A full-term appropriate for gestational age female infant born at our hospital (birthweight 3 kg) out of a consanguineous marriage, to a 27-year-old mother by lower segment cesarian section with an unremarkable antenatal history, presented at birth with pallor, palpable purpuric spots and ecchymotic patches, diffuse blueberry muffin rash of 1 to 3 cm (Fig. 1), and depressed neonatal reflexes. The craniofacial configuration was normal, but the anterior fontanelle was full. She had tachypnea and tachycardia. The abdomen was mildly distended; hepato-splenomegaly was evident on palpation.

Fig. 1. Blueberry muffin rash in a newborn with congenital leukemia and rubella infection.

Blood sugar (85 mg/dL), urea (13 mg/dL), creatinine (0.4 mg/dL) and bilirubin (total 2.7 mg/dL, indirect 2.1 mg/dL) were normal. SGOT (331 U/L), SGPT (120 U/L), alkaline phosphatase (1596 U/L), LDH (6189 IU/L) and GGT (337 U/L) were raised. Uric acid was 4 mg/dl, calcium was low (7.4 mg/dL), total protein was 5.5 gm/dL (albumin 3.5 gm/dL), and C-reactive protein was non-reactive. INR was raised (2.55), aPTT was 55 sec, and d-dimer levels were 8.5 µg/mL. Chest X-ray was normal. Ultrasound abdomen revealed an enlarged liver (7 cm), contracted gall bladder, and enlarged spleen (6.1 cm). Ultrasound brain revealed a dilated left lateral ventricle with slight midline shift to left side, suggestive of intracranial involvement. Skin biopsy was not done. TORCH profile by Pict Array TORCH ELISA (Nanoplex) was suggestive of positive Rubella IgM and IgG antibodies.

Flow cytometric immunophenotyping showed 60% circulating blasts, which expressed CD19, CD20, CD79a, HLA DR, CD34, and were negative for CD3, CD5, CD7, CD13, CD33, CD117, CD14, cytoplasmic CD3, and Myeloperoxidase. A diagnosis of B-Cell acute lymphoblastic leukemia (ALL) with congenital rubella infection was made. Despite ventilation in neonatal intensive care unit and blood component therapy, the baby survived only for 3 days.

This case fulfilled the criteria for diagnosis of congenital leukemia: (i) disease presentation at or shortly after birth, (ii) raised number of immature white blood cells, (iii) infiltration of cells into extra hemopoietic tissues, (iv) absence of other conditions like congenital syphilis, blood group incompatibility, which can cause leukemoid reaction [2].The differential diagnosis of congenital leukemia includes sepsis and intra-uterine infections, hemolytic disease of the newborn (HDN) and transient myeloproliferative disease (TMD) [1]. Infections are ruled out by serology and culture, while in HDN numerous erythrocyte precursors are seen in the peripheral smear. TMD is seen usually with Down syndrome, often with associated transient polycythemia and/or thrombocytosis, which were not found in this case.

Thrombocytopenia may be seen in up to 80% infants with CRS, which may be due to decreased megakaryocyte production [6]. Elevated leucocyte counts and severe thrombocytopenia, as seen in this child, are unusual for rubella. Patients can also develop a hemolytic anemia that can persist for months and potentially progress to red cell aplasia with variable leukocyte count [7].　There is paucity of reports of association of congenital rubella infection with malignancy; one case of lymphoblastoma has been reported after maternal rubella infection [8]. Acute myelomonocytic leukemia has also been reported with atypical congenital rubella [9]. Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus using cryo-electron tomography has also been described [10].

In any newborn presenting with palpable purpura, besides other causes like common neonatal rashes, leukemoid reactions, TORCH infection, and bleeding disorder, congenital leukemia should be considered as a differential diagnosis. On suspicion, immuno-phenotyping by flow cytometry, together with morphology and cytochemical stains should be performed. Association of ALL with rubella in this case suggest that the virus itself may have the potential to cause congenital leukemia.

Acknowledgment: Dr Priyansha Mathur, Assistant Professor in Pediatrics for technical help and writing assistance.

Contributors: KSY and SG contributed to diagnostic work-up of patient. DRB and RS supervised patient management. DRB drafted the manuscript, which was revised by KSY, SG and RS. All authors approved the final version of manuscript.
Funding: None; Competing interest: None stated.

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