Metabolic disorders \200\224rare. Laboratory investigation Criteria set out above will establish the diagnosis of haemolytic anemia. A +ve DAT points to an immune process \200\224probably Rh/ABO disease. If non-immun e, further tests to look for a congenital abnormality. The diagnosis may be made by 2 Peripheral blood findings. 2 Heinz body positive \200\224?ch emical/drug-induced haemolysis. 2 RBC enzyme screen to exclude G6PD or PK deficiency. 2 Hb electrophoresis to exclude Hb defects. 439 Often no definitive cause is found and the HA will be presumed 2 to underlying systemic i llness. Management 1. General supportive measures for hyperbilirubinaemia ((cid:9) p444). 2. Treatm ent of specific conditions \200\223 Haemolytic disease of the newborn \200\224(cid:9) p440. \200\223 Neonatal infect ion as appropriate. \200\223 Exchange transfusion almost never needed. Outlook Prognosis is that of the underlying condition. Anemia will usually respond as the c ondition is brought under control. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 440 Haemolytic disease of the newborn (HDN) Arises when there is blood group incompatibility between mother and fetus. Maternal Abs pro duced against fetal RBC antigens cross the pla- centa and destroy fetal RBCs. Most commonly caused by the rhesus D antigen, but maternal passive immunization with rhesus (Rh) D immun oglobulin (anti-D) introduced in the late 1960s transformed the outlook. Despite this, HDN due to anti-D and other red cell antibodies (e.g. anti-c, anti-Kell) still remains an impor tant cause of fetal morbidity. Pathogenesis Placental transfer of fetal cells7maternal circulation is maximal at delivery; the condition does not usually present in the firstborn (Note: ABO incompatibility is an e xception). Previous maternal transfusion, abor- tion, amniocentesis, chorionic villus sampl ing (CVS) or obstetric manipula- tions can cause antibody formation. Maternal IgG crosses p lacenta, reacts with Ag +ve fetal RBCs. Rh HDN classically presents as jaundice in first 24h of life. Mild HDN may go unnoticed and presents as persistent hyper- bilirubinaemia or late anemia w eeks after birth. Severe HDN may result in a macerated fetus, fresh stillbirth or severely anemic, grossly oe dematous infant (hydrops fetalis) with hepato- splenomegaly 2 to compensatory extramedull ary haemopoiesis in utero. Kernicterus: Neurological damage secondary to bilirubin deposition in the brain, depends on a number of factors including the unconjugated bilirubin level, maturity of the baby, the use of interacting drugs. 440 Diagnosis Rh HDN is the commonest cause of neonatal immune haemolysis; routine antenatal sc reening should identify most cases prior to delivery allowing appropriate action. In suspected case at delivery cord blood is tested for 2 ABO and Rh (D) group. 2 Presence o f antibody on fetal RBCs by DAT. 2 Hb and blood movie (spherocytes, increased polychromasia , NRBCs). 2 Serum bilirubin (4). Maternal blood is tested for 2 ABO and Rh (D) group. 2 Serum antibodies against fetal cells (by indirect antiglobulin test, IAGT). 2 Antibody titre. 2 Kleihauer test \200\224detects and quantitates fetal RBCs in maternal c ircula- tion. Diagnostic findings include 2 DAT +ve haemolytic anemia spherocytosis in the infant. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 441 Pediatric hematology 2 Maternal anti-D, or other anti Rh antibody \200\224the next most common to produce severe disease is anti-c. ABO HDN Theoretically should occur more frequently since 1 in 4/5 babies and mothers are A BO incompatible. Usually occurs in group O mothers who may have high titres of naturally oc curring IgG anti-A or B, and with a boost to this during pregnancy haemolysis can occur. Clinical features First pregnancies are not exempt, but condition is usually mild. Presenta tion is later than with Rh HDN (2 \200\2234d, but may be weeks after birth). Diagnosis May be difficult \200\224DAT commonly and puzzlingly \200\223ve, but offending a nti- body can be eluted from infant RBC. Antibody studies Maternal high titre anti-A/B almost always in a group O mother cord- blood /infant \200\231s serum-an inappropriate antibody (e.g. anti-A in a group A baby). Other blood group antibodies Can occasionally produce severe HDN; anti-Kell in particular. Serological testing will establish diagnosis. Maternal autoimmune haemolytic anemia may pro duce a similar picture to alloimmune HDN where the auto-anti- body cross-reacts with the in fant RBC. Usually the diagnosis will have been made antenatally. Severity in infant varies depending on maternal condition. 