Transient Abnormal Myelopoiesis: Aggressive and Potentially Lethal Progression-A Case Report

Abstract

Transient abnormal myelopoiesis (TAM) in newborns with Down syndrome (DS) often presents mildly and is managed symptomatically, but in rare cases, it can progress aggressively, requiring treatment with low-dose cytarabine. Here, we report a case of TAM that progressed aggressively despite 2 rounds of low-dose cytarabine treatment. Although the blast count decreased from 60% to 1%, the patient’s liver failure worsened, ultimately leading to his death. Recent advancements in understanding and managing TAM have improved overall prognosis, yet liver failure remains a challenging prognostic indicator.

Introduction

Newborns diagnosed with Down syndrome (DS) are at heightened risk of developing a specific myeloproliferative disorder referred to as transient abnormal myelopoiesis (TAM), transient myeloproliferative disorder, or transient leukemia. ¹ Typically, this condition is identified between 3 and 7 days post-birth, with nearly all cases diagnosed within the first 2 months of life. The majority of patients experience a mild clinical course, with approximately 80% achieving spontaneous remission within 3 months as blast counts gradually decrease. Approximately 10% of individuals with TAM succumb to complications like hepatic or multiorgan failure. Recent research has identified various adverse prognostic factors in infants with TAM and underscored the efficacy of low-dose cytarabine in managing severe cases. ² Following remission, about 20% of TAM patients may progress to acute myeloid leukemia (AML) linked to Down syndrome.^2,3 Both TAM and AML associated with DS exhibit common genetic abnormalities such as trisomy 21 and mutations in the GATA binding protein 1 (GATA1).^{4 -6} In rare instances, TAM may manifest aggressively, leading to a fatal outcome, thereby demonstrating the diverse clinical presentations observed in this condition. ⁷

Case Presentation

Here, we describe 1 patient with TAM who had a unique clinical presentation, illustrating the widely variable spectrum of this clinical entity.

Baby weighed 2.12 kg and was born late preterm at 36 + 6 weeks to a 33-year-old mother with hypothyroidism. Third-trimester ultrasound revealed severe oligohydramnios and intrauterine growth restriction. Shortly after birth, he developed upper gastrointestinal bleeding and was transferred to our hospital.

Upon examination, the infant showed hepatomegaly, a grade II ejection systolic murmur, and typical Down syndrome features. Laboratory tests indicated leuko-cytosis with 60% blasts, normal platelet count, and mild liver and kidney function abnormalities. Karyotype confirmed diagnosis of Down’s syndrome and echocardiography suggestive of Ostium Primum atrial septal defect with small patent ductus arteriosus(0.4 cm) with left to right shunt. Peripheral smear and cytochemical analysis confirmed transient abnormal myelopoiesis (TAM) with 60% blasts lacking myeloperoxidase and periodic acid-Schiff staining, flow cytometry showing 2 populations of blasts as shown in Figures 1a to b and 2. USG abdomen done was suggestive of large hepatomegaly (7.1 cm), diffuse mural edema of gall bladder and gross ascites. Treatment included plasma transfusion in view of deranged prothrombin time, low-dose cytarabine for 5 days, and management of ascites with diuretics and paracentesis. Circulating Blast counts decreased from 60% to 15% and 1% subsequently over 2 weeks, by 3 weeks of life baby had worsened liver failure while blast count was improved. Second dose was initiated, but stopped after 2 days i.v.o myelosuppression (leukopenia and thrombocytopenia). GATA1 analysis could not be done i.v.o non-avaliability, as per British guidelines 2018 it is not essential for diagnosis, trisomy 21 status is sufficient to diagnose TAM. Despite efforts, the infant passed away after 1 month due to progressive liver failure.

Figure 1.

(a) Photomicrograph depicting circulating blasts (block arrow) along with nucleated RBC (arrow; Giemsa stain peripheral smear 400x). (b) Inset shows same blasts with cytoplasmic blebs at greater magnification (Giemsa stain, peripheral smear 600x).

Figure 2.

