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. Outlook Poor due to cranial compression, and children usually die in early child- hood unle ss successful allogeneic BMT can replace normal osteoclast function. 460 12-Pediatric.qxd 10.12.2003 04.28 PM Page 461 Pediatric hematology 461 12-Pediatric.qxd 10.12.2003 04.28 PM Page 462 Neutropenia in childhood Apart from primary marrow failure due to aplastic anemia or other marrow failure syndromes ((cid:9) p122) or marrow suppression due to anti- neoplastic, immunosuppressive or antivira l chemotherapy, neutropenia can also arise as an immune phenomenon, a cytokine mediated pro blem or due to cyclic or non-cyclic disturbances of the homeostasis of neu- trophil product ion. Pathophysiology 2 Commonest cause of a clinically important low neutrophil count in children (<0.5 109/L) is myelosuppression due to drugs. 2 Primary marrow stem cell failure failure either involving all cell lines or granulopoiesis alone is rare. 2 Neutropenia can also be due to less serious inherited deficiencies of neutrophil producti on where neutropenia can be variable or cyclical and the problem seems to be one of product ion control rather than primary stem cell failure. 2 Probably due to cytokine disturbances, several microbial infections can cause paradoxical neutropenia, particularly in neonates but also in older children. 2 Autoimmune causes of neutropenia can arise in infancy or later in childhood. 2 Isoimmune neutropenia in the newborn \200\224due to maternal anti-neu- trophil antibodies and analogous to HDN. Homeostatic disorders 462 Cyclic neutropenia: Rare. Neutropenia arising every 21d lasting 3 \200\2236d. Counts may fa ll <0.2 109/L. Associated with episodes of fever, malaise, mucous membrane ulcers, lymph adenopathy. Serious infection can arise and deaths May improve after puberty. Usually posit ive family history when problem encountered in childhood. Treatment supportive with antibio tics. G-CSF may be useful. Chronic benign neutropenia: More common. Persistent rather than cyclical, though often vari able without clear periodicity. Neutrophil count usually >0.5 109/L, so clinically mild or silent. May have autosomal dominant or autosomal recessive family history. Variable seve rity, often mild with few problems. To be distinguished from severe congenital neutropenia ((cid:9) Kostmann \200\231s syndrome, p459) by milder clinical course and (usually) later p resentation. Therapy not usually necessary. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 463 Pediatric hematology Infections causing neutropenia Viruses RSV Malaria Influenza Measles Varicella HIV Bacteria Tuberculosis Typhoid/paratyphoid E coli (neonates) Others Rickettsiae 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 u sually relatively benign. Therapy supportive. Steroids not usually needed and can increase infection risk. IVIg has been used. Older children may get 2 Isolated AI neutropenia. 2 Neutropenia as part of Evans \200\231 s yndrome ((cid:9) p388). 2 Neutropenia as part of multi-system AI disease \200\224lupus eryt hematosus 2 Immune neutropenia following allogeneic BMT. 2 Felty \200\231s syndrome (rheuma toid arthritis with splenomegaly and hyper- splenic cytopenias \200\224(cid:9) p17) may als o be associated with neutrophil autoantibodies. 463 2 All are potentially more serious and complicated than the infant form and may require imm unosuppression as well as supportive therapy. Isoimmune neutropenia of the newborn 2 Maternal antibodies to fetal neutrophil antigens cro ss the placenta and give rise to neutropenia in the newborn child. 2 Most commonly antibodies directed at neutrophil-specific antigens NA1 and NA2. (Maternal HLA antibodies do not cause trouble because antigens expressed on many tissues so quickly a bsorbed.) 2 Estimated incidence up to 3% of newborns, so may be more common than generally appreciated; perhaps because usually clinically mild and neutropenia thought to be acquired due to drugs/infection. 2 Condition resolves by 2 months as antibody disappears. 2 Severely affected babies may sho w recurrent staphylococcal skin infec- tions. Therapy supportive. Need for exchange transfu sion very rare. 2 Diagnosis based on serology. Prognosis of neutropenia Whatever the cause, severe neutropenia (<0.2 109/L) is serious and incompatible with long survival if prolonged. It requires careful expert management. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 464 Disorders of neutrophil function Acquired Mild defects arise in many clinical situations; following some infections, associa ted with drugs (steroids, chemotherapy) and systemic disease (mal- nutrition, diabetes mell itus, rheumatoid arthritis, CRF, sickle cell anemia) \200\224here the underlying condition will 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 interaction of bacteria with complement and Ig (opsoni sation) and engulf them (phago- cytosis). 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 (5 chemotaxis, phagocytosis, motility) particularly if premature, jaundiced. Kill ing is normal. Classification Disorders of all aspects of neutrophil function are described and there is n o consensus as to how best to classify them. All are rare. In several of the best described conditions multiple defects are present. 464 Classification 55 Chemotaxis Lazy leucocyte syndrome Hyper IgE syndrome Chediak \200\223Higashi syndrome 5 Specific neutrophil granules 55 Opsonisation Complement C3 deficiency 55 Killing Chronic granulomatous disease MPO deficiency Clinical features All congenital syndromes are rare and diagnosis of the specific defect di ffi- 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 alt er the otherwise grim prognosis in many of these conditions. Lazy leucocyte syndrome: Leuco cyte adhesion deficiency due to 5 HMW membrane glycoproteins. Rare. Autosomal recessive. 4 Recurrent infections often in oral cavity, delayed wound healing. Lab features: 4 neutrophi l count, normal BM, abnormal chemotaxis on Rebuck skin 12-Pediatric.qxd 10.12.2003 04.28 PM Page 465 Pediatric hematology window test. The condition is relatively mild. Treatment is of specific infections with the need for prophylaxis in some patients. Hyperimmunoglobulin E syndrome: Also known as Job \200\231s syndrome ((cid:9) Old Testament ) because of recurrent staphylococcal abscesses. Autosomal recessive inheritance, associate d with atopic dermatitis and other autoimmune phenomena. Bacterial/fungal infection, chroni c dermatitis. Lab features: 4 IgE, 4 eosinophils. Complement deficiency: Autosomal recessiv e inheritance of C3 deficiency, homozygotes have severe recurrent bacterial infection, part icularly encapsulated organisms. Chronic granulomatous disease (CGD): Though rare, commonest life- threatening inherited neu trophil functional defect. More than one disorder. Most are sex linked and boys affected 7 more frequently than girls, but 3 autosomal mutations recognized. Presents in early life but also in adults; carriers asymptomatic. Multiple skin and visceral abscesses, systemic e tc.) \200\224bacterial/fungal, osteitis features: nitro blue lymphadenopathy, hepatosplenom egaly. Lab tetrazolium (NBT) test (an index of defective respiratory burst) +ve. Specific m utational analysis now possible for earlier and prenatal diagnosis. Outlook better than it used to be. Improved by aggressive antibiotic policy and IFN-g. BMT little used due to impr oving outlook with conservative/prophylactic treatment. Early results poor. Prospect of gen e therapy attractive but awaits development. infection (pneumonia, 465 Chediak \200\223Higashi syndrome: Rare autosomal recessive disorder. Multiple defects. Part ial oculocutaneous albinism, recurrent infection, lymphadeno- pathy, peripheral neuropathy and cerebellar ataxia. A fatal accelerated phase occurs in 85%, usually in the second deca de, with lymphocytic infiltration of liver/spleen/nodes/BM, pancytopenia. Lab findings 2 5 Hb, 5 neutrophil count, 5 platelet count. 2 Characteristic giant greenish gray refractile granules in neutrophils (also lymph inclusions). 2 Treatment is supportive. High dose ascorbic acid may help some patients. Anecdotal reports of successful BMT. Myeloperoxidase deficiency: Autosomal recessive. Commonest of neutrophil dysfunction condit ions (1:2000) but also least serious. Often asymptomatic. Manifest in diabetics with recurr ent infections \200\224commonly Candida albicans. Good prognosis. Lab findings 2 4 neutrophil/monocyte peroxidase on histochemical analysis. 2 Automated cell counters using MPO activity to count neutrophils may show spurious neutropenia.