441 Management \200\224prevention Routine antenatal maternal ABO and Rh D grouping and antibody testing carried out at booking visit ( 12 \200\22316 weeks). If antibody positive repeat at intervals to check the antibody titre. If antibody negative and Rh D negative repeat at 28 weeks \200\231 gestation. Establish if paternal red cells heterozygous, homozygous or negative for the specific Ag. Anti-D prophylaxis 2 250iu IM during pregnancy to Rh D negative women without anti- bodies to cover any intrauterine maneuver or miscarriage. 2 After delivery, a standard dose of 500iu anti-D within 72h unless baby is known to be Rh (D) \200\223ve. 2 If Kleihauer test result shows a bleed of >4mL give further anti-D. Treatment of affected fetus \200\224before delivery Treatment depends on past obstetric his tory, the nature and titre of the antibody and paternal expression of the antigen. The feta l genotype can be established by CVS, fetal blood sampling and PCR. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 442 Examination of the degree of hyperbilirubinaemia is indicated with a poor past history (exc hange transfusion or stillbirth in previous baby) and high titre (1:8 \200\2231:64) of an a ntibody likely to cause severe HDN (e.g. anti-D, anti-c or anti-Kell). The amniotic fluid b ilirubin at optical density 450nm dictates treatment according to the Liley chart (opposite ), which estimates the blood concentration. the amniotic fluid to assess Options include intrauterine transfusion (IUT) if fetus is not deemed mature enough for del ivery (check lung maturity on phospholipid levels) or induction of labor if it is. Intensiv e maternal plasmapheresis may be useful to reduce antibody titre. Advances in management of very premature babies are such that nowadays IUT rarely performed. After delivery 2 Full pediatric support \200\224metabolic, nutritional and respiratory. 2 I f unconjugated hyperbilirubinaemia not a problem, treat anemia (note: cord blood Hb <14.0g/dL) by simple transfusion. 2 Exchange transfusion with Rh (D) neg and (if possible) group specific blood for: \200\223 A severely affected hydropic anemic baby. \200\223 Hyperbilirubinaemi a (bilirubin level at or near 340mmol/L (20mg/dL) or rapidly rising level e.g. >20mmol/h) in first few days of life. \200\223 Signs suggesting kernicterus \200\224exchange transfusion may have to be repeated. 2 Phototherapy to reduce the bilirubin level. 2 Follow-up required \200\224late anemia can be severe particularly if exchange transfusion has not been carried out. 442 Outcome With modern techniques, the outlook is good even for severely affected infants. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 443 Pediatric hematology Liley chart 443 The amount of bilirubin can be quantitated by spectrophotometrically measuring absorbance a t 450nm wavelength in a specimen of amniotic fluid that has been shielded from light. The r esults (delta 450) are plotted on a \200\230Liley \200\231 curve, which is divided into th ree zones. A result in Zone I indicates mild or no disease. Fetuses in zone I are usually fol- lowed w ith amniocentesis every 3 weeks. A result in zone II indicates intermediate disease. Fetuse s in low Zone II are usually followed by amniocentesis every 1 \200\2232 weeks. A result ab ove the middle of Zone II may require transfusion or urgent delivery. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 444 Hyperbilirubinaemia Bilirubin results from the breakdown of haem, mostly Hb haem. It may be unconjugated water insoluble pre-hepatic (a mark of excessive RBC break- down) or conjugated soluble post-hepa tic (4 in cholestasis). Unconjugated bilirubin 4 in most neonates and is usually physiologi cal; conjugated hyper- bilirubinaemia, on the other hand, is almost always pathological. Pathophysiology Physiological jaundice is defined as a temporary inefficient excretion of b ilirubin which results in jaundice in full-term infants between the 2nd and 8th day of life . Occurs in 90% of healthy neonates. Hepatic immaturity and 4 RBC breakdown overloads the neonate \200\231s ability to handle the bilirubin which is mainly unconjugated. The bilirub in is rarely >100 mol/L, though between 2 \200\2235 days occasionally can be >200 in a ter m baby or 250 in a healthy pre-term. Levels much above this need investigation. Reaches a m aximum by days 3 \200\2236 and usually 5 to normal by day 10. In premature neonates it may take longer to settle. HDN due to blood group incom- patibility accounts for 10% cases of hyperbilirubinaemia and about 75% of those requiring exchange transfusion. Causes of hyperbilirubinaemia Unconjugated Physiological jaundice Haemolytic anemia Haematoma Polycythaemia Biochemical d efects Conjugated Mechanical obstruction Bile duct abnormalities (e.g. atresia, cysts) Hepatocellu lar disorders Hepatitis 444 Clinical features 2 Note: clinical jaundice in the first 24h of life is always pathological . 