Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome.код для вставкиСкачать
American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 142C:149 – 157 (2006) A R T I C L E Clinical Manifestations of Hematologic and Oncologic Disorders in Patients With Down Syndrome NATALIA DIXON,* PRIYA S. KISHNANI, AND SHERRI ZIMMERMAN Hematologic abnormalities are common in individuals with Down syndrome (DS). Increased erythrocyte mean corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in twothirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow failure disorders more challenging. Transient myeloproliferative disorder (TMD) associated with pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence of approximately 10%. In most cases, TMD regresses spontaneously within the first 3 months of life, but in some children, it can be life threatening or even fatal. Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20–30% of children with DS. The types of malignancy, response to therapy, and clinical outcome in children with DS are also unique. There is an increased risk of leukemia with an equal incidence of lymphoid and myeloid leukemia. Acute megakaryocytic leukemia (AMKL) subtype is the most common form of acute myeloid leukemia (AML) in this setting, and is uncommon in children without DS. Somatic mutations of the gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in children with DS. Myelodysplastic syndrome can precede AML. Children with DS and leukemia are more sensitive to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring for toxicity. Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma. ß 2006 Wiley-Liss, Inc. KEY WORDS: Down syndrome; chromosome 21; macrocytosis; transient myeloproliferative disorder; leukemia; solid tumor How to cite this article: Dixon N, Kishnani PS, Zimmerman S. 2006. Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome. Am J Med Genet Part C Semin Med Genet 142C:149–157. INTRODUCTION Hematologic and oncologic disorders account for approximately 1 to 2% of the medical complications in individuals with Down syndrome (DS). This review will provide an update to the already existent literature of the hematologic Dr. Dixon is a Pediatric Hematology–Oncology fellow at Duke University Medical Center. Currently she is investigating the prevalence of iron deficiency anemia in children with Down syndrome and the association between iron deficiency and behavioral problems in this patient population. She receives salary support from a National Institutes of Health training grant at Duke University Medical Center entitled: Research Training in Cancer Biology and Therapy. (Grant number 2T32 CA 09307) Dr. Kishnani is an Associate Professor in Pediatrics and Interim Chief of the Division of Medical Genetics at Duke University Medical Center. She is Co-Director of the Duke Comprehensive Down Syndrome clinic, established in 1995, which has an emphasis on continued care for patients with Down syndrome via a multidisciplinary approach. She is working with the other authors to establish the prevalence of iron deficiency anemia in Down syndrome and identify risk factors for its occurrence. Dr. Zimmerman is an Associate Professor of Pediatrics and Director of the Pediatric Hematology and Sickle Cell program at Duke University Medical Center. Her clinical interests include all aspects of non-malignant hematology, and her research focuses on the use of hydroxyurea and the prevention of stroke in children with sickle cell disease. She is working with Dr. Dixon and Dr. Kishnani to investigate the prevalence of iron deficiency anemia in children with Down syndrome. *Correspondence to: Natalia Dixon, M.D., Box 2916 DUMC, 222 Bell Building, Duke University Medical Center, Durham, NC 27710. E-mail: Natalia.Dixon@duke.edu DOI 10.1002/ajmg.c.30096 ß 2006 Wiley-Liss, Inc. and oncologic disorders that most commonly occur in patients with DS, including the diagnostic challenges based on variations in hematologic parameters seen in the DS population. The pathophysiology, relevant clinical features, treatment, and anticipatory guidelines for diagnosis and supervision of hematologic and oncologic disorders pertinent to individuals with DS will also be addressed. The association of GATA1 mutations with transient myeloproliferative disorders (TMD) and acute megakaryocytic leukemia (AMKL) in DS and findings of research on chemotherapy sensitivity in patients with DS are presented in this overview. HEMATOLOGIC FINDINGS Individuals with DS are more likely than typical children to develop 150 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c hematologic disorders. Abnormalities in any of the three hematopoietic cell lines can be seen and some of the abnormal hematologic findings can be associated with other medical complications frequently seen in individuals with DS. Polycythemia is a well-known consequence of cyanotic heart disease as a compensatory mechanism to increase oxygen-carrying capacity. Thrombocytopenia may also occur in the setting of cyanotic heart disease as a result of increased peripheral platelet destruction. However, polycythemia, thrombocytopenia, and other abnormal hematologic parameters such as an increased erythrocyte mean corpuscular