Our Second Christmas Cracker: Summary

The first clinical information we gave you is this blood film:

TAM2

You all felt that this film was very worrying and pointed out the numerous blasts, megakarytocyte fragments and abnormal nucleated erythrocytes.

When we revealed that this was a newborn baby your anxiety levels jumped a little further! We also established that she had marked hepatomegaly. A few people asked a very pertinent question – does the baby have a chromosomal disorder?

This is a classic case of Transient Abnormal Myelopoiesis (TAM) aka Transient Myeloproliferative Disorder (TMD).

This is a haematological disorder unique to infants with Down Syndrome (Trisomy 21). The film appearances are indistinguishable from AML, but for the megakaryocyte fragments which are frequently found and are seen on this film.

The differential diagnosis for ‘leukaemia’ in a newborn includes:

–leukaemoid reaction

–true congenital leukaemia (super rare)

–congenital infections

–erytroblastosis fetalis (aka HDFN)

TAM is present at birth. Hepatic infiltration is the major clinical issue and can be life-threatening, particularly due to respiratory compromise as a result of the organomegaly. In addition the infants may also experience liver or renal impairment, DIC and cardiac failure.

TAM AML
Blast ratio BM:PB PB>BM BM>PB
Organomegaly Hepatomegaly common Less common

TAM usually resolves spontaneously within 2 months. Chemotherapy is occasionally indicated in TAM when organomegaly is causing significant compromise. Low dose cytarabine is started until symptoms are ameliorated and patient is clinically stable. Overall mortality in TAMs patients is about 20%, but only 10% die from TAM related causes; congenital defects (eg cardiac) is the cause of death in the rest.

However although TAM is indeed transient, approximately 25% of TAM infants will develop AML by the age of 3. Children with Down Syndrome have a HIGHER cure rate for AML than the general paediatric population (but a lower cure rate for ALL). In fact the cure rate for AML in  Down Sydnrome children aged less than 4 is >80% .

TAM seems to require the presence of two genetic abnormalities – Trisomy 21 and a mutation in GATA1, a transcription factor that regulates erythroid and megakaryocytic differentiation. The precise interaction of these defects is unclear. About 4% of children with Down Syndrome will have a GATA1 mutation (found on the X chromosome) but only 10% of those with the mutation develop TAM or AMKL.

The GATA1 mutation seems to increase blast sensitivity to cytarabine and daunorubicin and explains why young Down Syndrome patients have a higher cure rate. In older Down syndrome patients (>4) the mutation is NOT normally seen and cure rates drop down to approx 35%.

By contrast ALL is not associated with the GATA1 mutation and the blasts are no more chemo-sensitive. Children with Down Syndrome are less likely to have favourable cytogenetics (High hyperdiploidy or RUNX1) than normal kids. There is also an increased rate of JAK2 mutations in Downs-associated ALL.

Infants with Down Syndrome struggle more with chemotherapy -related toxicity in a number of ways:

  1. Increased risk of cardiac toxicity with antracyclines.
  2. Increased rates of sepsis, partly due to hyperglycaemia
  3. Increased rates of MTX toxicity – need to use lower doses.

REFERENCES

 

About TeamHaem

Online education and discussion about all things haematological
This entry was posted in Acute leukaemia, Laboratory morphology, Paediatric haematology and tagged . Bookmark the permalink.

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