2 Presenting after this, the jaundice may/not be pathological \200\224usually not. Inadeq uate food/fluid intake with dehydration can aggravate the physiological bilirubin. A higher concentration is acceptable for the full- term breast-fed baby (serum bilirubin 240 mol/L ) than bottle-fed baby (190 mol/L). 2 Jaundice in an active healthy infant is likely to be physiological. 2 In a sick infant th e underlying cause of the jaundice may be clinically evident \200\224e.g. infection, anemia, shock, asphyxia, hemorrhage (may be occult). 2 Physical examination \200\224hepatosplenomegaly is pathological. 2 Maternal history (drug s, known condition) and family history may help. Laboratory investigation 2 FBC, reticulocyte count and movie-?haemolytic anemia. 2 Serum bi lirubin \200\224?conjugated or unconjugated \200\223 Unconjugated hyperbilirubinaemia. DAT, maternal and neonatal blood group serology. Infection evaluation including TORCH. Thyr oid function. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 445 Pediatric hematology Reducing substances. \200\223 Conjugated hyperbilirubinaemia. Abdominal USS, bile pigments in stool, liver pathology. 2 Further investigation as determined by results and clinical picture. Management 2 General \200\224adequate hydration, nutrition, other supportive measures. 2 Tr eat underlying cause \200\224antibiotics, metabolic disturbances. 2 Haemolytic anemia \200 \224blood transfusion. 2 Specific phototherapy (light source with wavelength between 400 \200\223500mm) effective in treating most causes of unconjugated hyper- bilirubinaemia. Note: contraindicated in conjugated hyperbilirubinaemia. 2 Exchange transfusion \200\224the indications are complex. Main indication is severe haemo lytic anemia and is used in full-term infants when the bilirubin is >340 mol/L and at a lo wer concentration in premature infants. 2 Hyperbilirubinaemia due to mechanical obstruction may need surgery. Outcome In most infants hyperbilirubinaemia resolves by 2 weeks. When pathology has been ex cluded the commonest cause of prolonged hyperbilirubi- naemia persisting beyond this period is breastfeeding. In 20% healthy breast-fed infants the bilirubin is still significantly 4 at day 21. Kernicterus is not a complication but the condition causes concern before it sp onta- neously remits. 445 12-Pediatric.qxd 10.12.2003 04.28 PM Page 446 Neonatal haemostasis Neonates can develop bruising and/or purpura due to defects in platelets, coagulation facto rs or both. Coagulation tests should be interpreted with caution because in the term infant the concentration of vitamin K-depen- dent proteins (II, VII, XI and X together with prote in C and protein S) are 50% of normal adult values, contact factors (XI, XII, PK and HMWK) are 30 \200\22350% of adult concentrations, and all are lower in pre-terms. Factors VIII, V and vWF are normal. Thrombin inhibitors antithrombin (AT, previ- ously called antithrombin III) and HCII are 5 but a2-M is 4. Platelet count is the same as adults in both term and p re-term infants. There are tech- nical problems in obtaining uncontaminated (heparin from c atheters or IV lines) and adequate venous samples from neonates, causing in vitro inhibi- t ion or pre-test activation of clotting factors or dilution due to short sam- pling and thus excess anticoagulant. All can give spurious results. Pathophysiology Haemostatic and fibrinolytic system in neonates is immature. Sepsis, liver disease, necrotising colitis and RDS can precipitate DIC easily. Thrombocytopenia can be ca used by DIC and also immune mechanisms or marrow failure. Disorders causing bleeding in neonates Inherited (rare) Acquired (common) Hemophilia DIC (sepsis, necrotising colitis, hypoxia, RDS) 446 von Willebrand \200\231s disease (only type 3) Vitamin K deficiency Other inherited factor deficiencies Liver disease Inherited thrombotic disorders Acquired thrombotic disorders Glanzmann \200\231s thrombasthenia Neonatal alloimmune thrombocytopenia Maternally derived ITP Endogenous ITP Aplasia Leukemia Clinical features 2 Petechiae indicate problems with small vessels or platelets, bruises ca n be due to platelet deficiencies and/or coagulation disorders. 2 Oozing from multiple venepunture sites in sick infants usually indicates generalized haemostatic failure and DIC. 2 Haemorrhagic disease of the newborn due to functional vitamin K defi- ciency presents in 3 forms with bruising, purpura and GI bleeding in oth- erwise well babies; early (within 24 h) usually due to maternal drugs such as warfarin, classical (days 2 \200\2235) in babies w ho have not been given ade- quate vitamin K prophylaxis and who have been breast fed and la te, a variant of the classical form (i.e. insufficient vitamin K, breast-fed) arising at 2 \200\2238 weeks and with a higher morbidity and 4 incidence of ICH. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 447 Pediatric hematology 2 Thrombosis usually catheter related, can be rarely associated with AT III deficiency or homozygous protein C and protein S deficiency (neonatal purpura fulminans \200\224a life-threatening condition with wide- spread peripheral gangrene). 