Down syndrome and leukemia
Down syndrome, also known as Trisomy 21, is a genetic condition characterized by the presence of three copies of chromosome 21, leading to developmental and physical differences. Individuals with Down syndrome face a significantly increased risk of developing certain types of leukemia, a form of blood cancer affecting white blood cells. Specifically, they are 10 to 20 times more likely to develop leukemia than the general population, with notable types including acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and megakaryoblastic leukemia, including transient leukemia (TL) and acute megakaryoblastic leukemia (AMKL).
Research indicates that approximately 10% of newborns with Down syndrome may develop TL, which typically resolves without chemotherapy, while those with TL have a 20 to 30% chance of later developing AMKL. Symptoms of leukemia in children with Down syndrome may include fatigue, fever, bruising, and enlarged lymph nodes, among others. Treatment options typically involve chemotherapy, with careful monitoring due to their heightened sensitivity to certain drugs. Despite the increased risk of leukemia, children with Down syndrome often have higher cure rates for AML and AMKL compared to their peers without the condition, although they may experience higher relapse rates. Understanding the connection between Down syndrome and leukemia remains a focus of ongoing research.
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Down syndrome and leukemia
ALSO KNOWN AS: Trisomy 21 and cancer of white blood cells
RELATED CONDITIONS: Transient leukemia (TL), transient myeloproliferative disorder, transient abnormal myelopoiesis
DEFINITION: In Down syndrome, the individual has three copies of chromosome 21 instead of two. Those with Down syndrome are at a significant risk of developing certain forms of leukemia, a blood cancer in which cancerous changes take place in marrow cells that form lymphocytes (white blood cells).
Risk factors: Children with Down syndrome have a ten to twenty times greater risk of developing leukemia. The types of leukemia they may develop are acute lymphocytic leukemia (ALL) (acute lymphoblastic leukemia), acute myeloid leukemia (AML), and two types of megakaryoblastic leukemia—transient leukemia (TL), a leukemia-like condition that occurs within the first month of life and may resolve without chemotherapy, and acute megakaryoblastic leukemia (AMKL). In 2000, Alvin Zipursky reported in Pediatric Research that children with Down syndrome have a five hundred times greater risk of developing AMKL than other children and that some 10 percent of newborns with Down syndrome develop TL. Further research indicated individuals with Down syndrome constitute about 2 percent of all pediatric ALL and 10 percent of pediatric AML cases. Additionally, individuals with Down syndrome are at a higher risk for developing B-cell acute lymphoblastic leukemia.
Etiology and the disease process: In TL and AMKL, blasts (immature blood cells) accumulate in blood and bone marrow, and white blood cell differentiation is abnormal. TL in the newborn goes into remission within a few months. Of those with TL, 20 to 30 percent will develop AMKL later in life. Although the relationship between Down syndrome and increased risk for leukemia is not understood, it has been observed that as well as having trisomy for chromosome 21, children who develop TL have mutations in the transcription factor GATA1, which plays an important role in the normal development of red blood cells, megakaryocytic, and basophilic cell lines. The GATA1 gene (also known as a hematopoietic growth factor) is on the X chromosome. It is thought that additional mutations must occur for AMKL to develop.
Incidence: The incidence of Down syndrome is about 1 in 750. Children born with Down syndrome are 33 percent more likely to develop ALL and 150 times more likely to develop AML. About 2 percent of children with Down syndrome will develop leukemia by age five and 2.7 percent will develop leukemia by age 30.
Symptoms: As with other leukemias, the symptoms associated with Down syndrome leukemias include fatigue, fever, infection, skin pallor, bruising, bleeding, difficulty in wound healing, enlarged lymph nodes, and joint pain.
Screening and diagnosis: Blood is analyzed in children with Down syndrome to test for signs of leukemia. In patients with Down syndrome with TL, analysis of blood and bone marrow shows variable numbers of blasts. The acute leukemia cell produces nonfunctional leukemia cells that crowd out normal cells.
Treatment and therapy: Children with Down syndrome and leukemia are typically treated with chemotherapy combined with central nervous system prophylaxis therapy with intrathecal chemotherapy. Blasts of Down syndrome TL are sensitive to low doses of cytosine arabinoside. Children with Down syndrome and leukemia are more sensitive than other children to some drugs used in chemotherapy, such as methotrexate, so children with Down syndrome must be carefully monitored for drug toxicity. Children over the age of four with Down syndrome can be treated in the same way as children without the syndrome. Other treatments include stem cell transplants, immunotherapy, biologics, and radiotherapy.
Prognosis, prevention, and outcomes: Down syndrome TL neonates have a 15 percent risk of developing a potentially fatal liver disease and an increased risk of developing cardiopulmonary failure and spleen necrosis. Though children with Down syndrome are at an increased risk of developing leukemias, they have a reduced risk of developing solid tumors. Children with Down syndrome have much higher cure rates for AML and AMKL than children in the general population—an 80 to 100 percent cure rate for AMKL and a 75 percent cure rate for AML. However, for those with ALL, the cure rate is 60 to 70 percent rather than the general population's 70 to 85 percent cure rate. Additionally, children with Down syndrome have a higher relapse rate than other children.
Bibliography
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"Down Syndrome." National Library of Medicine, 8 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK526016. Accessed 20 June 2024.
Kaneshiro, Neil K. "Down Syndrome." MedlinePlus, 26 Jan 2024, medlineplus.gov/downsyndrome.html. Accessed 20 June 2024.
Lane, A. A., et al. "Triplication of a 21q22 Region Contributes to B Cell Transformation through HMGN1 Overexpression and Loss of Histone H3 Lys27 Trimethylation." Nature Genetics, vol. 46, no. 6, 2014, pp. 618–623. doi:10.1038/ng.2949.
"Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ(R)): Children with Down Syndrome." National Health Institute, 5 June 2024, www.cancer.gov/types/leukemia/patient/child-aml-treatment-pdq#‗390. Accessed 20 June 2024.