Published online: 2021-08-06

CASE REPORT Congenital acute megakaryocytic

N. B. Mathur, Neha Joshi, Abstract T. Singh1, Meeta Singh1 Congenital leukemia (CL) is an extremely rare disorder in the newborn, significant Departments of Pediatrics, and proportion of which is of myeloid origin, primarily of M4 or M5 morphology. As 1 Pathology, Maulana Azad Medical compared to pediatric leukemia, CL is a more aggressive disease. Acute College, Delhi, India (AML‑M7) or acute megakaryocytic leukemia is a rare type of AML with an incidence of 0.5 per million per year. Median age of presentation is 6 years, and children may Address for correspondence: present with a broad variety of symptoms including low‑grade fever, diarrhea, easy Dr. Neha Joshi, 3073, B‑4, Vasant Kunj, bruising, failure to gain weight and life‑threatening conditions. New Delhi, India. E‑mail: joshineha_26@rediffmail. Key words: Congenital megakaryocytic leukemia, neonate, sepsis com

of the body. This was followed by the onset of small volume, INTRODUCTION non–foul‑smelling watery stools, up to 10–15 episodes/day. Acute megakaryocytic leukemia (AKML) or acute myeloid There was no history of fever, altered sensorium, decreased leukemia (AML‑M7) is a type of pediatric AML accounting oral acceptance or decline in urine output. At admission, for 3–10% of primary childhood AML and 50% of the the child was moderately hypothermic and lethargic, while AML in children with Down’s syndrome (DS). Median the vitals, hydration, oxygen saturation and blood sugar age of presentation is 6 years (ranging from 3 months levels were maintained. Weighing 3 kg, the baby displayed to 16 years). We report a rare case of congenital AKML a grossly distended abdomen with an inverted umbilicus manifesting in the neonatal period with no features of and no overlying skin changes. There was no dysmorphism, DS. Children may present with conditions simulating hypotonia, lymphadenopathy, mucocutaneous bleed septicemia and congenital infections. Course of the illness or nodular skin changes. Abdominal examination is one of rapid deterioration and death from hemorrhage revealed a girth of 39 cm, firm liver with sharp margins and infection in spite of aggressive therapeutic measures. reaching 9 cm below costal margin in the midclavicular line (spanning 12 cm) and a firm spleen palpable 9 cm below costal margin in the direction of the umbilicus. CASE REPORT There was no free fluid and bowel sounds were normal. Rest of the systemic examination was noncontributory. A 17‑day‑old female born to a 21‑year‑old primigravidae Laboratory parameters revealed hemoglobin 13.3 g%, out of a non‑consanguineous marriage, at term gestation, total leukocyte count 37,250 cells/mm3, platelet count presented with progressively increasing abdominal 3 distension for 4 days and loose stools for 2 days. Pregnancy 13,000/mm , I/T ratio 30%, C‑reactive protein (CRP) was unbooked, but antenatal period was uneventful with no levels of 65 mg/L and erythrocyte sedimentation rate complaints of fever, rash, nodular swellings or joint pains. (ESR) of 10 mm/hr. Peripheral smear reported 20% The neonate was predominantly breast fed along with sips neutrophils, 10% lymphocytes, 5% eosinophils and of water intermittently. Child remained well till day 13 of 65% blast cells containing high nuclear: ratio life when the mother noticed generalized but progressively with opened up nuclear chromatin showing one to two increasing abdominal distension, unaccompanied by prominent nucleoli. Tests to rule out congenital group of vomiting, overlying skin changes or swelling over any part infections were negative, and blood groups of both mother and child were B+ve. aspirate displayed Access this article online infiltration of the marrow with blasts comprising 65% of Quick Response Code: the marrow nucleated cells. Cytochemistry proved negative Website: www.ijmpo.org for (MPO) and Periodic acid Schiff (PAS). Immunophenotyping revealed markers negative for CD10 and positive for CD61 antigen, suggestive of AMKL. DOI: 10.4103/0971-5851.92821 Therapy with intravenous fluids and antibiotics was initiated. At 20 hrs of admission, the child had profound pulmonary