volume (MCV) can present without other co-morbidities in DS. The etiology of these hematologic abnormalities is not completely understood but seems to be related to the presence of an extra chromosome 21. Newborns and infants with DS often present with hematologic abnormalities such as anemia or polycythemia, thrombocytopenia, or thrombocytosis, leukemoid reactions, and TMD. Both the American Academy of Pediatrics (AAP) and the Down Syndrome Medical Interest Group (DSMIG) recommend screening newborns with DS with a complete blood count to evaluate for myeloproliferative disorders, polycythemia, and thrombocytopenia [Cohen, 1999; AAP 2001]. ERYTHROCYTES The first year of life is a period when blood cell production undergoes developmental changes in all infants. Fetuses are exposed to a hypoxic environment in utero; this low oxygen tension leads to an increase in red blood cell production such that infants are born relatively polycythemic. During the first postnatal day, the hemoglobin values are generally 16–20 g/dl, but as the newborn breathes in a fully oxygenated environment, red cell production drops dramatically. The production of red blood cells drops 10fold by the end of the first week of life. The hemoglobin and hematocrit values tend to stabilize after this first week but then gradually decrease to a physiologic nadir by 6–10 weeks of life. Preterm infants have a more rapid drop in their red cell counts during the initial weeks of life due to a reduced red cell survival, and often as a result of iatrogenic blood loss. Polycythemia, defined as a venous hematocrit above 65%, is frequently found among infants with DS during the first week of life and can be present up to the age of 2 months, regardless of whether they have associated cyanotic congenital heart disease [Kivivuori et al., 1996]. It has been postulated that this high incidence of neonatal polycythemia might be due to a chronic fetal hypoxemia resulting in increased erythropoietin levels [Widness et al., 1994]. The natural history of polycythemia is usually benign, and the treatment of symptomatic polycythemia is controversial. Some infants may need an erythrocyte partial exchange transfusion if the hematocrit is above 70% and the infant develops symptoms. Despite an increased hemoglobin and hematocrit commonly seen in the first months of life, infants with DS show a similar physiologic nadir compared to infants without DS with a median hemoglobin concentration seen at its lowest around 10 weeks of age. In all infants, the erythrocyte MCV averages 135 fl at 24 weeks gestation and gradually decreases to an average of 119 fl at term. The mean corpuscular hemoglobin (MCH) tends to be elevated and the MCV is abnormally high in newborns with DS. This elevated MCV or macrocytosis persists throughout life in about two-thirds of individuals with DS. This high MCV has been found regardless of the presence of heart disease or hemoglobin and hematocrit values, suggesting that this finding is probably directly associated with DS [Starc, 1992]. The etiology and physiologic significance of the macrocytosis is unknown, although several theories have been presented for its cause, including high cellular turnover, enzymatic abnormalities, alterations in the erythrocyte membrane, and changes in the genetic control of erythrocyte development due to the extra chromosome 21 [Bartosz ARTICLE and Kedziora, 1983; Akin, 1988]. A few studies have evaluated RBC life span in individuals with DS with contradictory results. Two studies reported a shortened RBC life span [Naiman et al., 1965; Wachtel and Pueschel, 1991], and another study found normal circulating RBC life span [David et al., 1996]. Normal hemoglobin F, hemoglobin electrophoresis, vitamin B12, and folate levels have been reported in DS, suggesting that these are not factors causing macryocytosis [Ibarra et al., 1990; Wachtel and Pueschel, 1991; Roizen and Amarose, 1993; David et al., 1996]. As the MCV may not appear reduced compared to laboratory norms for the general population, a diagnosis of microcytic anemia, such as iron deficiency anemia, lead toxicity, or thalassemia is problematic and can be missed in individuals with DS. Iron deficiency (ID) is the most common nutritional deficiency and the leading cause of anemia worldwide. Iron deficiency (without anemia) develops when the iron stores are depleted and begin to impair hemoglobin synthesis but the child maintains a normal hemoglobin concentration. Iron deficiency anemia (IDA) results when the iron supply is not sufficient, resulting in a hemoglobin concentration two standard deviations (SD) below the mean for age and gender. Very little is known regarding ID/IDA in the DS population. Some investigators examined the serum iron and total iron binding capacity (TIBC) in a subset of patients with DS and found no significant differences when compared to age and gender-matched normal controls [Ibarra et al., 1990]. In another report, DS subjects with normal or elevated hemoglobin and MCV in the presence of low levels of serum iron, elevated TIBC, decreased transferrin saturation (TS), and serum ferritin, showed improvement in these parameters after adequate iron supplementation, indicating iron deficiency [Starc, 1992]. At the present time, there are no specific recommendations regarding testing for IDA in patients with DS. Current guidelines propose a hematocrit at 1 year of age, which is similar to what is recommended for the general ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c population. This screening may miss the diagnosis of ID or IDA because the increased MCVand MCH values found in DS can mask the microcytosis typically associated with IDA in the general population. Therefore, it may not be appropriate to use reference values for MCV and MCH levels derived from normal populations for individuals with DS. Additional screening tests may be necessary to make a diagnosis of ID/IDA in individuals with DS, including serum ferritin, serum iron, total iron binding capacity, transferrin saturation, and erythrocyte protoporphyrins. Early identification and treatment of ID/IDA in DS is of great importance; not only because it would allow for replacement of iron and prevention of progression of hematologic effects, but also because iron is required for many relevant central nervous system processes, the most well studied being myelination and dopaminergic functioning [Beard and Connor, 2003]. Human infants with IDA scored lower on tests of mental development administered before treatment than infants without anemia. The performance on developmental tests and their behavior after a 2 to 3-month course of iron did not show improvement in test scores, even though they had a good hematologic response to iron therapy [Lozoff et al., 1982]. In another study, the children who had moderate IDA as infants still had lower scores on tests of mental and motor functioning after 5 years of age. These differences remained statistically significant after controlling for a comprehensive set of background factors [Lozoff et al., 1991]. An ongoing prospective research study at Duke University is investigating ID and IDA in a cohort of children with DS followed at the Duke Comprehensive Down Syndrome Clinic to determine the prevalence of ID/IDA in this population, to define additional laboratory tests that could help make the diagnosis and to identify risk factors for its occurrence. Future studies will include formal neuropsychiatric evaluations before and after iron therapy [Dixon et al., 2006]. PLATELETS, THROMBOPHILIA, AND BLEEDING DISORDERS Isolated neonatal thrombocytopenia is a common finding in patients with DS. In most cases, the cause of thrombocytopenia is unclear. In the neonatal period, thrombocytopenia may result from either a decreased production of platelets in the bone marrow versus increased peripheral destruction or consumption of platelets. In some cases, both mechanisms occur simultaneously. Children with cyanotic congenital heart disease have an increased incidence of thrombocytopenia when the hematocrit level is above 65% [Wedemeyer et al., 1972]. Congenital heart disease is found in approximately 40–50% of children with DS, and only a small proportion of this is cyanotic heart disease. The degree of thrombocytopenia correlates with the severity of the polycythemia. Although the exact mechanism of thrombocytopenia in this setting is unknown, it has been postulated that hyperviscosity may lead to tissue hypoxemia, which then triggers a consumptive or destructive process leading to shortened platelet survival. Platelet production in the bone marrow has been demonstrated to be normal. Thrombocytopenia may also occur in newborn DS patients without congenital heart disease [Hord et al., 1995]. In most cases, the thrombocytopenia is transient and the platelet count rises into the normal range by 2 to 3 weeks of life. Infants with DS can also demonstrate profound thrombocytosis from the age of 6 weeks to the end of the first year of life [Kivivuori et al., 1996]; however, this elevated platelet count is not usually clinically significant. There are no reports of increased predisposition for thrombosis or bleeding disorders in individuals with DS. However, it is important to consider that polycythemia can lead to falsely elevated prothrombin time and activated partial thromboplastin time measurements. This is observed because of a relative excess of citrate, the anticoagulant used when the sample is collected, compared to the amount of plasma in the sample. 151 LEUKOCYTES Leukocyte counts tend to be slightly depressed in one-third of patients with DS compared to age-matched controls without DS [Akin, 1988; Roizen and Amarose, 1993]. Also, it has been recognized for many years that neonates with DS can have massive leukemoid reactions with elevation of the total leukocyte count greater than 50 103 cells/ml. In fact, phenotypically normal infants who exhibit leukemoid reactions within the first 2 months of life should have peripheral blood chromosome testing to rule out mosaic trisomy 21 [Weinberg et al., 1982]. These leukemoid reactions typically remit spontaneously. Despite relatively normal leukocyte counts, there is an increased mortality rate due to infections, primarily respiratory infections, in children with DS compared to the general pediatric population. The highest mortality occurs during the first year of life, but the overall mortality rate is increased