Leukemogenesis in Infants and Young Children With Trisomy 21 - A Complete Guide

Introduction:

Chromosomal abnormalities are a common cause of disability and discomfort experienced by newborn infants and young children all around the world. Among such chromosomal disorders, trisomy 21 or Down’s syndrome is the most common. It is said that Down’s syndrome affects one in every 700 children born in the world. Being such a common disability, leukemogenesis is often noted in such children.

What Is Trisomy 21?

Trisomy 21 (Down’s syndrome) is a genetic abnormality affecting the 21st chromosome of the human body. In this syndrome, there is an extra number of the 21st chromosome. This manifests as several ailments affecting the physical, mental, emotional, and social stability of disabled kids.

Common Clinical Features Observed Are:

• Flat facial profile.

• Slanting eyes.

• Flat nasal bridge.

• Hypotonic muscles.

• Loss of muscle rigidity - leading to developmental delays.

• Short stature.

• Small discolorations in the iris of the eye.

• Cognitive disability.

• Lack of memory power.

• Impaired learning process.

• Vision problems.

• Extremely sensitive to emotions and other stimuli.

• Dementia.

• Premature aging.

Medical Conditions Associated With Trisomy 21 (Down Syndrome):

• Congenital heart defects.

• Hirschsprung disease.

• Gastroesophageal reflux disease.

• Diabetes mellitus.

• Atresia of the gastrointestinal tract.

• Hypothyroidism.

• Increased incidence of infectious diseases.

While all these medical conditions are common in children with Down syndrome, there can be a rare occurrence of leukemia.

What Is Leukemogenesis?

Leukemogenesis is a pathological process that occurs in the human body when normal cells tend to undergo transformation to form malignant cells. This results in the causation of a neoplastic condition called leukemia. This occurs when the biological processes in the body undergo derangement. In leukemogenesis, leukocyte formation and proliferation (white blood cells) are excessive and abnormal. The method of leukemogenesis involves multiple genetic and other molecular-level changes that cause the shift or conversion of normal hematopoietic stem cells or progenitor cells into leukemic cells. Aberrations in the chromosomal pattern due to deletion, translocation, or addition can cause normal bone marrow stem cells to grow abnormally. This also activates the oncogenes in the blood and reduces the action of tumor suppressor genes.

What Is Leukemogenesis in Trisomy 21?

In cases of Trisomy 21 or Down syndrome, several genetic, chromosomal, as well as environmental factors interplay together to induce the process of leukemogenesis. Among the various types of leukemia, acute megakaryoblastic leukemia (AMKL) is the most common subtype noticed in children with Down syndrome.

In Down syndrome, the additional 21st chromosome alters the cellular biological process, including hematopoiesis. This is because there is an alteration in the expression of involved genes. Among these genes, the GATA1 gene is of particular significance in leukemogenesis. GATA1 is a gene (transcription factor) responsible for normal hematopoietic development, specifically in megakaryocytic and erythroid lineages. In children with Trisomy 21, mutations in the GATA1 gene, known as GATA1s mutations, are nearly present in all cases of AMKL. These mutations disrupt normal megakaryocytic differentiation and contribute to leukemic transformation.

The increased expression of these genes can dysregulate cellular pathways involved in hematopoietic development, leading to aberrant proliferation and survival of leukemic cells. Additionally, alterations in the bone marrow microenvironment, such as abnormal cytokine signaling and impaired immune surveillance, may create an environment in the body for leukemic growth in individuals with Trisomy 21.

The process of this gene alteration and leukemogenesis starts right from the stage of intrauterine growth. The age-dependent nature of leukemia development in children with Down syndrome suggests that leukemogenesis begins in utero or during early fetal development. Studies have shown that hematopoietic cells from individuals with Trisomy 21 exhibit intrinsic differences in gene expression patterns and functional properties compared to cells without Trisomy 21. These inherent differences may predispose individuals with Down syndrome to leukemic transformation and contribute to the increased incidence of leukemia in this population.

What Are the Clinical Implications of Leukemogenesis in Infants With Trisomy 21?

• Every individual with Down syndrome should be evaluated for leukemogenic changes in the genes. This includes hematological investigations like complete blood count and peripheral blood smear to identify leukemic cells.

• Clinical features like easy bruising, petechiae, or rashes should be considered potential symptoms of leukemic changes in the body.

• Differential diagnosis should be carefully considered as children with Down syndrome are susceptible to developing simultaneous medical conditions.

• Treatment planning is also different for individuals with Down syndrome as the drug metabolism and toxicity can vary in this population. Chemotherapy is the main treatment option. Hematopoietic stem cell transplantation may be given as an option for suitable infants with Trisomy 21 and leukemia.

• Regular bone marrow assessments should be done for such infants and young children.

• Along with medical intervention, psychological therapies targeting the rehabilitation of mental and emotional health become essential.

Specific Treatment for Leukemia in Trisomy 21 Individuals:

• Chemotherapeutic agents, such as Cytarabine, anthracyclines (for example, Daunorubicin, Idarubicin), Etoposide, and Thioguanine, are commonly used in induction, consolidation, and maintenance phases of treatment.

• Close monitoring of treatment response and management of treatment-related toxicities, such as myelosuppression, infection, and gastrointestinal symptoms, are integral components of chemotherapy management.

• Since Trisomy 21 individuals are also susceptible to developing many infectious diseases due to reduced defense mechanisms in the body, regular antibiotic administration is necessary.

• Growth factor supports to stimulate the production of leukocytes are also given along with antibiotics.

• HSCT may be considered for infants with Trisomy 21 and AMKL who have high-risk disease features, refractory disease, or relapsed leukemia.

• HSCT is a process where hematopoietic stem cells from a compatible donor (allogeneic transplant) are infused to restore normal hematopoiesis and eradicate leukemic cells. However, post-transplantation care is of utmost importance in children with Down syndrome and leukemia. Strict prophylactic measures to prevent transplant rejection are necessary as it is the only modality for curing the condition.

• Emerging targeted therapies, such as tyrosine kinase inhibitors (Imatinib and Dasatinib), may hold promise for treating AMKL with specific genetic abnormalities, such as rearrangements involving the platelet-derived growth factor receptor alpha (PDGFRA) gene.

Conclusion:

Research is necessary as therapy targeting the leukemic cells should be suitable for children with Down syndrome. By elucidating the molecular pathways driving leukemia in individuals with Trisomy 21, clinicians and researchers can develop targeted therapies and personalized treatment approaches. Integrating basic science knowledge with a clinical approach is essential in such children.