SECTION IV Stem Cell Dysfunction Copyright © 2008 by The McGraw-Hill Companies, Inc Click here for terms of use This page intentionally left blank CHAPTER PEDIATRIC BONE MARROW FAILURE SYNDROMES 10 FANCONI’S ANEMIA (CONGENITAL APLASTIC ANEMIA) 186 CONGENITAL HYPOPLASTIC ANEMIA (DIAMOND-BLACKFAN ANEMIA, ERYTHROGENESIS IMPERFECTA) 187 TRANSIENT ERYTHROBLASTIC ANEMIA OF CHILDHOOD 188 RED CELL APLASIA ASSOCIATED WITH PARVOVIRUS B19 INFECTION 189 PEARSON SYNDROME 190 DYSKERATOSIS CONGENITA 191 A wide range of disorders that arise during infancy and childhood disrupt cell production by one or more of the three hematopoietic lines Some of the disorders affect a single lineage while others produce pancytopenia Some disorders, such as Fanconi’s anemia (FA), commonly cause derangements in nonhematopoietic cells and tissues with the consequent finding of associated congenital anomalies Most of the disorders present in the neonatal period or early in childhood Improved diagnostic tools along with recognition of the variability inherent in these conditions now reveal mild manifestations or forme fruste in adolescents or even young adults The uneven clinical texture of these conditions is a continuing challenge to clinicians 185 Copyright © 2008 by The McGraw-Hill Companies, Inc Click here for terms of use 186 STEM CELL DYSFUNCTION SECTION IV FANCONI’S ANEMIA (CONGENITAL APLASTIC ANEMIA) In 1927, Professor Guido Fanconi of Zurich, Switzerland, described several families in which there were children with striking congenital anomalies including absent radii, abnormal thumbs, short stature, and hyperpigmentation Children with no obvious congenital anomalies have also been described These children develop hematological abnormalities at a mean age of about years; initially thrombocytopenia followed progressively by neutropenia and anemia FA is a heterogeneous conglomeration of disorders derived from a collection of impendent mutations involving genes on several chromosomes.1 Cell fusion studies done in vitro show that cellular components from two unrelated patients with FA can combine to eliminate the Fanconi phenotype In other words, cells from the two FA patients complement each other and correct the defect Of the 11 currently known complementation groups, gene identification data exist for 8.2 Three genes, FANCA, FANCC, and FANCG, account for 90% of FA cases Interestingly, FANCD1 is identical to the breast cancer susceptibility gene BRCA2 The molecular details of the cellular action of the FA complementation group proteins are unclear A number of the proteins appear to be components of a molecular complex that fosters chromosomal stability.3,4 Absence of the FA proteins impairs the function of the complex Deranged regulation of apoptosis in FA cells and aberrant telomere shortening could be consequences of deranged chromosome stability factors In the fully developed syndrome, the patients have pancytopenia and the bone marrow is hypocellular The red cells are macrocytic with increased Hb F content that can precede marrow failure The usual diagnostic test for FA involves culturing peripheral blood lymphocytes in the presence of a DNA cross-linking agent such as diepoxybutane (DEB) In FA, the chromosomal metaphases show DNA repair abnormalities evidenced by a high proportion of chromatid breaks, gaps, and rearrangements and endoreduplications Androgen therapy improves the anemia in about two-thirds of patients, but most become resistant to the treatment over time Complications of synthetic androgen therapy include masculinization, severe acne, and hepatic damage (hepatic peliosis and liver tumors) Supportive treatment with red cell and platelet transfusions then is often required Total bone marrow failure with consequent death within a few years of its onset is the fate of most patients Longer survival of some patients with FA has unveiled a high cumulative incidence of myelodysplasia and leukemia, in the range of 10% over 25 years.5 Long-surviving patients are also 50 times more likely than normal to develop solid tumors involving particularly the esophagus and oropharynx.6 The prognosis is dismal in such cases Stem cell transplantation is the only cure for FA.7 However, because the cells of these patients cannot repair DNA damage, conditioning procedure with immunosuppressive agents and radiation must be modified with reduced intensity Cures have been obtained using HLA-compatible stem cells from siblings, and most recently with cord blood stem cells CHAPTER 10 PEDIATRIC BONE MARROW FAILURE SYNDROMES 187 CONGENITAL HYPOPLASTIC ANEMIA (DIAMOND-BLACKFAN ANEMIA, ERYTHROGENESIS IMPERFECTA) In 1938, Drs Louis K Diamond and Kernneth Blackfan described four children with severe, aregenerative, macrocytic anemia that developed in the first year of life The anemia was so severe that regular RBC transfusions were necessary to sustain life The other formed elements of the blood were normal, so it was classified as a “pure red cell anemia.” In the subsequent years more than 500 cases have been formally reported, but a current national registry includes more than 1000 cases.8 The disease appears in 2–7 per million live births Diamond-Blackfan anemia (DBA) affects most ethnic groups, but Caucasian children predominate among the reported cases Although repeat cases have been noted in a some families, suggesting a genetic cause, the preponderance of cases is sporadic.9 Although the cause of DBA has not been established in most cases, about 25% of patients studied to date have mutations involving RPS19, a ubiquitously expressed ribosomal protein required for efficient translation in all cells The mutations in DBA disrupt its normal localization in the nucleolus.10 In vitro experiments that disrupt production of RPS19 in hematopoietic precursor cells produce a phenotype very similar to that seen in DBA.11 Anemia (or pallor) is noteworthy at or shortly after birth, and instances of profound intrauterine anemia causing hydrops fetalis have been described Two-thirds of children are diagnosed by months and virtually all are identified before year of age At the time of diagnosis, hemoglobin levels can be as low as 2.0 g/dL The red cells are macrocytic with a higher than normal Hb F content The reticulocyte count is very low (