2 Hemophilia and other coagulant deficiencies can cause large haematomas but rarely cause trouble in the neonatal period except factor XIII lack \200\224 typically presents with bleeding from the umbilical stump. 2 In well babies, petechiae and bruises with thrombocytopenia suggests immune basis \200 \224antibody usually from mother (alloimmune or autoim- mune). Rarely, infants under a mont h can develop endogenous ITP. 2 Clear symptoms of thrombocytopenia with normal platelet cou nt sug- gests major functional defect \200\224Glanzmann \200\231s. 2 Marrow failure due to infiltration, aplasia. 447 12-Pediatric.qxd 10.12.2003 04.28 PM Page 448 Neonatal alloimmune thrombocytopenia (NAIT) Occurs when mothers form alloimmune antibodies against fetal platelet- specific antigens th at their own platelets lack. These antibodies react with fetal platelets in utero causing t hrombocytopenia which can be severe, and in some cases life threatening in late pregnancy a nd early life. A more serious condition with greater morbidity than thrombocytopenia due to maternal autoantibodies against platelets \200\224i.e. where the mother has ITP. Pathophysiology In >90% cases the mother will be HPA-1a (old term PLA1) \200\223ve with an ti- HPA-1a antibodies against the HPA-1a +ve fetus; only 2% population are HPA-1a \200\223 ve (i.e. homozygous HPA-1b). Incidence of NAIT is 1/1000 preg- nancies and accounts for 10 \200\22320% cases of neonatal thrombocytopenia. Other antigens may be involved e.g. HPA-5 ( Br) and HPA-3 (Bak) are the commonest. Clinical features 2 Commonly presents in first born infant and recurs in 85 \200\22390%. 2 Maternal platelet count normal with no past history of ITP. 2 Bleeding manifestations in 10 \200\22320% evident within the first few days of life e.g. umbilical hemorrhage, petechiae , ecchymosis, internal haem- orrhage, intracranial hemorrhage (ICH). 2 Baby \200\231s platelet count 4 to normal over the next 2 \200\2233 weeks as the anti- body is cleared. 2 Hemorrhage in utero with fatal ICH in 1% cases. 448 Laboratory diagnosis Baby Severe thrombocytopenia Parents Mother \200\231s platelet count normal Serology platelets <20 109/L in 50% BM has megakaryocytes ++ (not usually necessary) Mother \200\231s platelets usually HPA-1a \200\223ve Rarer Ab include anti-HPA-3a, HPA-5b, HPA-4 (Yuk/Pen) Mother \200\231s serum contains anti-platelet antibody (Note: antibody tit re cannot predict degree of thrombocytopenia in fetus in subsequent pregnancies) Father \200\231s platelets carry offending antigen Management Of bleeding neonate: transfuse platelets \200\223ve for Ag (usually HPA-1a \200\223ve); use random donor platelets in an emergency. Maternal platelets (irradiated) ar e a good source. Repeat platelet transfusion PRN. IVIg as for 12-Pediatric.qxd 10.12.2003 04.28 PM Page 449 Pediatric hematology ITP can be used in exceptional cases (response within days). Close observation (ICH is pote ntially lethal \200\224screen using USS). Of subsequent pregnancies: cordocentesis in utero at 24 weeks; take 1 \200\2233mL blood fo r platelet count and phenotype. If affected, treatment needs to be started immediately. Options 1. In utero CMV \200\223ve compatible platelet transfusions at 2 \200\2234 weekly inter- vals (depending on severity and history). Invasive and technically demanding. Keep platelet cou nt >50 109/L (platelets 5 rapidly so fre- quent follow-up mandatory). 2. Maternal administration of IVIg (1g/kg) weekly from 24 weeks onwards: check fetal plate let count 4 weeks later and again near term; response variable \200\224around 75% respond \200\224transfuse platelets if non-responsive. Check cord blood at birth and treat as neces sary. Outcome With aggressive treatment the outcome is good, death in utero and ICH occur rarely. A history of a previous ICH correlates with severe thrombo- cytopenia in subsequent pregna ncies. 449 12-Pediatric.qxd 10.12.2003 04.28 PM Page 450 Congenital dyserythropoietic anaemias A rare group of inherited lifelong anaemias with morphologically abnormal marrow erythrobla sts and ineffective erythropoiesis. Three clinically dis- tinguishable types are recognized where inheritance may be recessive (types I and II) or dominant (type III). A number of fa milies have been described that share some features but do not fit with the typical pattern s. Pathophysiology Ineffective erythropoiesis (cell death within the BM); RBC survival in PB i s not much reduced (III). Abnormal serological and haemolytic characteris- tics (type II CD A) and membrane abnormalities are described but as yet no defining shared defect in all cas es of CDA. Type Bone marrow Blood findings Inheritance I Megaloblastic + intranuclear chromatin bridges Macrocytic RBC Recessive II (HEMPAS)* Bi/multinuclearity with Normocytic RBCs pluripolar mitosis Lysis in acidified serum (not autologous serum) Recessive III Giant erythroblasts with multinuclearity Macrocytic Dominant 450 Hereditary erythroblast multinuclearity with positive acidified serum test; commonest form, found in 66% cases Clinical features 2 Age of presentation variable; but usually in older children (>10 years) . Can rarely present as neonatal jaundice and anemia. 