TAM, also called transient myeloproliferative disorder and transient leukaemia, is a haematological disorder virtually confined to Down syndrome and presents during fetal life or in the neonatal period. An identical disorder with the same natural history can also be found in neonates without Down syndrome but who have an acquired trisomy 21 confined to the haematopoietic cells.5
A similar, but distinct, disorder can be seen in some neonates with Noonan syndrome.6
However, true TAM is strictly associated with trisomy 21. The importance of TAM is its potential to transform into an acute leukaemia, known as myeloid leukaemia of Down syndrome (ML‐DS), which is estimated to occur in ~20–30% of babies with TAM, although the exact frequency is not known.7
TAM can therefore be considered as a leukaemic or “pre”‐leukaemic syndrome (reviewed by Zipursky7
). Clinically, TAM is conventionally defined by a combination of its haematological and clinical features (see box 2, and discussed in detail below). Using these criteria, about 10% of all newborns with Down syndrome have TAM. However, molecular genetic studies have recently shown that neonates with TAM have mutations in the key megakaryocyte transcription factor GATA1,9
which offers the opportunity to more accurately identify the true incidence of TAM in Down syndrome, since some infants with TAM do not have symptoms and may not previously have been diagnosed as having the condition. All cases of TAM should be referred to a paediatric haematologist because the neonate may need specialised intervention and also to ensure the appropriate tests are done to clinch the diagnosis (see below). Another reason for referral is that follow‐up is required as there is risk of the infant developing ML‐DS later.
Box 1 Haematological abnormalities in Down syndrome
- Transient abnormal myelopoiesis
- Non‐specific changes associated with intrauterine growth restriction and trisomies: neutropenia, thrombocytopenia, erythroblastosis and polycythaemia
- Subtle myelodysplastic features: abnormal myeloid cell granulation, giant platelets
Infants and children
- Myeloid leukaemia of Down syndrome
- Acute myeloid leukaemia
Other: many non‐malignant haematological abnormalities have been reported; their clinical importance remains to be defined. They include polycythaemia due to cardiac disease, reduced numbers of B lymphocytes3
TAM has a variable clinical presentation.7
Although it may occur during fetal life, it mostly presents after birth. During gestation it usually presents with hydrops fetalis and anaemia. There is often tissue infiltration with blast cells (hepatosplenomegaly and myocardial infiltration). The outlook for TAM presenting in fetal life seems to be poor compared with cases presenting after birth14
although spontaneous resolution of TAM in utero has been described.
After birth, a diagnosis of TAM can mostly be made simply on the basis of circulating blast cells with or without a mild leucocytosis.8
The remainder present with any combination of the following: hydrops, a greatly elevated white blood cell count with circulating blasts, bruising, skin infiltrates, exudative effusions (pleural, pericardial and ascites), respiratory distress and hepatomegaly. Liver dysfunction with jaundice may be severe and in rare cases leads to fatal hepatic failure secondary to fibrosis. However, most cases of TAM resolve spontaneously within 3 months after birth.
Box 2 Clinical and laboratory features of transient neonatal leukaemia in Down syndrome
- Pericardial effusion
- Pulmonary oedema
- Hepatic fibrosis
- Liver failure
- Obstructive jaundice
- Leucocytosis (but white blood cell count may be normal)
- Persistent peripheral blood blast cells
- Abnormal platelet count: often reduced or raised (but may be normal)
- Haemoglobin: may be reduced, raised or normal
- Skin rash (vesicopapular)
The haemoglobin level and neutrophil count are usually normal in TAM, but the platelet count is often abnormal—both thrombocytopenia and thrombocytosis are reported. The blood film may show nucleated red cells, giant platelets and megakaryocyte fragments. The characteristic and invariable feature on the blood film is the presence of deeply basophilic immature blast cells (fig 1B). These are usually indistinguishable from the blast cells that are seen frequently in preterm babies. However, they are present in greater numbers than in healthy neonates and, unlike blast cells in neonates without Down syndrome, TAM blast cells persist for several weeks or months. Therefore, although the diagnosis of TAM may not be clear in the first few days of life, particularly in a preterm baby, there is usually no diagnostic difficulty once the baby is a few weeks old.
One helpful investigation in doubtful cases is flow cytometry to characterise the immunophenotype of the blast cell population. Blast cells in TAM have been shown to express early myeloid (CD34, CD33), megakaryocyte (CD41, CD61) and erythroid (CD235a, glycophorin A) antigens and may express CD7 (a T‐cell antigen). Cytochemical stains can also be used to characterise the blast cells (they stain positive for acid phosphatases and non‐specific esterase and negative for myeloperoxidase, Sudan black, chloroacetate esterase and period acid–Schiff) but this test is rarely used in clinical practice now. Diagnostic difficulty is common in infants with phenotypically normal mosaic Down syndrome in which the only clue to the diagnosis is a blood film picture typical of TAM. Therefore any infant with blood film abnormalities suggestive of TAM should have cytogenetic analysis to look for trisomy 21. The bone marrow findings mirror those in blood, and add little where the diagnosis is indicated by clinical findings and examination of the blood.
Most children with TAM only need observation as the clinical and laboratory abnormalities spontaneously resolve within 3 months after birth. However, symptomatic babies, especially those with high blast counts or liver dysfunction may benefit from low‐dose cytosine arabinoside (10–20 mg/m2
/day for up to 7 days). As TAM blasts are highly sensitive to cytarabine, there is generally a rapid response. Severe liver disease, with fibrosis due to the production of megakaryocyte‐derived growth factor from blast cells, has a poor prognosis and may not respond to treatment. Despite resolution in most cases of TAM, up to 20% of infants who present to haematology centres still die of disease.8
Although 10% of neonates with Down syndrome are said to develop TAM and 10% of fetuses with Down syndrome die in utero, possibly due to TAM, the true incidence of TAM is unknown. Neonates with more subtle presentations of TAM probably escape notice as blood counts and smears are not routinely performed on all neonates with Down syndrome. To date, there have been retrospective studies1
and one small prospective study from a specialised paediatric unit (and not representative of the Down syndrome population as a whole)15
documenting blood cell abnormalities at birth. Thus, there is a need for a prospective study on a large population of unselected newborns with Down syndrome documenting full blood counts and blood films. Such studies are ongoing in the UK, USA, Ireland and Europe. The UK study, coordinated by Oxford and York, is currently recruiting centres. Further information about this study is available from the corresponding authors. Until data are available from these studies we recommend taking full blood counts and blood films in all neonates with Down syndrome.