Transient Abnormal Myelopoiesis (TAM) or Transient Myeloproliferative Disorder (TMD) is a pre-leukaemic syndrome that occurs in neonates or infants under 3 months of age and is characterised by the coexistence of trisomy 21 and a mutation in the GATA 1 gene [1].

Approximately 10% of newborns with trisomy 21 have TAM, with symptomatic forms allowing diagnosis, but also asymptomatic forms characterised by low levels of circulating blasts and identical genetic alterations [2]. The pathogenesis of this disease is still poorly understood, but is thought to be due to defects in fetal hepatic haematopoiesis caused by trisomy 21, in addition to acquired mutations in the GATA1 gene. GATA1 regulates the normal differentiation of megakaryocytes, erythroids, mast cells and eosinophils. The main mutations are located in exons 2 and 3.1 of the gene, resulting in the expression of a truncated GATA1s protein, which is found in all cases of TAM [3].

TAM can occur in a patient with a T21 phenotype, as the case in our observation, but also in a child with a normal phenotype with genetic mosaicism for T21 in the bone marrow [4]. 

The circumstances in which it is discovered are most often incidental or systematic during a polymalformative work-up.

Clinical manifestations vary from silent presentation with incidental diagnosis of haemogram and blood smear abnormalities to life-threatening complications. The diagnosis may be made during the clonal proliferation phase, at the time of complications, or during the spontaneous resolution phase. Therefore, it is important to systematically evaluate the haemogram and blood smear of every newborn with T21 [5].

Clinically, hepatomegaly and jaundice are the most common signs. Splenomegaly, skin lesions, pleurisy and pericarditis have also been described. Prolonged jaundice should raise suspicion of post-TAM hepatic fibrosis, which may be fatal [2].

Physical signs can be used to classify patients into different groups at risk of death. Three groups were identified. Patients without hepatomegaly or life-threatening complications were considered to be at low risk, with an overall survival rate of over 90%. Our patient with hepatomegaly alone was at intermediate risk. Patients with hepatomegaly and major complications were in the high-risk group [3]. Biologically, the main haematological abnormalities were hyperleukocytosis and high peripheral blasts, generally greater than 10%. Hyperleukocytosis is found in almost 50% of cases at the expense of neutrophils, myelocytes, monocytes and basophils [6-8].

Our patient presented with a severe hyperleukocytosis, which was detected with a significant peripheral blast count. There was also significant thrombocytosis. Variable platelet counts have been described in the literature. Abnormalities of fetal haematopoiesis in T21 include an increase in the number of megakaryocytic-erythroid precursors in the fetal liver and dysmegakaryopoiesis [9,10].

Anaemia is not common, but lower haemoglobin levels have been reported in newborns with TAM compared with newborns with T21 without TAM [7,8]. Blood cell abnormalities have been described in 20-25% of cases [4].

Megakaryoblastic blasts with basophilic cytoplasm, as in our patient, have been described in cases of TAM.  Chopra et al. described agranular circulating megakaryoblasts.  These different cytological characteristics were also found in our patient, although a wide variability in the morphology of the blasts was noted [6]. Similarly, immunophenotyping of the blasts shows variable profiles. They can show co-expression of stem cell markers (CD34 and CD117), myeloid markers (CD33/CD13), platelet glycoproteins (CD36, CD42, CD61) as well as CD56 and CD7 markers [11,12].

There is no consensus on the level of peripheral blasts required to diagnose TAM without identification of the GATA1 mutation [2]. Blast cells are found in the blood smear of the majority of patients with T21 and represent almost 15% of circulating leukocytes in neonates without the GATA1 mutation. Definitive diagnosis is based on the presence of more than 10% blasts associated with the presence of the GATA1 mutation [6].

This poses a challenge for the diagnosis of TAM, especially in resource-limited countries where genetic testing is difficult to access.

In our patient, the hepatomegaly resolved and haematological parameters returned to normal within the timescales described in the literature.  Spontaneous resolution is generally observed. Consequently, therapeutic management consists of a “wait and see” approach with close monitoring, as was the case in our patient. Medical treatment is only initiated in the event of major complications: hydrops, organ failure, disseminated intravascular coagulation, cholestasis [13]. This is a short course of cytarabine-based chemotherapy aimed at reducing the leukaemic burden to allow resolution of symptoms. Depending on the study, the doses used vary between 0.4 and 1.5 mg/kg, administered intravenously or subcutaneously for 4 to 12 days.  A reduction in complications and mortality has been reported with these protocols [8,14]. The majority of cases progress to spontaneous remission within 3 months of diagnosis. This is defined as complete resolution of symptoms, normalisation of haematological parameters and complete and permanent remission of the GATA1 mutation [2]. In 10-30% of cases, Transformation Disease (TD) progresses to Acute Myeloid Leukaemia (AML) within 5 years of diagnosis, with persistence of haematological abnormalities and acquisition of new oncogenic mutations. The median age of transformation was 16 months. Cytarabine treatment does not reduce the risk of progression to AML, for which the factors predicting transformation have not yet been elucidated [15,16].