealed by longer survival. Diagnosis Distinguish from cyclical neutropenia (by observation); benign congenital neutrop enia (by WBC), and reticular dysgenesis, a severe inherited immu- nodefi ciency with congen ital lack of all white cells, including lymphocytes. Outlook Good provided response to G-CSF satisfactory and maintained. Non- responders may ne ed BMT. Shwachman \200\223Diamond syndrome \200 Congenital exocrine pancreatic insuffi ciency; ch ronic diarrhea, malabsorption, and growth failure associated with neutropenia and skeletal abnormalities. BM failure \200\224usually leads to neutropenia but can evolve to pancytopenia. BM morphology varies \200\224may be dysplastic/hypo-/aplastic. \200 Autosomal recessive, majority of patients have mutations in the SBDS gene on 7q11. Psychomotor delay common. Diagnosis \200 Exclude cystic fi brosis (by normal sweat test). \200 Exclude FA (by nor mal chromosome fragility). 598 CHAPTER 12 Pediatric hematology Pearson syndrome clinically similar with severe pancreatic insuffi ciency but with anemia rather than neutropenia and marrow shows ring sideroblasts a nd vacuolization of red and white cell precursors. Genetic diagnosis now possible in majority of patients. Treatment \200 Supportive with pancreatic enzymes, G-CSF, and antibiotics. \200 Greatly i risk (up to 25%) of progression to MDS/leukemia (AML > ALL). Limited experience with BMT for aplasia/leukemia; may be i risk of cardiotoxicity \200\224ventricular fi brosis seen at autopsy in 2/5 patients who died po st BMT. Outlook Depends on development of severe aplasia or leukemia; long survivors few if so. Pan creatic insuffi ciency improves as childhood progresses. Seckel syndrome \200\224bird-headed dwar \201 sm \200 Rare autosomal recessive disorder with (proportionate) very short stature and mental defi ciency. Facial features fancifully described as bird-like. \200 The ATR (ataxia-telangiectasia an d Rad3-related protein) gene is mutated in Seckel patients. Progression to aplastic anemia common, clinically similar to FA (E see Fanconi anemia, p.594) but chromosome fragility usually has diff erent features to F A. Infantile osteopetrosis \200 Pancytopenia can arise in this autosomal recessive disorder where the marrow cavity is obliterated with cortical bone due to a functional defi ciency of oste oclasts. It is a 1 marrow failure in the sense that there is no marrow, but is a failure of the mi croenvironment rather than haemopoietic stem cells. Outlook Poor due to cranial compression, and children usually die in early childhood unless successful allogeneic BMT can replace normal osteo- clast function. 599 RARE CONGENITAL MARROW FAILURE SYNDROMES 600 CHAPTER 12 Pediatric hematology Neutropenia in childhood Apart from 1 marrow failure due to aplastic anemia, or other mar row failure syndromes ( E Aplastic anemia, p.102), or marrow suppression due to antineoplas tic, immunosuppressive, or antiviral chemotherapy, neu- tropenia can also arise as an immun e phenomenon, a cytokine mediated problem or due to cyclic or non-cyclic disturbances of th e homeostasis of neutrophil production. Pathophysiology \200 Commonest cause of a clinically important low neutrophil count in children (<0.5 \227 109/L) is myelosuppression due to drugs. 1 marrow stem cell failure failure either involving all cell lines or granulopoiesis alone is rare. Neutropenia can also be due to less serious inherited defi ciencies of neutrophil productio n where neutropenia can be variable or cyclical and the problem seems to be one of producti on control rather than 1 stem cell failure. Probably due to cytokine disturbances, several microbial infections can cause paradoxical n eutropenia, particularly in neonates but also in older children (Table 12.7). Autoimmune causes of neutropenia can arise in infancy or later in childhood. Isoimmune neutropenia in the newborn \200\224due to maternal antineutrophil antibodies and analogous to HDN. Homeostatic disorders Cyclic neutropenia Rare. Neutropenia arising every 21d lasting 3 \200 \2236d. Counts may fall <0.2 \227 109/L. Associated with episodes of fever, malaise, mucou s mem- brane ulcers, lymphadenopathy. Serious infection can arise and deaths. May improve a fter puberty. Usually +ve family history when problem encoun- tered in childhood; due to mu tations in neutrophil elastase (ELA2) gene. Treatment supportive with antibiotics. G-CSF ma y be useful. Chronic benign neutropenia More common. Persistent rather than cyclical, though often varia ble without clear periodicity. Neutrophil count usually >0.5 \227 109/L, so clini- cally m ild or silent. May have autosomal dominant or autosomal recessive family history. Variable severity, often mild with few problems. To be dis- tinguished from severe congenital neutro penia (E Kostmann syndrome, p.597) by milder clinical course and (usually) later presentati on. Some of these patients will have mutations in ELA2. Therapy not usually necessary. 