2 Anemia \200\224in type I, Hb 8.0 \200\22312.0g/dL; type II anemia may be more severe, patient may be transfusion dependent. Type III (rare) anemia is mild/moderate. 2 Jaundice (2 to intramedullary RBC destruction). 2 Gallstones. 2 Splenomegaly common. Laboratory diagnosis 2 Peripheral blood \200\224normocytic/macrocytic RBC with anisopoikilo cytosis. 2 WBC and platelets usually normal; reticulocytes slightly 4. 2 BM appearance \200 \224striking, showing 4 cellularity with excess abnormal erythroblasts. 2 Type II shows positive acidified serum test. 2 4 Serum ferritin due to 4 Fe absorption; h aemosiderosis can occur without transfusion dependence. Type III very occasionally Fe deficient due to intravascula r haemolysis and haemosiderinuria. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 451 Pediatric hematology Differential diagnosis 2 CDA variants \200\224not all CDA falls neatly into 3 subtypes on B M findings, serology or clinical features. 2 PNH \200\224acidified serum test is +ve with heterologous and autologous serum. In HEMPAS +ve with heterologous serum only. 2 Other megaloblastic/dyserythropoietic anaemias \200\224including vitamin B12 and folate deficiency. 2 Primary/acquired sideroblastic anemia. 2 Erythroleukaemia (M6 AML). Treatment 2 Mostly unnecessary. 2 Avoid blood transfusion if possible (iron overload) \200 \224iron chelation as necessary. 2 Splenectomy not curative but may decrease transfusion requirements. 2 Type I may respond to high dose IFN-a; not recommended as routine therapy. Natural history Severity of CDA varies considerably and many patients have good quality of life with no therapy. Haemosiderosis is a long term complication which may impact on surviv al. 451 12-Pediatric.qxd 10.12.2003 04.28 PM Page 452 Congenital red cell aplasia Diamond and Blackfan first described congenital red cell aplasia in infants in 1938 giving rise to the name of Diamond \200\223Blackfan anemia (DBA). Incidence now estimated to be 4 \200\2237/million live births. Pathophysiology Probably always due to an as yet undefined germline genetic mutation, eithe r inherited or arising in the affected infant. Familial patterns with both autosomal domina nt and recessive inheritance have been described. Surviving sporadic cases (i.e. non-famili al) have transmitted the disease to their children. Nature of underlying defect not known. Gene(s) involved not yet identified despite multiple associated developmental abnormali- ti es. Anemia likely to be due to intrinsic RBC progenitor cell defect rather than one of the microenvironment. 5 sensitivity of these cells to Epo and other cytokines described. Clinical features 2 Usually presents in the first year of life: in 25% at birth and 90% <6 months of age. Rarely presents >1 year. 2 Mildly affected individuals may rarely be detected as older children or adults during family studies. 2 Associated physical anomalies in 50%; abnormal facies with abnormal eyes, webbed neck, ma lformed (including triphalangeal) thumbs, other skeletal abnormalities, short stature, cong enital heart lesions, renal defects. 2 Anemia usually severe and child commonly transfusion dependent. 2 Susceptibility to infec tion is not 4. 2 Hepatosplenomegaly absent. 2 Family history is +ve in only 10 \200\22320% cases; most are sporadic. 2 4 risk of AML in long survivors; 5% in biggest series reported to date. 452 Laboratory diagnosis 2 Hb 5, reticulocytes 5, MCV 4 (> normal for age), WBC and platelets not 5. 2 Red cells \200\224normal morphology, have 4 i antigen positivity, 4 ADA activity. 2 HbF 4, Epo 4, serum Fe/ferritin 4. 2 BM findings \200\224usually absent erythroid precurs ors; other cell lines normal. 2 No evidence of parvovirus infection. 2 Radiological investigation to define other congeni tal defects. Differential diagnosis 2 Transient erythroblastopenia of childhood ((cid:9) following secti on; later presentation, transient, no other defects). 2 Drugs, malnutrition, infection. 2 Haemolytic anaemias in hypoplastic phase, with parvovir us B19, delayed recovery in HDN. 2 Megaloblastic anemia in aplastic phase. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 453 Pediatric hematology Treatment 2 Prednisolone 2mg/kg PO in divided doses, slowly 5 over weeks; 70% respond well. Titrate to lowest dose to maintain Hb >7g/dL. Many achieve this on almost homeopathic dose s despite true dependence. Around 10% need high dose maintenance and have trouble with side effects. 