A neonate with a unique non‐Down syndrome transient proliferative megakaryoblastic disease

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM).³² Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision‐making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single‐nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1–5q31.3 and 8q23.2q24).     

Transient myeloproliferative disorder and acute nonlymphoblastic leukemia in Down syndrome

Two infants with Down syndrome had transient myeloproliferative disorder (TMD) during the neonatal period and subsequently acute nonlymphoblastic leukemia (ANLL). Histochemically, the blast cells in TMD were indistinguishable from those in ANLL. Only the constitutional chromosome (trisomy 21) was found in TMD, whereas new cytogenetic abnormalities emerged in ANLL. A mixed growth pattern in stem cell cultures during TMD suggested the existence of an abnormal clone that might be responsible for the evolution into ANLL at a later date. Serial cytogenetic studies and culture studies of peripheral blood cells may help to understand the pathophysiology and risk of ANLL in patients with TMD.     

Spontaneous remission of congenital acute nonlymphoblastic leukemia with normal karyotype in twins

BACKGROUND: Congenital acute nonlymphoblastic leukemia (cANLL) is an extremely rare event and represents only 0.5-1% of the leukemias in the first year of life. It is usually more common among patients with chromosomal abnormalities. Transient myeloproliferative disease (TMD) is an hyperleukocytosis entity that occurs almost exclusively in Down syndrome patients and remits spontaneously. Spontaneous remission of congenital leukemia has been reported and related to the presence of an extra chromosome 21. PROCEDURE: A pair of non-Down syndrome newborn twins presented with a clinical picture of skin rash and hyperleukocytosis. Twin B had full-blown cANLL with bone marrow, peripheral blood, skin, CSF, and placental invasion. Twin A presented transient peripheral blood and skin involvement by the same type of blast cells. No cytotoxic therapy was given. With 2 years follow-up, they continue to do well. RESULTS: Histologic and immunophenotypical analysis of placentas, cord blood, skin, CSF, bone marrows, and peripheral blood revealed a consistent picture of intrautero cANLL in twin B, with transplacental invasion of twin A. Normal and blast cells were found to be karyotypically normal. Spontaneous remission occurred. CONCLUSIONS: cANLL with karyotypically normal blasts can develop a self-limited clinical course, which has resemblances to TMD.     

Transient myeloproliferative disorder associated with trisomy 21, a wide range syndrome: Report of two cases with trisomy 21 mosaicism

Transient myeloproliferative disorder (TMD) is an uncommon syndrome strongly associated with abnormalities of chromosome 21. Blast transient proliferation appears most frequently at neonatal age and usually resolves spontaneously in two or three months. Two patients, a girl and a boy, with neonatal onset of TMD are reported. They both presented trisomy 21 mosaicism according to bone marrow cytogenetic analysis. Patient 1, on one end of the spectrum, showed a “classic” benign course with rapid resolution and favorable outcome. Patient 2, on the other hand, had two blast outbursts both followed by spontaneous remissions. He failed to thrive and never reached a good general condition, dying at 5 months of age from a respiratory infectious complication. The necropsy showed generalized extramedullary hemopoiesis without evidence of bone marrow blast infiltration or myelofibrosis. TMD has some clinical and laboratory features that make it unique and distinguishable from true congenital leukemia with which it may be initially mistaken. It usually has a benign course followed by a favorable outcome. As trisomy 21 mosaicism may not have overt phenotypic stigmata, it is possible that many cases of TMD in these children may have a silent, non-detected course. We also conclude that a favorable outcome is not always to be expected in TMD. © 1995 Wiley-Liss, Inc.     

Transient myeloproliferative disorder in Down's syndrome: three cases with megakaryocytic markers.

In this paper we describe three infants with Down's syndrome and transient myeloproliferative disorder. The blast cells of all three displayed positive megakaryocytic markers. One patient developed acute megakaryoblastic leukemia in his second year, with blasts identical to those of the initial episode. The other two cases remain well at 12 and 15 months of age.     

Transient neonatal myeloproliferative disorder without Down syndrome and detection of GATA1 mutation

Transient myeloproliferative disorder is a form of self-limited leukemia that occurs almost exclusively in neonates with Down syndrome. The authors report an unusual case of a newborn without constitutional trisomy 21 who developed undifferentiated leukemia and subsequently achieved clinical and molecular remission without chemotherapy. Cytogenetics and molecular analysis have shown trisomy 21 and GATA1 mutation restricted to leukemic cells. G-to-T transversion was detected, which is predicted to result in a premature stop codon (c.119G>T; pGlu67X) in diagnosis samples. These findings emphasize that there must be a powerful interaction between GATA1 and trisomy 21 in leukemogenesis process.     