601 NEUTROPENIA IN CHILDHOOD Table 12.7 Infections causing neutropenia Viruses Bacteria Others RSV Tuberculosis Rickettsiae Malaria Typhoid/paratyphoid Infl uenza E. coli (neonates) Measles Varicella HIV Autoimmune neutropenia (AIN) Infant form of isolated autoimmune neutropenia occurs within 1 st year of life; demonstrable autoantibodies. Not familial; girls >boys. Self- limiting and usually relatively benign. Therapy supportive. Steroids not usually needed and can increas e infection risk. IVIg has been used. Older children may get \200 Isolated AI neutropenia. \200 Neutropenia as part of Evans syndrome (E Immune thrombocytopenia, p.490). Neutropenia as part of multisystem AI disease \200\224lupus erythematosus. \200 Immune ne utropenia following allogeneic BMT. \200 Felty syndrome (rheumatoid arthritis with spleno megaly and hypersplenic cytopenias may also be associated with neutrophil autoantibodies. All are potentially more serious and complicated than the infant form and may require immun osuppression as well as supportive therapy. Isoimmune neutropenia of the newborn \200 Maternal antibodies to fetal neutrophil antigen s cross the placenta and give rise to neutropenia in the newborn child. Most commonly antibodies directed at neutrophil-specifi c antigens NA1 and NA2. (Maternal H LA antibodies do not cause trouble because antigens expressed on many tissues so quickly ab sorbed.) \200 Estimated incidence up to 3% of newborns, so may be more common than genera lly appreciated; perhaps because usually clinically mild and neutropenia thought to be acqu ired due to drugs/infection. Condition resolves by 2 months as antibody disappears. \200 Severely aff ected babies may show recurrent staphylococcal skin infections. Therapy supportive. Need for exchange trans fusion very rare. Diagnosis based on serology. Prognosis of neutropenia Whatever the cause, severe neutropenia (<0.2 \227 109/L) is serio us and incompatible with long survival if prolonged. It requires careful expert management. 602 CHAPTER 12 Pediatric hematology Disorders of neutrophil function Acquired Mild defects arise in many clinical situations; following some infections, associa ted with drugs (steroids, chemotherapy) and systemic disease (malnutrition, diabetes mellit us, rheumatoid arthritis, CRF, sickle cell anemia) \200\224here the underlying condition wi ll dominate the clinical picture. Congenital Inherited defects rare but several important and disabling syndromes occur in ch ildren. Pathophysiology Neutrophils produced in BM are released into circulation where they survive for only a few hours. Fundamental role is to kill bacteria. Do this by moving to site of i nfection drawn there (chemotaxis) by interac- tion of bacteria with complement and Ig (opso nization) and engulf them (phagocytosis). Killing is accomplished by H2O2 generation, relea se of lysosomal enzymes, neutrophil degranulation (respiratory burst). Several enzyme syste ms are involved (MPO, cytochrome system, HMP shunt). In the neonate neutrophil function is defective (d chemotaxis, phagocytosis, motility) particularly if premature, jaundiced. Kill ing is normal. Classi \201 cation Disorders of all aspects of neutrophil function are described and there is no consensus as to how best to classify them. All are rare. In several of the best desc ribed conditions multiple defects are present (Table 12.8). Table 12.8 Classifi cation d Chemotaxis d Opsonization d Killing Lazy leucocyte syndrome Complement C3 defi ciency Chronic granulomatous disease Hyper IgE syndrome MPO defi ciency Chediak \200\223Higashi syndrome d Specifi c neutrophil granules Clinical features All congenital syndromes are rare and diagnosis of the specifi c defect d if- fi cult. Few hematological/immunological labs are set up to perform the required range of tests. Specialist referral for diagnosis and treatment is indicated and may be able to a lter the otherwise grim prognosis in many of these conditions. Lazy leucocyte syndrome Leucocyte adhesion defi ciency (LAD) due to mutations in the gene e ncoding the -subunit of the 2-integrins (LAD1) or defective glycosylation of ligands on leucocytes recognized by selectin family (LAD2). Rare. Autosomal reces- sive. i Recurrent infections often in oral cavity, delayed wound healing. 