as much as fivefold throughout the life span of patients with DS [Ganick, 1986]. This observation has prompted investigations of the immune system in DS, but thus far there are no consistent immune laboratory markers to explain the increased susceptibility to and mortality from infection. Abnormalities in circulating granulocyte and monocyte function have been demonstrated in some patients with DS. Neutrophils may have a lower mean lobe count and a reduced number of Barr bodies [Mittwoch, 1964]. In addition, peripheral blood monocytes and neutrophils may have reduced chemotaxis in vitro [Miller and Cosgriff, 1983]. Humoral and cellular immune function in children with DS includes variation in immunoglobulin levels, lymphocyte populations, and lymphocyte function. In children with DS who are younger than 6 years of age, the levels of serum immunoglobulins do not differ from healthy controls, but after age 6, elevated levels of IgG and IgA have been found. IgM levels decrease during adolescence and are lower than normal in the majority of DS adults [Burgio et al., 152 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 1975]. Patients with DS have a normal or slightly reduced proportion of CD4þ T-lymphocyte helper-cells [Burgio et al., 1983] and a marked imbalance in the CD4þ subpopulations has been documented. The percentage of suppressor-cytotoxic CD8þ lymphocytes is markedly increased. Evaluation of T-cell function in DS patients, using mitogeninduced proliferation of lymphocytes, has shown a normal reponse to phytohemagglutinin and concavalin A in the first decade of life and a progressive decline thereafter [Burgio et al., 1975]. APLASTIC ANEMIA Aplastic anemia is a bone marrow failure disorder characterized by marrow hypoplasia and peripheral pancytopenia. There are few case reports of idiopathic aplastic anemia in patients with DS, but it is not clear if a true association exists. TRANSIENT MYELOPROLIFERATIVE DISORDER TMD is a disorder found almost exclusively in newborns with DS, although its true incidence is unknown. Small series of patients have estimated an incidence of 10%, but this estimate could be falsely low because of the frequency of stillbirths caused by the disorder [Zipursky et al., 1997, 1999]. TMD results in abnormalities of one or more hematopoietic cell lines, and although its etiology is unclear, there is evidence that TMD represents a disorder of fetal liver hematopoiesis, with the process originating in utero. Fetuses have been diagnosed with TMD as early as 25 weeks gestation [Robertson et al., 2003], and there have been reports of prenatal diagnosis of fetal hydrops and hepatosplenomegaly in fetuses with DS [Smrcek et al., 2001]. The majority of patients present with TMD at birth or within the first few weeks of life and the time period of spontaneous remission correlates well with the timing of the switch from fetal liver to bone marrow hematopoiesis [Lange, 2000; Crispino, 2005a,b]. The pathophysiology of TMD is characterized by an uncontrolled proliferation of a clonal population of blasts often expressing megakaryocytic and sometimes erythroid markers. The clinical manifestations of TMD result from the accumulation of immature megakaryoblasts in the peripheral blood, liver, and bone marrow. Most commonly, infants with TMD present with anemia, thrombocytopenia, and blasts detected on the peripheral smear. Some infants who appear otherwise healthy may have hepatosplenomegaly or cutaneous infiltrates. TMD is not always benign, and may result in fetal hydrops from pronounced anemia and tissue infiltration by leukemic cells. This leads to serious pericardial, pleural, or peritoneal effusions, generalized edema and hepatosplenomegaly. For patients who develop multi-organ infiltration, particularly hepatic infiltration with resulting severe liver fibrosis, TMD may be life-threatening or even fatal. TMD can be distinguished from congenital acute leukemia primarily by its spontaneous resolution, typically in the first 3 months of life. The long-term prognosis of TMD is good with complete resolution in the majority of cases. In 20 to 30% of patients, however, TMD is a preleukemic disorder that predisposes to the development of AMKL within the first 4 years of life [Homans et al., 1993; Zipursky et al., 1994; Ma et al., 2001] suggesting that residual TMD blasts remain at a sub-clinical level after resolution. Currently, there are no identifiable clinical, hematological, or cytogenetic parameters that can predict if patients with TMD will subsequently develop AMKL. Infants with a history of TMD warrant close surveillance with blood counts every 3 to 6 months for the first few years of life and parental education must be provided regarding the presentation of AMKL. In most cases, management of TMD is conservative, with supportive care and no chemotherapy. Leukopheresis should be considered when the WBC count exceeds 200,000/ml to avoid complications from hyperleukocytosis [Nakagawa et al., 1988]. There is considerable controversy about which ARTICLE patients with TMD should be treated with cytotoxic therapy and when such therapy should be initiated. Some advocate that therapy should be considered in cases with progressive or persistent