Isolated trisomy 21 in blasts of an acute lymphoblastic leukemia

A two years and four months old boy without evidence of Down's syndrome exhibited a trisomy 21 in his acute lymphoblastic leucemic cells. During remission this chromosomal change disappeared. The cytogenetic examination of malignant cells serves an important tool in diagnosis and follow-up of acute leucemia as well as bone marrow transplantation.     

Acute myeloid leukaemia in patients with trisomy 21 (Down syndrome) treated by bone marrow transplantation

Patients with trisomy 21 have an increased incidence of haematological disorders, including neonatal 'leukaemoid reaction'(transient myeloproliferative disorder [TMD]) and acute leukaemias. In the past it has been felt that patients with trisomy 21 and acute leukaemia do not tolerate, and hence may not warrant, therapy as intensive as those without the syndrome. The present authors' experience and the current literature do not support this view. Two cases are reported of acute myeloid leukaemia in children with trisomy 21, successfully treated with intensive chemotherapy and bone marrow transplantation.     

Acute nonlymphocytic leukemia after transient myeloproliferative disorder in a patient with Down syndrome

An infant with Down syndrome (DS) and RH isoimmunization developed transient myeloproliferative disorder (TMD) during the neonatal period. At 16 months she presented with acute nonlymphocytic leukemia (ANLL). Cytogenetic studies during TMD showed trisomy 21 only but new abnormalities emerged during ANLL. She is now in complete remission 5 years after diagnosis. Patients with TMD have either trisomy 21 or mosaic 21 in blood and bone marrow but in phenotypically normal children this cell line disappears with resolution of the TMD. A review of the literature indicates that there are no clinical, hematological, or cytogenetic differences between DS children with TMD who subsequently develop acute leukemia and those who do not. However, the leukemia in the former group may differ in presentation, type, and possibly survival time from other DS children who develop leukemia de novo.     

Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome

The cellular events that lead to transient myeloproliferative syndrome (TMS) in patients with trisomy 21 mosaicism confined to the hematopoietic system are poorly understood. The authors attempt to define the event that led to the development of TMS in a single patient with clonal trisomy 21. A phenotypically normal neonate with clonal trisomy 21 is described. At the time when his TMS was resolving, fluorescent in situ hybridization analysis was performed on cell populations sorted by flow cytometry to determine what cell populations contained trisomic cells. Trisomy 21 was found in cells of the erythrocytic and monocytic lineages, but not in the stem cells, progenitor compartment, megakaryocytes, lymphocytes, or neutrophils. These results support the hypothesis that, in this neonate, trisomy 21 occurred in a multipotent hematopoietic progenitor, and a subsequent event led to the appearance of the blast population.     

Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review

Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome.     

Transient abnormal myelopoiesis in non‐Down syndrome neonate

We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low‐dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non‐DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted.     

Congenital transient leukemia: a case report]

Neonates with Down's syndrome have an increased risk for congenital leukaemia, particularly acute megakaryoblastic leukaemia (FAB, M7) which most often resolves spontaneously and is called transient leukaemia. It can be observed in non-constitutional trisomy 21 infants then presenting trisomy 21 on blasts cells. OBSERVATION: We report a transient leukaemia with an isolated pericardial effusion in a phenotypically normal neonate. Trisomy 21 was found on blasts cells. Complete remission remains after 32 months. DISCUSSION: Congenital leukaemias, with trisomy 21 on blasts cells have a good prognosis that justifies observation before using chemotherapy.     

Transient neonatal myeloproliferative disorder in the absence of Down syndrome

Transient neonatal leukemia or transient neonatal myeloproliferative disorder is commonly associated with Down syndrome. It usually resolves spontaneously in 4-5 months. However, 25 % of patients will subsequently develop acute megakaryoblastic leukemia or myelodysplastic syndrome. It has seldom been described without constitutional anomalies and is even less frequent in twins. We present three phenotypically normal patients with this disorder. One of them was diagnosed because he presented blueberry muffin syndrome. Diagnosis was guided by pathological examination of the skin lesions. The other two patients were monochorionic triplets. Their bichorionic sister presented no hematological disorders. Constitutional chromosomal abnormalities were ruled out in all three patients. They received support treatment only without chemotherapy. The clinical course was favorable with disappearance of marrow and peripheral blastosis in 4-5 months. Follow-up of 18 and 19 months has not revealed any hematological disorders. Caution must be exercised before initiating chemotherapy in these patients. We discuss the differential diagnosis with congenital leukemia and the prognostic and therapeutic implications that this entails.     