603 DISORDERS OF NEUTROPHIL FUNCTION Lab fi ndings: i neutrophil count, n BM, abnormal chemotaxis on Rebuck skin window test. Th e condition is relatively mild. Treatment is of specifi c infections with the need for prop hylaxis in some patients. Hyperimmunoglobulin E syndrome Also known as Job syndrome (Old Testament) because of recurr ent staphylococcal abscesses. Autosomal recessive inheritance, associated with atopic derma titis and other autoimmune phenomena. Bacterial/ fungal infection, chronic dermatitis. Lab fi ndings: i IgE, i eosinophils. Complement de \201 ciency Autosomal recessive inheritance of C3 defi ciency, homozygotes h ave severe recurrent bacterial infection, particularly encapsulated organisms. Chronic granulomatous disease (CGD) Though rare, commonest life-threatening inherited neutr ophil func- tional defect. >1 disorder. Most are sex linked, boys aff ected 7 \227 more fr equently than girls, but 3 autosomal mutations recognized. Presents in early life but also in adults; carriers asymptomatic. Multiple skin and visceral abscesses, systemic infection (pneumonia, osteitis, etc.) \200\224bacte- rial/fungal, lymphadenopathy, hepatosplenomegaly . Lab features: nitro blue tetrazolium (NBT) test (an index of defective respiratory burst) +ve. Specifi c mutational analysis now possible for earlier and prenatal diagnosis. Outloo k better than it used to be. Improved by aggressive antibiotic policy and IFN- . BMT littl e used due to improving outlook with conservative/prophylactic treatment. Early results poo r. Prospect of gene therapy attractive with some early progress. Chediak \200\223Higashi syndrome Rare autosomal recessive disorder due to mutations in lyso somal traf- fi cking regulator, CHS1/LYST, gene. Multiple defects. Partial oculocu- taneous albinism, recurrent infection, lymphadenopathy, peripheral neuropathy and cerebellar ataxi a. A fatal accelerated phase occurs in 785%, usually in the 2nd decade, with lymphocytic in fi ltration of liver/ spleen/nodes/BM, pancytopenia. Lab fi ndings \200 d Hb, d neutrophil count, d platelet count. \200 Characteristic gian t greenish gray refractile granules in neutrophils (also lymph inclusions). Treatment is supportive. High-dose ascorbic acid may help some patients. Anecdotal reports of successful BMT. Myeloperoxidase de \201 ciency Autosomal recessive. Commonest of neutrophil dysfunction co ndi- tions (1:2000) but also least serious. Often asymptomatic. Manifest in diabetics with recurrent infections \200\224commonly Candida albicans. Good prognosis. Lab fi ndings \200 i neutrophil/monocyte peroxidase on histochemical analysis. \200 Aut omated cell counters using MPO activity to count neutrophils may show spurious neutropenia. 604 CHAPTER 12 Pediatric hematology Childhood immune (idiopathic) thrombocytopenic purpura ITP occurring in children diff ers f rom the adult form of the disease (E Immune thrombocytopenia, p.490) in 2 ways \200\224fi r st, most cases are of abrupt onset and rapidly self-limiting, and secondly those that pro- gress to chronicity have a lower morbidity and mortality. Epidemiology Incidence of ITP in children overall around 4 \200\2235 per 100,000 per year. 10 \200\22320% become chronic \200\224i.e. last >6 months. Pathophysiology Thrombocytopenia mediated by antibodies opsonizing platelets that are then destroyed by the reticuloendothelial system. Antibodies can be part of immune complexes non -specifi cally attached to platelet Fc receptors (as in typical acute childhood ITP) or tru e autoantibodies usually targeted at glycoproteins IIb/IIIa and Ib (as found in up to 75% o f chronic childhood ITP and commonly in adults). Clinical features \200 Onset of bruising petechiae abrupt (80 \200\22390%) or insidiou s (10 \200\22320%). \200 May have gingival and oral mucosal bleeding or epistaxis. \200 Life-threatening bleeding extremely rare. \200 Child otherwise perfectly well. \200 Ma y have history of recent infection; specifi c (rubella, varicella) or non-specifi c (URTI). \200 Can follow vaccination. Laboratory diagnosis \200 Isolated thrombocytopenia; blood count otherwise n. \200 Marr ow shows abundant megakaryocytes and is otherwise n (not necessary to investigate unless clinical course or presenting features unusual). Platelet antibody studies diffi cult to perform and not necessary in most cases since they do not alter management. \200 Exclude EBV infection (infectious mon onucleosis). \200 Exclude multisystem autoimmune disease (ACL, ANA, +ve DAT test \200\224not necessary unless disease becomes chronic. Exclude underlying immunodefi ciency