cholestatic liver disease or in patients with severe cardiopulmonary disease [Al-Kasim et al., 2002; Dormann et al., 2004]. Others recommend withholding this therapy until definitive progression of the leukemic process is observed or cytogenetic analysis suggests progression to acute myeloid leukemia (AML) [Avet-Loiseau et al., 1995]. At this point, treatment must be individualized based on the clinical manifestations, degree of organ dysfunction, co-morbid conditions, and clinical progression of cytopenias and organomegaly. Low-dose cytarabine therapy has been effective for treating TMD in some patients and should be considered for severe forms of the disease. ONCOLOGIC DISORDERS The distribution of malignant disorders among patients with DS shows a unique profile with an overrepresentation of some tumors. Malignancies that occur more frequently include: (1) leukemia, (2) gonadal and extragonadal germ cell tumors, and (3) perhaps retinoblastomas. Tumors that occur less frequently in patients with DS than in other patients include: (1) intracranial and peripheral nerve tissue tumors, (2) pediatric renal tumors, and (3) adult bronchial, nasopharyngeal, urinary, uterine, breast, and cutaneous carcinomas. ACUTE LEUKEMIA Children with DS have a 10 to 20-fold increased risk of developing leukemia. This risk extends into adulthood. The predisposition to develop leukemia is common not only in children with complete trisomy 21 but also in children with mosaic trisomy 21, who may or may not demonstrate other phenotypic abnormalities. There is an equal incidence of lymphoid and myeloid leukemias. This increased risk of leukemia suggests an important role of chromosome 21 in leukemogenesis. Genes ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c present on chromosome 21 that may be involved, include the ETS (ETS2 and ERG) gene family, interferon response genes, cystathionine beta synthetase, superoxide dismutase, and carbonyl reductase. The AML1 gene located on chromosome 21q22 is involved in 25% of childhood ALL and 15% of childhood AML cases and is a critical regulator of normal hematopoiesis. ACUTE MYELOID LEUKEMIA Most cases of AML in children with DS occur between the age of 1 and 5 years, with a median age at presentation of 2 years. AMKL subtype is the most common type of AML in these children. Children with DS are estimated to have a 500-fold increased risk of developing AMKL. Leukemic blasts in children with DS express the myeloid surface antigens CD33 and/or CD13 or CD11b, in addition to at least one platelet-associated antigen, such as CD41 or CD61. Cytogenetic abnormalities that commonly present in AML, such as t(8; 21), t(15; 17), inv (16), 5q-, or 7q-, are rarely found in DS children with AMKL. Similarly, the t(1; 22) (p13; q13) that occurs in AMKL in the absence of DS is not found in DS-AMKL [Lange et al., 1998]. DS is by far the most frequently encountered predisposing condition in childhood myelodysplastic syndrome (MDS). It occurs in 25% of patients with a morphological diagnosis of refractory anemia (RA), RA with excess of blasts (RAEB), or RAEB in transformation (RAEB-T) [Hasle et al., 1995, 1999, Hasle, 2001]. In 20 to 69% of AML cases in DS, MDS occurs first [Zipursky et al., 1992, 1997; Lange et al., 1998]. This MDS may present with cytopenias, most often thrombocytopenia and with increased macrocytosis. A bone examination is indicated when there is clinical or laboratory suspicion of MDS. Bone marrow morphological changes in patients with DS and MDS include dysplastic changes in both erythroid and megakaryoblastic precursors and increased number of megakaryocytes in the presence of thrombocytopenia suggesting ineffective thrombopoiesis. Frequently, there is significant fibrosis of the bone marrow, making it difficult or even impossible to obtain an adequate specimen by aspirate. A bone marrow biopsy is thus invaluable in assessing marrow cellularity and morphology and may be the only means of making a diagnosis in the presence of marrow fibrosis. The time of progression from MDS to AML ranges from several months to up to few years [Creutzig et al., 1996]. Based on morphologic examination, it is extremely difficult to differentiate MDS from AML in children with DS; therefore these entities are generally considered together, although by definition, AML requires >20% blasts in the bone marrow. It is probably wise to initiate therapy for MDS when repeated platelet transfusions or erythrocyte transfusions are required to control bleeding or to treat anemia rather than waiting for patients to meet criteria for a diagnosis of AML. Recently, somatic mutations in the gene encoding the hematopoetic growth factor GATA1 were detected exclusively and almost uniformly in all cases of TMD and AMKL of DS [Wechsler et al., 2002; Hitzler et al., 2003; Mundschau et al., 2003; Ahmed et al., 2004]. GATA1 encodes a transcription factor that is required for proper development of megakaryocytes, erythroid cells, mast cells, and eosinophils. GATA1 mutations have never been found in samples from DS patients with other leukemias, including ALL or non-AMKL. However, GATA1 mutations have been reported in children without DS who harbor trisomy 21 in their leukemic blasts [Rainis et al., 2003]. Some data support the theory that these mutations occur in a hematopoietic progenitor in the fetal liver [Crispino, 2005a,b]. Given that 20– 30% of patients with TMD eventually develop AMKL, it has been postulated that GATA1 mutations could be used as a stable molecular marker to monitor for the presence of minimal residual disease (MRD) after resolution of TMD, and to assess treatment response of DS-AMKL. Some investigators have reported the use of clone-specific GATA1 mutations and 153 quantitative PCR to monitor for MRD [Pine et al., 2005]. This may become an important clinical tool once such testing is more readily available. Patients with DS and AML have an increased sensitivity to cytarabine and daunorubicin [Taub and Ge, 2005]. DS myeloblasts are 10 times more sensitive to cytarabine than non-DS blasts and the intracellular concentration of cytarabine is significantly higher in DS myeloblasts. Cystathionine-b-synthetase and superoxide dismutase concentrations, measured by quantitative RT-PCR, were 12 times and 4 times higher, respectively in the blasts of patients with DS than in non-DS individuals. The cystathionineb-synthetase transcript level correlated with the in vitro cytarabine sensitivity and increased cystathionine-b-synthetase activity may contribute in modulating cytarabine metabolism [Taub et al., 1999]. Recently, decreased transcription of the gene encoding cytidine deaminase, a cytarabine-catabolizing enzyme, was demonstrated in blasts of individuals with DS. Decreased intracellular metabolism of cytarabine might account at least in part for increased drug sensitivity of AMKL in DS [Ge et al., 2004]. It has been postulated that GATA1 mutations may result in differential regulation of target genes, contributing to the increased cytarabine sensitivity and high event-free survival (EFS) rates of DSAMKL [Taub and Ge, 2005]. The most remarkable clinical feature of AML in DS patients is the extremely high EFS rates and lower rates of relapse compared to non-DS-AML. Cooperative group trials have shown that DS children with AML have a higher rate of remission and chance for EFS with lower doses of chemotherapy than non-DS children with AML [Lange et al., 1998]. The reason for these observations is unclear but likely results from biologic differences between nonDS-AML and DS-AML combined with differences in metabolism and tolerance of chemotherapy [Gamis, 2005]. Toxic deaths, rather than relapse, are more common events among patients with DS and AML. In addition, one Children’s Cancer Group (CCG) study demonstrated that there was no therapeutic gain 154 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c from bone marrow transplantation in children with DS in first remission because of increased toxicity. Stem cell transplantation, however, can be considered for those with recurrent disease [Lange et al., 1998]. Age has been reported to be a prognostic factor for DS-AML. Multivariate analysis of a prior clinical trial demonstrated that the only risk factor for relapse and worse survival was age at diagnosis of 2 years or older. The reason for the poorer outcome in the DS children older than 2 years of age was primarily resistant disease rather than toxicity [Gamis et al., 2003]. On the other hand, the karyotype of the leukemic blasts or an increased WBC at diagnosis are not prognostic factors in DS-AML, since even patients with DSAML who had monosomy 7 in the leukemic blasts, which is an unfavorable prognostic factor in non-DS-AML, had responsive disease [Lange et al., 1998; Gamis et al., 2003]. Current studies seek to improve the treatment of DS-AML by maintaining the high EFS while decreasing treatment-related toxicity. ACUTE LYMPHOBLASTIC LEUKEMIA Acute lymphoblastic leukemia (ALL) in DS presents in older children, with a peak frequency from 3 to 6 years of age. ALL in children with DS is not very different from ALL in non-DS patients, however, some clinical differences have been observed. ALL in DS very rarely presents prior to age 1 year. Children with DS and ALL also have been noted to have a modestly lower mean platelet count at diagnosis, and are less likely to present with splenomegaly, lymphadenopathy, a mediastinal mass, and perhaps CNS involvement. Leukemic blasts with a T-cell immunophenotype and hyperdiploidy greater than 50 chromosomes have been observed less frequently in patients with DS-ALL when compared to non-DS-ALL [Lange, 2000; Whitlock et al., 2005]. The most frequent cytogenetic abnormality in childhood ALL, t(12;21) (p13;q22), which results in TEL/AML1 rearrangement, and other common translocations seen in non-DS-ALL such as, t(1;19)(q23;p13), are infrequently seen in children with DS [Pui et al., 1993; Lanza et al., 1997; Lange, 2000]. The leukemic cells from patients with DS have been found to lack t(9; 22) and t(4; 11), translocations that are generally associated with a poor prognosis in patients with non-DS-ALL [Lange, 2000; Whitlock et al., 2005]. Alternatively, rare cytogenetic abnormalities like t(8;14)(q11;32), and an extra X chromosome, may be more common in DS-ALL [Pui et al., 1993]. A unique feature of patients with DS and ALL is the increased sensitivity to methotrexate therapy. Methotrexate