30% steroid resistant (try high dose methylprednisolone). 2 Transfusion dependenc y usual in those who cannot be maintained on very low dose steroids. Need chelation to prev ent iron overload. Use CMV \200\223ve leucocyte-depleted packed RBC. 2 Splenectomy not helpful (unless hypersplenism). 2 Bone marrow transplantation worth consi dering for transfusion depen- dents with suitable donor; risk stratification as for severe thalassaemia (iron overload). Complicated decision due to chance of spontaneous remission e ven after years of transfusion dependency. Natural history Spontaneous remission in 10 \200\22320% (even after several years). Median sur- vival estimated at 30 \200\22340 years, though data patchy. Death due to haemosiderosi s, complications of steroid therapy, or evolution of AML or aplastic anemia. BMT may offer better outlook. DBA Registry established in 1993 is prospectively gathering new data. 453 12-Pediatric.qxd 10.12.2003 04.28 PM Page 454 Acquired red cell aplasia Isolated failure of erythropoiesis. Most commonly transient \200\224either due to parvoviru s B19 infection or transient erythroblastopenia of childhood (TEC). Acquired pure red cell aplasia (PRCA) seen in adults with or without thymoma and probably autoimmune in nature ((c id:9) p122) virtually unknown in childhood, though very occasionally seen in adolescents. Parvovirus B19 infection Clinical features 2 Causes transient reticulocytopenia and (occasionally) neutropenia and thrombocytopenia in otherwise healthy individuals. 2 In children with increased red cell turnover for any reason (compen- sated haemolysis, ineffective erythropoiesis) or those with reduced red cell production (ma rrow suppression or hypoplasia) can produce dra- matic falls in Hb. 2 Can affect any age. 2 Self-limiting as infection subsides following antibody response, 7 \200\22310d. 2 In immun osuppressed 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 454 Pathogenesis Serum and cellular inhibitors of erythropoiesis and defective bone marrow resp onse to stimulating cytokines have been demonstrated. The condition may be idiopathic or as sociated with viral infection. It is uncommon but not excessively rare and there may be man y subclinical cases where a blood count is not done. Clinical features 2 Boys and girls equally affected: age range 6 months to 5 years; most commonly around 2 years. 2 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. 2 Associated infections are usually viral (EBV, mumps), preceding the onset of TEC by some weeks. 2 Fever is rare. 2 Pallor may be striking. 2 No lymphadenopathy or hepatosplenomegaly. 2 No physical abnormalities. Laboratory diagnosis 2 Normocytic, normochromic anemia which may be severe (Hb <5g/dL). 2 R eticulocytes absent unless in early recovery phase; WBC and platelets usually normal. 2 Blood movie shows no abnormality other than anemia. 2 Biochemical profile normal. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 455 Pediatric hematology 2 Bone marrow shows normocellular picture with absent erythroid pre- cursors. Iron content is normal. 2 No karyotypic abnormalities. 2 Exclude parvovirus infection ((cid:9) p454). 2 No other in vestigation is of diagnostic help. Differential diagnosis 2 Exclude acute blood loss and anemia of chronic disease. 2 Exclude common ALL. 2 Diamond \200\223Blackfan anemia (see previous section). Usually presents within the first 6 months of life and other abnormalities (skeletal mal- formation, short s tature, abnormal facies) are commonly present. 2 Parvovirus infection (see above). Treatment Blood transfusion should be avoided but may be necessary if symptomatic. 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. 455 12-Pediatric.qxd 10.12.2003 04.28 PM Page 456 Fanconi \200\231s anemia First described by Fanconi in 1967, Fanconi \200\231s anemia (FA) is a clinically heterogen eous disorder usually presenting in childhood with the common feature being slowly progress ive marrow failure affecting all 3 cell lines (RBC, WBC and megakaryocytes) and manifest by peripheral blood pan- cytopenia and eventual marrow aplasia. It is a recessively inherited dis- order with several different germline genetic mutations involving at least 8 genes, 4 of which have been identified and characterized, and all of which are on different chromos omes. Pathophysiology of Fanconi \200\231s anemia. FA affects all cells of the body and the cellu lar phenotype is characterized by increased chromosomal breakage, hypersensitivity to DNA c ross- linking agents such as diepoxybutane (DEB) and mitomycin C (MMC), hypersensitivity to oxygen, increased apoptosis and accelerated telomere shortening. The increased chromosomal fragility is characteristic and used as a diagnostic test. Apart from progressive marrow f ailure, 70% of FA patients show somatic abnormalities, chiefly involving the skeleton. 