syndrome (HIV, Wiskott \200\223Aldrich). Diff erential diagnosis \200 Congenital or familial throm bocytopenias. \200 Leukemia or aplastic anemia. \200 Other rare thrombocytopenias (e.g. type IIB vWD). \200 Multisystem autoimmune disease \200\224Evans syndrome (AIHA + immune thrombocytopenia), systemic lupus erythematosus. \200 Immune thrombocytopenia associated with immunodefi ciency due to other disease \200\224HIV infection, Hodgkin disease, Wiskott \200\223Aldrich syndro me. 605 CHILDHOOD IMMUNE THROMBOCYTOPENIC PURPURA Management Newly presenting Seldom require urgent therapy though this is frequently given, either polyvalent IVIg 0.8g/kg (single dose) or prednisolone 1mg/kg for 7d. Never justifi e d in the absence of obvious bleeding since neither therapy without risk. Simple observation for spontaneous recovery should be preferred. Chronic No therapy is needed based on platelet count alone. Absence of symp- toms and signs is suffi cient. Excessive restriction of activities is seldom justifi ed. Open access to e xpert help and advice provides reassurance to families and teachers. If therapy required to control symptoms (recur- rent nosebleeds, menorrhagia) try local measures or hormonal cont rol. Regular IVIg or steroids seldom eff ective and may produce more prob- lems than untrea ted disease. For the most diffi cult cases (very rare) sple- nectomy still worth considerin g, though post-splenectomy mortality may be greater than that of untreated ITP. Newer thera pies include danazol and rituximab, though experience still anecdotal and long-term risks n ot yet evaluated. Life-threatening hemorrhage or other emergency Risk of life-threatening hemorrhage very sma ll (<1/1000 in 1st week after diagnosis) though is a function of a platelet count <10 \200 \22320 x 109/L and the time exposed to this. Risk consequently rises in rare children with chronic unremitting severe disease for >1 \200\2232 years for whom more adventurous therapy (splenectomy, rituximab) can be contemplated, though risk still small and those of treatme nt may be higher. If a large intracranial (ICH) or other catastrophic bleed occurs, this ca n be dealed with by simultanous massive platelet transfusion, IVIg, IV methylpred- nisolone and (if the diagnosis is beyond doubt) emergency splenectomy. Mortality of major ICH <50% given active therapy. Outlook Most children with ITP recover irrespective of therapy, usually within weeks or occ asionally within months. Even 75% of those whose problem persists for >6 months eventually spontaneously remit, some- times several years later. It is very rare for children to carry ITP into adult life and beyond, and the occasional individuals who do are unlikely to be m uch troubled by it or to develop autoimmune disease of other systems. Further reading Guidelines for the investigation and management of idiopathic thrombocytope nic purpura in adults, children and in pregnancy (2003). Br J Haematol, 120, 574 \200\22396 . 606 CHAPTER 12 Pediatric hematology Haemolytic uraemic syndrome Characterized by a triad of microangiopathic haemolytic anemia (MAHA), renal failure, and thrombocytopenia. More common in children than adults and of 2 t ypes; the more common epidemic form and the less common sporadic form closely related to th rombotic thrombocytopenic purpura (TTP) \200\224a disease primarily of adults that also rar ely occurs in children. TTP has the same triad of signs with two others \200\224fever and n eurological disturbances (E Thrombotic thrombocytopenic purpura, p.538) Pathogenesis HUS usually occurs in outbreaks and in 90% is due to Escherichia coli 0157 and other verocytotoxin-producing E. coli. Food sources of the infection include uncooked/unde rcooked meats, hamburgers, and poor food hygiene. The verocytotoxin causes endothelial dama ge, particularly of the renal endothelium, leading to the formation of fi brin-rich micro- thrombi and MAHA. Familial haemolytic uraemic syndrome (5 \200\22310% of cases) have a defi ciency or dysfunction of complement factor H, which results in excessive C3 activation. Clinical features \200 Young children (<4 years) are especially prone to the disease. \200 Acute onset with a history of abdominal pain and bloody diarrhea. \200 Onset of d u rine output heralding renal failure occurs days later. \200 In 710% onset is non-epidemic and insidious \200\224can be associated with chemotherapy/TBI. Other symptoms: anemia (may be severe), jaundice, bruising, bleeding. \200 Absence of fev er and neurologic signs distinguish it from TTP. Laboratory \201 ndings \200 MAHA may be severe. \200 Movie shows fragmented RBCs/schi