Flow cytometry plots on 3 laser 10 color Beckman colter Navios analyzer identified 2 population of blasts Myeloblasts (red): CD34+, CD117+, CD56+,CD117+, CD 36+,HLADR+, CD 20−, CD 3−, CD 13−, CD 41 -Megakaryoblasts (black): CD34−, CD 41+, CD 56+, CD 71−, CD117 Dim+.

Discussion

Transient leukemia of Down syndrome (TL-DS) is a distinctive congenital condition observed in neonates with Down syndrome (DS) or mosaic trisomy 21, presenting as transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD). It involves the clonal expansion of megakaryoblasts and dysplastic changes in peripheral blood cells, driven by mutations in the GATA1 gene exclusively associated with trisomy 21.^5,8,9 TL-DS can exhibit diverse clinical features or may be identified through genetic analysis or peripheral smear examination. ¹⁰

TL-DS and myeloid leukemia of Down syndrome (ML-DS) share identical GATA1 mutations, indicating clonal linkage. ¹⁰ Diagnosis of TL-DS typically hinges on genetic findings, including the presence of a GATA1 mutation in neonates with DS or mosaic DS, along with an elevated blast count (>10%) or clinical signs suggestive of TL-DS. ⁹ Silent TL-DS, marked by a GATA1 mutation with ≤10% peripheral blood blasts, carries a low risk of progression to ML-DS. ⁹

The pathogenesis commences prenatally with disrupted hematopoiesis in trisomic hematopoietic stem cells, leading to an expansion of megakaryocyte-erythroid progenitors (MEPs). Subsequent acquisition of GATA1 mutations triggers TAM during fetal or early neonatal stages. No retrospective studies have systematically screened neonates for GATA1 mutations, a genetic marker specific for TAM and ML-DS. So, current definitions of TAM neither specify the percentage of blasts considered abnormal in DS neonates nor the role of GATA1 mutation analysis in the diagnosis. ¹¹ While most cases of TAM resolve spontaneously by 6 months, approximately 10% progress to ML-DS before age 5 due to additional genetic or epigenetic alterations. ⁹

Clinical manifestations of TL-DS vary widely and encompass organomegaly, hepatopathy, skin rash, effusions, extreme leukocytosis, and coagulopathy. Progressive hepatopathy and cholestasis significantly contribute to mortality. Poor prognostic indicators include hyperleukocytosis, severe liver disease, hydrops fetalis, ascites, and coagulopathy.^2,9

Management entails vigilant monitoring for life-threatening symptoms (LTS) and regular laboratory assessments until normalization. Severe cases necessitate treatment with cytarabine, typically administered at 1 to 1.5 mg/kg/day for 5 to 7 days. ¹² However, the efficacy of repeated cytarabine courses in cases of persistent liver dysfunction requires careful evaluation due to potential myelosuppressive risks. ³

In our case, despite a notable decrease in blast counts following low-dose cytarabine, liver function continued to deteriorate, consistent with previous observations. ¹³ Spontaneous resolution of peripheral blast cells usually occurs within weeks to months, with limited data available on the benefits of repeat cytarabine administration. ³ Therefore, decisions regarding additional treatment courses must carefully consider potential therapeutic benefits versus risks, particularly in the context of ongoing liver dysfunction.

This case of TAM is unique in several ways: the infant presented immediately after birth with gastrointestinal bleeding and hepatomegaly; the blast count initially increased but responded to treatment, yet showed an inverse relationship with liver failure; this is in contrary to the findings from 1 prospective study which shows worse outcome with higher blast counts. ¹⁴ Two distinct populations of blasts were identified, with myeloblasts being particularly unusual in the early phase of TAM; and it also underscores the lack of response to retreatment in fatal cases, particularly those involving liver failure.

Conclusion

Therefore, in infants with Down syndrome presenting with liver failure, TAM should always be considered a critical diagnostic consideration, especially when TAM involves liver complications that worsen despite cytarabine treatment, with additional doses potentially not leading to improvement and resulting in a severe outcome.