90% develop marrow failure and survivors show an increased risk of devel- oping leukemia, chief ly AML. Rarely, FA can present as AML. There is also an increased risk of liver tumors and squamous cell carcinomas. Clinical features 2 Autosomal recessive inheritance: in 10 \200\22320% the parents are rela ted. 2 Phenotypic expression of the disease varies widely, though similar in any given kind red. Most commonly presents as insidious evolution of pancytopenia, presenting in mid-child hood with a median age of pre- sentation of 9 years. Cell lines affected asynchronously; is olated throm- bocytopenia may be first manifestation, lasting 2 \200\2233 years before othe r cytopenias occur. 456 2 10% present in adolescence or adult life, 4% present in early infancy (<1 year). 2 Disorders of skin pigmentation common (60%) \200\224caf -au-lait spots, hypo- and hyperpigmentation. 2 Short stature in 60%, microcephaly and delayed development in >20%. 2 Congenital abnormal ities can affect almost any system \200\224skeletal defects common, >50% in the upper limb especially thumb, spine, ribs. 2 Characteristic facies described \200\224elfin-like, with tapering jaw line. Diagnosis Laboratory findings 2 Pancytopenia and hypoplastic marrow \200\224patchy cellular ity. 2 Bone marrow may also show dyserythropoietic morphology. 2 Anemia varies in its sever ity and may be macrocytic (MCV 100 \200\223120fL). 2 Excessive chromosomal breaks/rearrange ments in culture of peripheral blood lymphocytes challenged with clastogens (DEB or MMC) is the defining abnormality, and can be used on fetal cell culture for antenatal diagnosis. 2 Direct probing for mutations in the FA genes that have been identified and characterized permits molecular diagnosis in around 80% of patients, but is complex and slow. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 457 Pediatric hematology 2 Further investigation for systemic congenital abnormalities is indicated. Differential diagnosis 2 Acquired aplastic anemia ((cid:9) p122). 2 Other congenital or inh erited childhood marrow failure syndromes \200\224 see following page. 2 Bloom \200\231s syndrome \200\224clinically like Fanconi \200\231s anemia with similar co n- genital defects, spontaneous chromosomal breaks and a predisposition to leukemia but wit hout pancytopenia, or bone marrow hypoplasia. Autosomal recessive. Characteristically have photosensitivity and telangiectatic facial erythema. Genetic mutation mapped to chromo- som e 15q26. Treatment General 2 Supportive \200\224blood transfusion with iron chelation as required. 2 Treatment of associated congenital anomalies where necessary. Specific 2 Combined therapy with steroids (moderate dosage alternate days) and androgens (oxymethalone 2 \200\2235mg/kg/d). Most patients respond to treatment but eventua lly become refractory. 2 Haemopoietic growth factors may offer temporary relief from neu- tropenia and anemia. 457 2 BMT is potentially curative, but FA patients hypersensitive to condi- tioning agents cycl ophosphamide and radiation. Using low doses, matched sibling grafts give 70% actuarial surv ival at 2 years; unrelated donor results less good but improving. Early survivors showed 4 risk of tumors, especially head and neck. 2 Much interest in gene therapy. Early trials have occurred, but no major therapeutic succe ss. Theoretically should be possible to transduce patient stem cells from those with known mutations with the appro- priate wild type FA gene, and for these stem cells to have a natu ral growth advantage over FA cells. So far responses have been disap- pointing and short-li ved. Outcome Median survival of conventional treatment responders who do not undergo BMT is 25 years. Non-responders have a median survival of 12 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. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 458 Rare congenital marrow failure syndromes Amegakaryocytic thrombocytopenia (congenital amegakaryocytic thrombocytopenia) Presents in infancy (usually at birth or within 2 months) with profoundly 5 platelets and associated ph ysical signs (petechiae and bruising). Around 40% of affected children also have other cong enital abnormalities \200\224chiefly neurologic or cardiac. Developmental delay is common. The marrow completely lacks megakaryocytes and the disorder evolves to severe aplastic anem ia in around 50% of sufferers, usually in the first few years of life. Has none of the unst able DNA features of Fanconi \200\231s anemia (see pre- vious page). Also quite distinct fr om the syndrome of thrombocytopenia with absent radius (TAR syndrome, see below) since it i s a trilineage problem with a much greater mortality. Usually sporadic, but familial cases occur and disorder thought to be inherited. No gene yet identified. Outlook Without BMT, mortality from bleeding, infection or (occasionally) pro- gression to leukemia near 100%. Amegakaryocytic thrombocytopenia with absent radii (TAR syndrome) 2 Usually diagnosed at bi rth because of lower arm deformity due to bilateral radial aplasia. 