Congenital B-Cell Acute Myeloid Leukemia Associated With Down's Syndrome

Congenital Leukemia (CL) is an extraordinarily rare condition in newborns, which is typically diagnosed at birth or within the first month of life1. It makes a medical diagnostic challenge, as its clinical features are similar to prenatal/or natal sepsis. Most CLs are myeloid contrasting pediatric leukemia, which is frequently lymphoid in origin; prognosis is evenly poor [1,2]. The course of congenital leukemia ordinarily leads to rapid deterioration and expiry due to infection or hemorrhagic events. We introduce a neonate presenting with clinical manifestations of sepsis; however, the patient was then confirmed as CL.

A full-term female child presented to the pediatric emergency department with complaints of a rash over her face and respiratory distress since birth. She was born out of a non-consanguineous marriage with a birth weight of 2.5 kg. Her 25-year-old primigravida mother had a normal antenatal course with normal routine tests including HIV & HBsAg, RPR test, TSH, urine microscopy, and ultrasound were normal. The maternal TORCH profile was normal. The baby had normal APGAR scores. 

On examination, her craniofacial configuration was abnormal with a flattened round face, depressed bridge of the nose, upward slanting almond-shaped eyes, small low set ears, with skin folding on the pinna, short neck with skin folding, small hands with palmer crease, small fingers curved towards the thumb and small feet with bilateral wide spaced great toes and second toes - features suggestive of Down's syndrome. The baby had a macular rash with tiny red spots on the face (Figure 1). The anterior fontanelle bulged and the head circumference was 32 cm. The abdomen was mildly distended (abdominal girth – 38 cm) and hepatosplenomegaly on palpation with the liver 4 cm below the costal margin and spleen 3 cm below the costal margin. He was tachypneic with a respiratory rate of 70 per minute. Respiratory system examination revealed subcostal and intercostal retractions and central cyanosis. On auscultation, occasional crepitations were audible. Cardiovascular examination suggested abnormal heart sounds and murmur. 

 Figure 1: Down's Syndrome 

Blood investigations are depicted in table-1. Complete blood counts suggested total leucocyte counts 78x103/Cumm, Serum calcium was 7.3 mg/dl, phosphorus was 3.69 mg/dl, and serum uric acid levels were 7.0 mg/dl, LFT & RFT were normal. 25 LDH was elevated (5032 U/L). TSH was 4.331 micro-IU/ml with normal T3&T4. PT/PTTK INR (1.9) was abnormal (Table 1). Chest X-ray and 2D ECHO suggested a cyanotic congenital heart disease- PDA (3.7 mm, PG – 5.0 mmHg) with the left to right shunting and LALV enlarged. 

Table 1: Hla & Advanced Hematology Lab Report 

Peripheral Blood Film examination reported normocytic normochromic red cells with moderate anisocytosis & adequate density. 30 n-RBC / 100 WBC were noted. White Blood Cell examination suggested leukocytosis with differentials as – blast + promyelocytes -18%, myelocytes -4%, metamyelocytes 3%, band+ neutrophils -28%, lymphocytes 41 %, monocytes 5% and eosinophils 1%. Platelets were reduced in number. 

Peripheral Blood Film examination by an Advanced hematology lab suggested abnormal pathologic features including leukocytosis, lymphocytosis anisocytosis, monocytosis, basophilia, reticulocytosis, blasts, and giant platelets.

Ultrasound brain suggested immature parenchyma with increased echogenicity of the gangliothalamic region suggestive of HIE. Ultrasound abdomen suggested enlarged liver of 74 mm with sludge in the gall bladder with peri gall bladder fluid and portal vein diameter of 4.3 mm. bilateral kidneys were bright with peri renal edema and ascites. Ultrasound chest reported that the Right basal region showed consolidation and air bronchogram, left lobe also showed peripheral consolidation. TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) infections were ruled out based on a negative TORCH screen. 

A karyotype done to rule out chromosomal abnormalities on the blood sample by stimulated peripheral blood lymphocyte culture revealed 47, XX, +21[20] [ISCN 2020] & presence of an additional copy of chromosome 21, suggestive of trisomy 21, indicative of female child with down syndrome (figure 2).

 Figure 2: Karyotyping Suggesting Down's Syndrome 

Supportive care was restricted to intravenous fluids and antibacterial therapy. Flow cytometric immunophenotyping further confirmed congenital B-Cell ALL (figure 3). 

 Figure 3: Flow Cytometry-Blast Cells 

Flow Cytometry 

Peripheral blood smear shows 40% Blasts. On CD 45 gating the Blasts show the antigenic expression suggestive of Acute myeloid leukemia with megakaryocytic differentiation and aberrant CD 7 (Table 2). 

Table 2: Flow Cytometry

Congenital leukemia (CL) has an incidence of 4.3 - 8.6 per million live births [2,3]. Intrauterine environmental insults, infections, exposure to radiation during pregnancy, and chromosomal derangements are among the etiologies of congenital leukemias. CL is found associated with Down's syndrome, Turner syndrome, Klippel-Feil syndrome, and Ellis-van Creveld syndrome [4,5]; CL was accompanied by Down's syndrome with dysmorphic clinical presentations in our case. Clinical features of leukemia might be apparent at birth with hepatosplenomegaly, ecchymosis, and petechial lesions. About 25-30% of newborns suffering from CL present specific cutaneous infiltrates named leukemia cutis looking like firm red or blue nodules 'Blueberry Muffin' [6,7] Unlike the current case. Most CLs are of the myeloid lineage, unlike pediatric leukemia, which is usually lymphoid in origin (1-3, and 8-11). About half of congenital AMLs are of M4 or M5 in terms of morphology; there is the translocation of the MLL gene at band 11q23 and positive CD14 in these cases. The t (9; 11) translocation is the next common genetic defect detected followed by the t (11; 19) translocation [8, 9].

The differential diagnosis of CL comprises mainly sepsis and intra-uterine infections termed TORCH; other possible reasons consist of hemolytic disease of the newborn (HDN) and transient myeloproliferative disease (TMD) [1-3]. Infections were excluded through serology and culture in our present case, numerous erythrocyte precursors were not detected in the peripheral smear in this current case, unlike HDN. TMD of neonates is seen typically linked with Downs syndrome. They often have associated transient polycythemia and/or thrombocytosis, but hematological abnormalities persisted in our case [10]. The prognosis is poor, with merely 23% of cases surviving at 24 months [11, 12]

We are reporting a newborn with congenital B-cell -AML. Congenital leukemia should be considered in the differential diagnosis of neonates having syndromic features and peculiar blood abnormalities. TMD may be excluded appropriately by flow cytometric analysis.

Funding 

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 

Conflicts of interest/Competing interests 

None

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