Neonate with Down's syndrome and transient congenital leukemia. In vitro studies

A white female neonate with clinical manifestations of Down's syndrome was found to have a peripheral white count of 74,000/mm3 with 65% blast forms. Bone marrow aspirate revealed 36% blasts. On chromosomal analysis of bone marrow and peripheral blood, two cell lines were found, one with trisomy 21 and another with pentasomy 21. Colony cultures on the patient's bone marrow cells revealed an adequate growth pattern of CFU/GM. Cells were reactive with myeloblast alloantisera. At the age of 3 weeks, peripheral counts were within normal limits as was morphology of the repeat bone marrow aspirate. Chromosome analysis at that time showed complete absence of pentasomy 21 cell line, and repeat cell colony studies revealed normal growth, differentiation, and maturation of CFU/GM. Maternal serum totally inhibited colony growth of the patient's remission marrow and allogeneic blast cells. This serum inhibitor actually disappeared 1 month postpartum. The patient has had no recurrence of blast cells up to the present age of 3 years.     

Transitorisch myeloproliferatives Syndrom bei Neugeborenen mit Down-Syndrom

Transient myeloproliferative syndrome (TMS) is a disorder of neonates with Down syndrome (trisomy 21) and occurs at an incidence of up to 10%. Typical for this entity is a proliferation of myeloid blasts with megakaryoblastic and/or erythroblastic features detectable in the peripheral blood. In the majority of cases TMS is asymptomatic, and only a small percentage of children show clinical symptoms due to hyperleukocytosis, thrombocytopenia, anemia, or hepatomegaly. Almost all children will achieve spontaneous remission after 2–4 months (disappearance of myeloid blasts and regression of clinical symptoms). Patients with initial hyperleukocytosis and hepatomegaly, however, carry a particular risk of developing hepatopathy followed frequently by lethal liver fibrosis. Chemotherapy with cytarabine is indicated in patients with clinical symptoms of hyperleukocytosis or early signs of hepatopathy. Within the first 4 years the risk of developing acute myeloblastic leukemia (AML) is high at 20–30%; therefore, regular follow-ups are advised. This analysis is based on one of the largest databases for TMS.     

Papillary Pore Counts: A Method of Studying Developmental Aberrations in Diseased Juvenile Kidneys

Counts of the number of pores of primary collecting tubules (ducts of Bellini) on renal papillae, and values calculated by adjusting the counts of compound papillae to those of “virtual” single papillae, were determined for kidneys of patients with end-stage renal failure. Values for chronic glomerulonephritis, Alport's disease, infantile polycystic disease, trisomy 18, and trisomy 13 were not abnormal. Kidneys of patients with CUTO showed significantly low pore counts, indicating that this process in some cases is a true hypoplasia, with mean reduction of number of ducts of Bellini of 26%. FGS showed a high proportion of single papillae (80% vs. normal 60%) with high virtual pore counts, suggesting that a developmental abnormality underlies this disorder (or this outcome of nephrotic syndrome). Cystinosis showed a high proportion of compound papillae (80% vs. 40%) but low virtual pore counts, implying that this genetic disorder causes both maldevelopment and postnatal functional abnormality of the kidneys. A Jeune syndrome kidney produced very low pore counts (mean 8 vs. 16.6 for virtual pore counts), and Down's syndrome also showed low pore counts (mean VPC 15.1 vs. normal 16.6), indicating that the low kidney weights demonstrated by others with Down's syndrome reflect a true hypoplasia.     

Further observations of ocular pathology in Down's syndrome

We studied the eyes of two children with proven trisomy 21 and updated the microscopic ocular findings. The ocular malformations, generally of a minor nature, comprise a variety of nonspecific hyperplasia or hamartomata, hypoplasias, tissue defects and heterotopias, and involve virtually every portion of the globe. Ocular and extraocular abnormalities in Down's syndrome do not correlate well embryologically, cytogenetically or in regard to incidence or severity. The type of ocular anomalies usually encountered in trisomy 21 suggests that the globe was affected by the chromosomal anomaly rather late in its development.