2 No hyperpigmentation. 2 Isolated thrombocytopenia with other ce ll lines normal. 2 Bone marrow lacks megakaryocytes; has adequate WBC/RBC precursors. 2 No chromosomal breaks in cell culture. 2 Autosomal recessive; no gene yet identified. 2 Thromb opoietin 4; platelets gradually increase as child grows. 2 Bleeding problems greatest in in fancy. 2 Supportive therapy only needed. 458 Outlook Usually good, with problems receding as childhood proceeds. Occasional patients con tinue to have problems with 5 platelets. No 4 malignancy. Dyskeratosis congenita 2 Inherited disorder of mucocutaneous and haemopoietic systems. 2 Cl inical triad of skin pigmentation, leucoplakia of the mucous mem- branes, dystrophic nails and, in 50% patients, severe aplastic anemia develops, usually in the second decade. 2 Usually sex-linked inheritance through single gene at Xq28, though 15% autosomal so pheno type dependent on more than 1 gene. 2 Other congenital and immunological abnormalities described. 2 Chromosome fragility on cha llenge with DEB or mitomycin C normal \200\224 important to distinguish DC from Fanconi \200\231s anemia (see previous page). 2 Despite this some evidence of DNA instability; results of BMT for aplastic anemia in DC p atients poor, perhaps because of this. 2 Anecdotal reports of good response to haemopoietic growth factors. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 459 Pediatric hematology Outlook 10% develop cancers before the age of 40 \200\224mostly epithelial, but also MDS/AM L. Life expectancy depends on development of aplasia or malig- nancy. 30% survive to middle age. Kostmann \200\231s syndrome (congenital neutropenia) 2 Autosomal recessive. 2 Severe neutro penia with neutrophils <0.2 109/L. 2 Marrow shows maturation arrest at promyelocyte/myel ocyte stage. 2 High risk of severe infection in untreated state. 2 Not due to germline muta tion in G-CSF receptor gene, though abnormal receptor may be present in myeloid precursors. 2 90% will respond to pharmacological doses of G-CSF and continue to do so for years. 2 Up to 10% develop AML/MDS \200\224role of G-CSF not clear, but probably complication of disease revealed by longer survival. Diagnosis Distinguish from cyclical neutropenia (by observation); benign congenital neutrop enia (by WBC) and reticular dysgenesis a severe inherited immun- odeficiency with congenita l lack of all white cells, including lymphocytes. Outlook Good provided response to G-CSF satisfactory and maintained. Non- responders may ne ed BMT. 459 Shwachman \200\223Diamond syndrome 2 Congenital exocrine pancreatic insufficiency; chronic diarrhea, malab- sorption and growth failure associated with neutropenia. 2 Bone marrow failure not usually trilineage, though platelets and red cells can be involved. 2 Bone marrow varies \200\224may be dysplastic/hypo/aplastic. 2 Probably autosomal recessiv e, but no gene yet identified. 2 Psychomotor delay common. Diagnosis 2 Exclude cystic fibrosis (by normal sweat test). 2 Exclude Fanconi \200\231s ane mia (by normal chromosome fragility). 2 Pearson \200\231s syndrome clinically similar with severe pancreatic insuffi- ciency but with anemia rather than neutropenia and marrow shows ring sideroblasts and vacuo lisation of red and white cell precursors. Treatment 2 Supportive with pancreatic enzymes, G-CSF and antibiotics. 2 Greatly increased risk (up to 30%) of progression to MDS/leukemia (AML > ALL). 2 Limited experience with BMT for aplasia/leukemia; may be increased risk of cardiotoxicity \200\224ventricular fibrosis seen at autopsy in 2/5 patients who die d post BMT. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 460 Outlook Depends on development of severe aplasia or leukemia; long survivors few if so. Pan creatic insufficiency improves as childhood progresses. Seckel \200\231s syndrome \200\224bird-headed dwarfism 2 Rare autosomal recessive disorder with (proportionate) very short stature and mental deficiency. 2 Facial features fancifully described as bird-like. 2 Gene(s) responsible unknown. 2 Progr ession to aplastic anemia common, clinically similar to Fanconi \200\231s anemia (see previous page) but chromosome fragility normal. Infantile osteopetrosis 2 Pancytopenia can arise in this autosomal recessive disorder where the marrow cavity is obliterated with cortical bone due to a functional deficiency of oste oclasts. 2 It is a primary marrow failure in the sense that there is no marrow, but is a failure of the microenvironment rather than haemopoietic stem cells.