treatment-related toxicity is more severe in individuals with DS and manifests primarily as mucositis and profound bone marrow suppression. This sensitivity may derive from gene dosage effects on chromosome 21. Three enzymes implicated in purine metabolism map to chromosome 21 and it is postulated that an elevated rate of purine synthesis resulting from increased activity of these genes confer a higher demand for tetrahydrofolates and a greater sensitivity to antifolate agents such as methotrexate [Blatt et al., 1986; Belkov et al., 1999]. There appears to be a direct relationship between chromosome 21 and methotrexate therapy for both DS and non-DS-ALL patients. The reduced folate carrier gene, localized on chromosome 21, encodes the transmembrane protein which transports intracellularly reduced folates including methotrexate. Hyperdiploid acute lymphoblastic cells with extra copies of chromosome 21, have an increased expression of the reduced folate carrier gene and intracellular transport of methotrexate, therefore, generating higher levels of the active methotrexate metabolite. The high expression of the reduced folate carrier gene may also account for increased methotrexate-associated toxicity of DSALL, and its expression in various body tissues including the gastrointestinal tract, may further contribute to the methotrexate toxicity in patients with DS [Taub and Ge, 2005]. In contrast to the superior outcome of DS-AML, DS children with ALL ARTICLE have a worse outcome than non-DS children with ALL. A recently published study demonstrated that children with DS-ALL treated on the CCG trials had decreased overall survival (OS), EFS, and disease free survival (DFS) when compared with non-DS children with ALL. In this study, the authors reported that DS children with ALL were less likely to attain remission by day 28 of chemotherapy [Whitlock et al., 2005]. Other authors observed a significantly higher risk of death during induction for DSALL patients compared with non-DSALL patients, with most deaths due to infections [Robinson et al., 1984]. It has been recognized for years that the prognosis of childhood ALL is better for patients who have standard-risk ALL (SR ALL) compared to patients who have high-risk ALL (HR ALL). SR ALL is defined as having an age at diagnosis between 1 and 9 years and an initial WBC of less than 50,000/ml, and HR ALL as having an age at diagnosis of less than age 1 year or older than 10 years, or an initial WBC count greater than 50,000/ml. In recently published data, DS children with SR ALL had a worse outcome when compared with non-DS with SR ALL and children with HR ALL had similar outcomes regardless of whether they had DS [Whitlock et al., 2005]. Intensive therapy in patients with HR ALL has resulted in an outcome comparable with non-DS ALL. Delivery of intensive therapy is thus warranted to treat HR ALL in DS patients, with careful attention to complications such as mucositis and infections. Dose reductions in chemotherapy agents in the DSALL population due to concerns of toxicities may adversely affect the outcome and thus should be avoided in the absence of chemotherapy intolerance. New strategies need to be developed for DS ALL patients who have standard risk features [Whitlock et al., 2005]. SOLID TUMORS Solid tumors are infrequently reported in patients with DS. The reduced risk to develop solid tumors in these individuals occurs across the life-span, with no ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c significant change with age [Hasle et al., 2000; Hasle, 2001]. Some solid tumors, including neuroblastomas and Wilms tumors, are unusually rare in children with DS [Satgé et al., 1998b]. The infrequency of neuroblastoma in DS may be due to an overproduction of the chromosome 21 coded S-100 b protein. This protein induces differentiation of neural cells and inhibition of growth of neuroblastoma cell lines in vitro [Satgé et al., 1998a]. There are case reports of patients with DS and retinoblastoma and some authors support an association between DS and this type of tumor. Two large population-based studies looked at the standardized incidence ratio (SIR) of cancer in individuals with DS. One study reported higher than expected numbers of retinoblastomas but without a statistically significant increase in the SIR [Hasle et al., 2000]. The other study found no cases of eye tumors among the DS population [Patja et al., 2006]. Some investigators have suggested that DS may predispose to other neoplasms of the hematopoietic tissue including lymphoma, with a predominance of Hodgkin disease [Satgé et al., 1998b]. Other studies have found no significant increase in cases of lymphoma among patients with DS [Hasle et al., 2000; Patja et al., 2006]. Breast cancer is the most common malignancy in women; however, very few cases have been reported in women with DS with a frequency nearly 10-fold less than in the general population [Satgé and Sasco, 2002]. Women with DS experience earlier menopause [Schuypf et al., 1996; Roizen and Patterson, 2003], which could explain the decreased risk for breast cancer. Another reason could be lack of systematic longitudinal studies. Although the risk for breast cancer is low among women with