They include

• Transient abnormal myelopoiesis
• Down Syndrome associated Acute leukemias
• MDS with thrombocytopenia
• Aplastic anemia

Transient abnormal myelopoiesis (TAM)

Introduction:

• Clonal disorder with presence of circulating megakaryoblasts and dysplastic changes in peripheral blood.
• It has myeloproliferative picture with large number of circulating blasts. Morphologically it is indistinguishable from acute megakaryoblastic leukemia.
• Disappears spontaneously over several weeks to 3 months in >90% patients
• In 20-30% of TAM patients, acute megakayoblastic leukemia develops at 1-3 years of age.

Epidemiology:

• Seen in 25-30% newborns with Down syndrome

Pathogenesis:

• Hypothesis- TAM originates in primitive cell of fetal hepatic haematopoiesis. The cell involutes and is replaced by normal marrow blast cells.
• Associated with acquired or constitutional GATA 1 mutation

Clinical features:

• Presents with thrombocytopenia and hepatosplenomegaly.
• This disease originates in liver, hence most of the patients have hepatomegaly. 
• Some have skin nodules, splenomegaly, jaundice and pericardial effusion.

Complications:

• Cardiopulmonary failure
• Hyperviscosity
• Splenic necrosis
• Progressive hepatic fibrosis

Investigations:

• Peripheral smear: Variable number of blasts (often less than 20%) are seen
• Bone marrow may not be involved.
• Immunophenotyping
  • Positive- CD34, CD56, CD117, CD13, CD33, CD7, CD4dim, CD41, CD42, TPO-R, IL-3R, CD36, CD61, CD71, CD235a
  • Negative- MPO, CD15, CD14, Glycophorin A
• GATA-1 mutation can be done by NGS

Criteria for diagnosis:

Essential:

• Confirmation of constitutional trisomy 21.
• Peripheral blood leukocytosis with increased blasts
• Detection of exon 2/3 GATA1 mutation (GATA1)

Prognosis:

• Poor prognostic markers include:
  • Preterm delivery
  • Ascites
  • TLC >1lac/cmm
  • Hepatomegaly
  • Coagulopathy

Indications for treatment:

• Severe hepatic dysfunction
• Very high WBC count (>1,00,000/cmm)
• Hydrops fetalis
• Multi-organ failure
• Splenomegaly beyond umbilicus
• Pleural/ pericardial effusion
• Renal failure
• DIC

Treatment:

• Very low dose cytarabine as blasts are extremely sensitive to cytarabine. Dose- 0.5-1.5mg/Kg- BD- daily for 5-7 days.
• Repeat doses may be given if severe liver dysfunction persists. But hepatomegaly may take months to resolve, hence hepatomegaly is not an indication for 2^nd course of cytarabine.

Down Syndrome associated Acute leukemias

• Patients with Down syndrome have 10-100-fold higher risk of leukemias
• Leukemias are seen usually at age <5 years
• Acute megakaryobastic leukemia- Seen in 20-30% patients with TAM. 
• Criteria for diagnosis of ML-DS:
  • Essential:
    • Confirmation of constitutional trisomy 21.
    • Myeloid neoplasm with persistent increased peripheral blood and/or bone marrow blasts (may be <20%).
    • Detection of exon 2/3 GATA1 mutation.
  • Desirable:
    • Mutation profiling and detection of mutations in other genes, e.g. cohesion complex, EZH2, KANSL1 and/or JAK3.
• ML-DS has better prognosis than AML in children without Down syndrome. Overall survival rate- 90%.
• Treatment: These cases respond well to chemotherapy. There are Down syndrome specific protocols which are available.
• Other AML or ALL also can occur in Children with Down syndrome

MDS with thrombocytopenia

• Often associated with trisomy 8 or monosomy 7

Aplastic anemia- Rare

Recent advances:

Inherent genome instability underlies trisomy 21-associated myeloid malignancies

Constitutional trisomy 21 (T21) is linked with a high incidence of childhood acute myeloid leukemia (AML) and is preceded by transient abnormal myelopoiesis (TAM) triggered by GATA1s mutations. Our study suggests individuals with T21 have increased chromosomal copy number variations (CNVs), indicating genome instability in hematopoietic lineages, which predisposes them to TAM and AML. GATA1s mutations further augment genome instability in T21 hematopoietic progenitor cells (HPCs). Elevated dosage of the chr21 gene DYRK1A impairs DNA repair, promoting leukemogenic mutations. 

https://doi.org/10.1038/s41375-024-02151-8