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The most common human chromosome aneuploidy, trisomy 21 (Down syndrome [DS] and Down syndrome mosaic), is associated with a wide spectrum of hematologie abnormalities in the three hematopoietic lines. Included in these abnormalities are peculiar hematologie findings in the neonate, transient leukemia (TL), high mean corpuscular volume throughout life, high incidence of acute megakaryoblastic leukemia (AMKL) in infancy, increased incidence of leukemia throughout life, and abnormalities of the immunologie system. Most of the newborns with any of the above-mentioned hematologie abnormalities may not have any other clinical sign or symptom. However, some infants with TL may present with massive hepatosplenomegaly, cutaneous infiltrates, hydrops fetalis (Zipursky et al. 1999) or liver fibrosis (Yagihashi et al. 1995; AlKasim et al. 2002). Although, TL is thought to be a benign self-limited disorder, it can be fatal at initial presentation. Moreover, leukemia may develop in one-third of the patients who initially recover from TL (Homans et al. 1993).

Recent reports estimate an approximately 20-fold higher incidence of leukemia in children with Down’s syndrome compared to non-Down’s syndrome children and a marked increase of the megakaryoblastic subtype (FAB M7)[l]. Twenty-six of 42 children with Down’s syndrome were enrolled in our studies since 1987 were classified as FAB M7 or presented with a preleukemic phase (myelodysplastic syndrome, MDS) with increased megakaryoblasts. All patients were under 3 years (0.4-2.6 median 1.8 years) and generally had a low leukocyte count (1.6-177 median 7.75 x 103/mm3) and a low platelet count (4.0-210 median 26.0 x 103/mm3). Karyotype abnormalities other than +21c or [t(21;21)c] were found in 11/15 patients, predominantly trisomies (8/15) involving the chromosomes #8 (n = 5), #21 (n = 2), #11 (n = 2), #10, #14, #18, #19, and #22 (n = 1). Only nine children initially presented with > 30% blasts in the bone marrow (BM). In ten patients diagnosis of M7 leukemia was based on morphology alone, and in 16 patients confirmed by immunophenotyping. A preleukemic phase with thrombocytopenia for at least 2 months was recorded in nine of the 17 patients presenting with a low blast count (≤30%) and myelodysplasia in the BM. Four children had a history of transient neonatal leukemia. Sixteen children were left untreated or received only minimal treatment and subsequently died due to progressing leukemia. In two of the untreated patients, a spontaneous improvement or a stable disease (with retinoids) lasting for several months was observed. Ten patients were treated. Three out of ten had an end-stage disease and received inadequate dosages of therapy and died early. Six of seven children treated according to the AML-BFM protocols including high-dose cytosine arabinoside were in continuous complete remission for 0.2-4.6 years. We conclude that M7 leukemia in Down’s syndrome is often preceded by a preleukemic phase with thrombocytopenia. Patients treated according to the AML protocol showed good results. Further studies are warranted to clarify whether Down’s syndrome patients with a preleukemic phase of M7 would also benefit from an early and intensive treatment.

The clinical implication of cell surface marker expression has been less well established in acute myeloid leukemia (AML) compared with acute lymphoblastic leukemia (ALL). Diagnosis of AML is largely based on morphology and cytochemistry for the differentiation between AML and ALL and for the subclassification according to the FAB criteria [3,4]. Immunophenotyping is required for diagnosis of the minimal differentiated acute myeloid leukemia (Mo) [2] and the acute megakaryoblastic leukemia (M7) [5], which cannot be identified with sufficient certainty by morphological criteria.

In recent multiparameter studies, ultrastructural morphology and cytochemistry of undifferentiated or minimally differentiated acute leukemia’s have been investigated (Lee et al. 1987; Matutes et al. 1988; Campana et al. 1990; Van Wering et al. 1990; Heil et al. 1991). Detection of myeloperoxidase (MPO) and platelet peroxidase (PPO) at the ultrastructural level appeared to be useful for myeloid leukemia’s (Bennett et al. 1991) and supportive for the diagnosis of megakaryocytic leukemias (Breton-Gorius et al. 1978; Bennett et al. 1985). We investigated 12 light-microscopically unclassifiable acute childhood leukemia’s by immunological marker analysis and by electron microscopy (EM), including peroxidase cytochemistry. The combined results appeared to provide information to diagnose conclusively cases of minimally differentiated acute myeloid leukemia’s (AML M0; Bennett et al. 1991) and acute megakaryoblastic leukemia (AML M7; Bennett et al. 1985).

Classic morphology and cytochemistry are the basic techniques for the classification of acute myeloid leukemias (AML) according to the FAB- criteria. While the main categories existed before, the borders of the morphologic subtypes were not precisely defined. The FAB group made proposals for different categories originally including the following six subtypes: Ml, M2, and M3 for granulocytic leukemia, M4 and M5 for myelomonocytic and monocytic leukemia, and M6 for erythroleukemia. After the addition of the variant form of M3 (M3v), the M4 subtype with abnormal eosinophils (M4Eo), and acute megakaryoblastic leukemia (M7) in 1985, the FAB classification consisted of ten subtypes including the variants of M5 (Bennett et al. 1985).

Acute megakaryoblastic leukemia (M7) recently included in the French-American- British (FAB) classification for acute leukemias [1] is a rare hematological disease with poor prognosis. We present a case of acute megakaryoblastic leukemia with poor response to cytostatic treatment and a review of the therapeutic attempts in the literature.

Although described as early as 50 years ago [20], acute leukemia of megakaryocytic lineage (AMegL) was only recently added to the French-American-British (FAB) classification as FAB-M7 [2, 3]. To establish the diagnosis for this category, sophisticated techniques like ultrastructural cytochemistry or immunological techniques are required. The limited data available suggest a frequency of 3%-12% in adult acute nonlymphoblastic leukemia (ANLL) [15]. In childhood only 20 cases with a definitive diagnosis of AMegL hade been reported up to the year 1986 [5]. To the best of our knowledge the present case is the first in which cranial chloroma was associated with AMegL.

I begin this discussion with an old prejudice: Down syndrome is not a condition associated with premature aging. Criteria for deciding when premature aging occurs were set forth by Casarett (1964) and hold, in brief, that the mortality curve is advanced in time without alteration in shape and that all diseases and causes of death are proportionally advanced in time, as are all morphological and physiological manifestations of the aging process. When radiation effects and Werner syndrome, an autosomal recessive condition associated with a set of specific degenerative changes that mimic aging, were measured against these criteria, they did not pass the test for premature aging (Casarett 1964; Epstein et al 1966; Epstein 1985). Similarly, Down syndrome does not pass the test, at least based on current knowledge. Although the mortality curve for individuals with Down syndrome has, in the past, certainly been advanced in time, recent years have witnesssed a greater longevity of such persons (Masaki et al 1981; Dupont, Vaeth and Videbech 1986; Baird and Sadovnick 1987), and it is not presently known what the true Down syndrome mortality curve is or whether it indeed has the same shape as the curve for the general population. Furthermore, it is far from certain that there is a proportional advancement in time of the onset of either specific diseases or causes of death. Although congenital heart defects and leukemia are major causes of death early in life, the leading general cause of death at all ages in Down syndrome appears to be infection, Conditions such as cancer (excluding the unusual acute megakaryoblastic leukemia of childhood) and cardiovascular disease (excluding congenital heart defects) are, if anything, less prominent than in the general population (Scholl, Stein and Hansen 1976; Baird and Sadovnick 1988).