DS, general screening guidelines for breast cancer surveillance should be the same as in the general population. The current recommendation for women with DS over 18 years of age is a yearly clinical breast examination [Cohen, 1999]. There is no consensus on the age at baseline mammogram screening. There are two different recommendations: a mammogram every other year beginning at age 40, and yearly beginning at age 50 [Chicoine et al., 1994]; the other recommendation is yearly mammogram screening beginning at age 50, unless there is a first-degree relative with breast cancer [Heaton, 1995]. The prevalence of gynecologic malignancies such as genital cancer appears to be lower in women with DS [Patja et al., 2006]. Screening guidelines have been developed by the DSMIG [Cohen, 1999]. Physicians who take care of patients with DS should follow these recommendations. GERM CELL TUMORS Testicular cancer, particularly testicular germ cell tumors, with a predominance of seminomas has been reported in DS. In the general population, testicular tumors occur at an incidence rate of 4 cases per 100,000 person-years. In one study, the risk of testicular cancer in individuals with DS was reported to be approximately 50-fold higher, and another study reported a 5-fold increase in the risk to develop testicular cancer than the general population [Satgé et al., 1997; Patja et al., 2006]. Currently, the mechanism of this increased risk is not well understood. Cryptorchidism and hypogonadism have been implicated as risk factors. An excess of luteinizing hormone and follicle-stimulating hormone gonadotropins and overexpression of ETS2 gene through gene dosage effect could also predispose patients with DS to the development of testicular germ cell tumors [Satgé et al., 1997]. Testicular tumors can occur at very early ages and close surveillance of the gonads of male patients with DS is critical. An annual testicular examination is recommended [Smith, 2001]. Non-gonadal abdominal germ cell tumors as well as a high proportion of intracranial germ cell tumors in patients with DS have been reported suggesting that individuals with DS may be prone to abnormal proliferation of germ cells in different locations. 155 CONCLUSIONS Some hematologic disorders are more common in children with DS than in other children, particularly in the first year of life. Newborns frequently have polycythemia or transient thrombocytopenia. Thrombocytosis can be seen from age 6 weeks until the end of the first year of life. WBC and neutrophil counts are in the low normal range among patients with DS. These variations in the WBC, platelets, and hemoglobin should be taken into consideration when interpreting the results of laboratory tests performed in these individuals. When screening children with DS for iron deficiency anemia, it should be noted that the baseline MCV is elevated in two-third of these individuals, potentially masking the diagnosis of iron deficiency and other microcytic anemias. Norms for hematologic parameters need to be established for patients with DS at different ages. TMD is morphologically indistinguishable from AMKL; it is often asymptomatic, resolving spontaneously without treatment. In 20 to 30 percent of patients with DS and TMD, AML may occur later in childhood. Children who develop TMD need to be monitored very closely with complete blood counts for several years after the onset of the TMD. There is an overall increased leukemia risk among patients with DS. AMKL is the most common subtype of AML seen in the DS population and is frequently preceded by a history of MDS. A bone marrow aspirate can be difficult to obtain due to the fibrosis commonly seen in these patients; therefore a bone marrow biopsy is invaluable in assessing marrow cellularity and morphology. The cytotoxic drug sensitivity in individuals with DS is increased when compared to the general population and should be taken into consideration prior to start chemotherapy. The recent discovery of somatic mutations involving the gene encoding the hematopoietic growth factor GATA1 has been a significant advance in the understanding of the biology of TMD/ AMKL in DS. 156 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c GATA1 mutations could be used as a molecular target useful to monitor MRD in TMD and AMKL. Prospective studies are needed to assess the clinical relevance of this new tool and to compare the sensitivity between bone marrow and peripheral blood samples. Also, future studies will provide an assessment of GATA1 mutations in children with DS of all ages and with AML subtypes. DS is associated with an increased risk of hematopoietic malignancies in childhood and a marked decrease in the risk for solid tumors at all ages with the exception of germ-cell tumors, and perhaps retinoblastoma and lymphoma. More studies are needed to establish the true link between DS and these types of tumors. Although the reported risk for solid tumors is lower among patients with DS, cancer screening should follow the same standard guidelines as used in the general population. There is limited information on many aspects of hematologic and oncologic disorders in patients with DS. 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