Indian Journal of Medical and Paediatric | Jul-Sep 2011 | Vol 32 | Issue 3 165 Mathur, et al.: Congenital AML M7 bleed culminating in respiratory failure and circulatory of pediatric AML in Asians and Hispanics. The median shock. Bleeding profile revealed thrombocytopenia and age of presentation is 6 years, ranging from 3 months to prolonged prothrombin time, suggestive of disseminated 16 years, but cases (40%) have been seen in children of age intravascular coagulopathy (DIC). Investigations such 41 months or younger.[9] The youngest reported case of as fibrinogen levels, d‑dimer assays to support DIC and AML‑M7 reported earlier was a 4‑week‑old neonate who karyotype analysis were planned; however, parents refused presented with hepatic infiltration only.[10] investigations on the child due to financial constraints. Ventilatory support, volume resuscitation, inotropic, Etiological considerations in CL have included chromosomal vasopressor support and blood products were appropriately defects, intrauterine environmental insults, viral infections administered; however, the neonate succumbed to the and exposure to radiation in pregnancy.[11] Children illness at 36 hrs of admission. Post‑mortem liver biopsy may present with a broad variety of atypical symptoms disclosed infiltration of tissue with giant cells containing including low‑grade fever, diarrhea, easy bruising, irregular nuclei with high nuclear:chromatin ratio. On failure to gain weight and life‑threatening conditions.[12] cytochemistry, these blasts were negative for MPO, PAS The clinical signs of leukemia may be evident at birth [11] and Sudan black. Immunophenotyping revealed the cells with hepatosplenomegaly, petechiae and ecchymosis. to be negative for CD10 and positive for CD61. Leukemia cutis is less common. Severe infection may occur due to diminished neutrophil count and function. As compared to pediatric leukemia, CL is a more aggressive DISCUSSION disease with increased incidence of leukocytosis, massive hepatosplenomegaly, thrombocytopenia and DIC.[13] As in Congenital leukemia (CL) is an exceedingly uncommon the present case, complications due to bleeding are known disease in the newborn. A study in northern region of to contribute to 7–10% of the mortality that is observed England reported its incidence to be between 4.3 and during the first few days after diagnosis.[14] 8.6 per million livebirths.[1] AML‑M7 or AMKL is a very rare type of AML which represents approximately 1% The diagnosis of FAB AML‑M7 relies on multiple of all during childhood, with an incidence of criteria including peripheral blood and bone marrow 0.5 per million per year. To the best of our knowledge,

aspirate smear morphology, routine cytochemistry such an early presentation of this rare leukemia has not stains, immunophenotyping and ultrastructural studies. been reported before. Over the last 10 years, its incidence Cytochemically, megakaryoblasts show no reactivity with has been estimated to be 4–7% of pediatric AML by large MPO or Sudan black. The standard for diagnosis of FAB [2] co‑operative group studies in developed countries. AKML M7‑ is demonstration of CD41/61 by immunophenotyping. accounts for 50% of AML in children with DS and there Ultrastructural platelet peroxidase reaction by cytochemistry is a 500‑fold increased risk of AKML in these patients.[3] is also diagnostic; however, as these are difficult to perform, they are largely replaced by immunophenotyping.[6] It is Criteria for diagnosis of CL are as follows: a) disease pertinent to mention here that transient myeloproliferative presentation at or shortly after birth (<30 days), disorder (TMD) and AML in DS show strikingly similar b) proliferation of immature white cells, c) infiltration of cytomorphological features. TMD usually manifests the cells into extra hematopoietic tissues, and d) absence of during the first few days of life, with normal hematocrit [4] any other condition that mimics CL. A large proportion and platelet counts. While hematogenic and cytogenic of CLs are of myeloid lineage, while pediatric leukemias differences have been cited, none of them absolutely are usually of lymphoid origin.[4] AML‑M7 is defined differentiate between the two.[15] Reported survival in TMD under FAB classification by more than 20% blasts of is good.[16,17] megakaryocytic lineage in bone marrow aspirate as determined by morphology and immunocytochemistry.[5] Myeloablative treatment in the form of intensive multidrug The marrow may be difficult to aspirate as more than two or radiotherapy followed, whenever possible, thirds have significant fibrosis, the latter as a result of the by allogeneic or autologous bone marrow transplant is the stimulation of the normal fibroblasts by the local secretion treatment of choice. Patients with AML‑M7 have a dismal of platelet‑derived growth factor by the leukemic cells. prognosis. The outcome of children with non‑Down’s Under such circumstances, bone marrow biopsy proves syndrome AMKL is generally poor. helpful.[6,7] With this report, we would like to create awareness regarding About half of congenital AML is of M4 or M5 the unusual early presentation and encourage clinicians to morphology.[8] There is no gender preponderance; keep a high index of suspicion of megakaryocytic leukemia however, there is ethnic variation with a higher incidence even in the neonatal period.