stocytes/spherocytes. \200 Thrombocytopenia. \200 Coagulation tests: PT/APTT \200\224us ually n; Fgn and F/XDPs also n; reduced large vWF multimers. Proteinuria and haematuria. \200 Biochemical evidence of renal failure. \200 Stool cult ure may be +ve for E. coli. Diff erential diagnosis \200 TTP (E Thrombotic thrombocytopenic purpura, p.538). \200 O ther causes of MAHA and renal failure. Complications \200 ARF l CRF rare but more likely in older children and those with sporadic insidious onset HUS. Microvascular thrombosis and infarction of other organs. Treatment \200 Renal failure \200\224fl uid restriction, correct electrolyte imbalance. \200 If anuria persists >24h \200\224dialysis as necessary. \200 Blood transfusion for a nemia. 607 HAEMOLYTIC URAEMIC SYNDROME Platelet transfusion rarely needed \200\224may i thrombotic risk. \200 Severe persistent disease may require plasmapheresis as for TTP (E Thrombotic thrombocytopenic purpura, p.538). Specifi c treatment: none of proven value. In familial form replacement of factor H with FFP may be helpful. Outcome Epidemic HUS has a good prognosis, patients usually recover and it rarely recurs. C RF does occur occasionally. Insidious onset HUS has a poorer prognosis. Overall mortality 7 5%. 608 CHAPTER 12 Pediatric hematology Childhood cancer and malignant blood disorders Epidemiology In Europe 1 child in 600 develops cancer before the age of 15. Annual incidenc e 1:10,000; 71200 new cases/year in UK. Pattern of child- hood cancers is very diff erent f rom that seen in adults: carcinomas are rarely seen. Overall, childhood cancer is slightly more common in boys than girls. \200 Leukaemias account for about 35% of the total: 80% a re some type of ALL, 15% some type of AML. 5% CMLs, (adult and juvenile types) or myelodysp lastic syndromes. CLL does not occur in children. Brain tumors are commonest solid malignancies, 25% of the total. Diff erent tumor types from adults; commonest medulloblastoma in posterior fossa. Embryonal tumors 15%, seen almost exclusively in children. Include neuroblastoma, nephrobla stoma (Wilms tumor), rhabdomyosarcoma, hepatoblastoma. Bone tumors 5% osteosarcoma, Ewing sarcoma. \200 Lymphomas 9% \200\224NHL and Hodgkin dis ease. NHL in children closely related biologically to ALL; low-grade disease very rare. Remainder of cases are mainly germ cell and primitive neuroectodermal tumors (PNETs), including retinoblastomas. Etiology \200 Childhood cancer generally represents aberrant growth and development. Defective repair and renewal may also be important in some cancers. Growths arising in infancy are mostly congenital and the genetic mutations concerned arise in utero. Causes of such mutations and those arising later in chi ldhood largely unknown. Although isolated cases are attributable to high-dose radiation (e.g. thyroid cancer in Chernobyl survivors), there is no convincing link to levels of back ground radiation or electromagnetic fi elds. Population mixing studies have suggested that patterns of exposure to infection may contribute to some cases of ALL in the peak years of incidence (2 \200\223 6 years). Childhood cancer rarely familial, but study of retinoblastoma (rare tumor that is commonly familial) has led to better understanding of tumor suppressor genes; germline mutation in 1 allele of RB gene in aff ected families only gives rise to tumors in cells where there is an acquired mutation in the other, healthy, wild type allele (the \200\230two hit \200\231 hypothesis). Cancer arising in older children may still be due to intrauterine event as concordance stud ies in identical twins with ALL have shown identical genetic mutations in malignant cells s ome years after birth. This suggests twin l twin transfer of potentially malignant clone th rough shared circulation. 609 CHILDHOOD CANCER AND MALIGNANT BLOOD DISORDERS Hematological eff ects of non-haemic tumors (for leukaemias, lymphomas, and MDS see appropr iate sections) \200 Marrow infi ltration may be evident at the time of presentation (most commonly neuroblastoma, less commonly Ewing sarcoma, rhabdomyosarcoma). Associated with anemia, occasionally other cytopenias. Blood count hardly ever n if marrow involved. Peripheral blood may show leucoerythroblastic picture, but not as commonly in adult cancers metastasizing to BM. Non-haemic tumors appear on cytomorphology as poorly diff erentiated fragile blast cells, o ften in sheets or clumps (unlike leukaemic blasts). Marrow infi ltration may arise as a late event in terminally progressive disease in other t umors, including CNS malignancies, PNETS, and germ cell tumors.