166 Indian Journal of Medical and Paediatric Oncology | Jul-Sep 2011 | Vol 32 | Issue 3 Mathur, et al.: Congenital AML M7

1999;4:225‑40. ACKNOWLEDGMENT 9. windebank KP, Tefferi A, Smithson WA, Li CY, Solberg LA Jr, Priest JR, et al. Acute megakaryocytic leukemia (M7) in children. Dr. Mathur conceptualized the idea. He and Dr. T Singh edited and Mayo Clin Proc 1989;64:1339‑51. approved the final version. Dr. Neha drafted the manuscript and 10. Lewis MS, Kaicker S, Strauchen JA, Morotti RA. Hepatic involvement in congenital acute megakaryoblastic leukemia: along with Dr. Meeta contributed toward literature search. A case report with emphasis on the liver pathology findings. Pediatr Dev Pathol 2008;11:55‑8. 11. Prakash KP, Rau AT, BhatST, Rau AR. Congenital leukemia – A REFERENCES diagnostic dilemma. Indian J Med Paediatr Oncol 2008; 29:41‑3. 1. Bajwa RP, Skinner R, Windebank KP, Reid MM. Demographic 12. Campwell WA, Macafee AL, Wade WG. Familial neonatal study of leukaemia presenting within the first three months leukemia. Arch Dis Child 1962;37:93‑8. of life in the northern health region of England. J Clin Pathol 13. Stark B, Vogel R, Cohen IJ, Umiel T, Mammon Z, Rechavi G, 2004;57:186‑8. et al. Biologic and cytogenetic characteristics of leukemia in 2. carroll A, Civin C, Schneider N, Dahl G, Pappo A, Bowman P, infants. Cancer 1989;63:117‑25. et al. The t(1;22)(p13;q13) is nonrandom and restricted to 14. creutzig U, Ritter J, Budde M, Sutor A, Schellong G. Early infants with acute megakaryoblastic leukemia: A Pediatric deaths due to hemorrhage and leukostasis in childhood acute Oncology Group study. Blood 1991;78:748‑52. myelogenous leukemia. Associations with hyperleucocytosis 3. Dastugue N, Lafage‑Pochitaloff M, Pages MP, Radford I, and acute . Cancer 1987;60:3071‑9. Bastard C, Talmant P, et al. Cytogenetic profile of childhood 15. Hayashi Y, Eguchi M, Sugita K, Nakazawa S, Sato T, Kojima S, and adult megakaryoblastic leukemia (M7); A study of the et al. Cytogenetic findings and clinical features in acute Groupe Francais de Cytogenetique Hematologique (GFCH). leukemia and transient myeloproliferative disorder in down Blood 2002;100:618‑26. syndrome. Blood1988;72:15‑23. 4. McCoy JP Jr, Overton WR. Immunophenotyping of Congenital 16. Gary V. Dahl, Howard J Weinstein. leukemia. Cytometry 1995;22:85‑8. in Children. In: Hoffman R, Furie B, Benz EJ, McGlave P, 5. Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Silberstein LE, Shattil SJ, editors. : Basic Principles Gralnick HR, et al. Proposed revised criteria for the and Practice. 5th ed. Churchill Livingstone/Elsevier, 2009 classification of acute myeloid leukemia of megakaryocytic p. 1121‑2. lineage (M7). A report of the French‑American–British 17. Karandikar NJ, Aquino DB, McKenna RW, Kroft SH. Transient cooperative group. Ann Intern Med 1985;103:460‑2. myeloproliferative disorder and acute myeloid leukemia an 6. Kenneth BM, Pihan G. Clinical manifestations of acute myeloid leukemia. In: HoffmanR, Furie B, Benz EJ, McGlaveP, down syndrome. An immunophenotype analysis. Am J Clin Leslie ES, Sanford JS, Editors. Hematology: Basic Principles Pathol 2110;116:204‑10. and Practice. 5th ed. Churchill livingstone; 2009 p. 1089.

7. Baer MR, Greer JP. The acute leukemias: Acute myeloid How to cite this article: Mathur NB, Joshi N, Singh T, Singh M. leukemia in adults. In:Greer, Foerster, Rodgers, Paraskevas, Congenital acute megakaryocytic leukemia. Indian J Med Paediatr Glader, Arber, Means editors. Wintrobe’s clinical hematology. Oncol 2011;32:165-7. Pub. 12th ed. Lippincot Williams and Wilkins; 2008. p. 1858. Source of Support: Nil, Conflict of Interest: None declared. 8. Felix CA, Lange BJ. Leukemia in infants. Oncologist

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