Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia, and Acute Myeloid Leukemia Associated with Complete Or Partial Monos

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Leukemia (1999) 13, 376–385  1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7 H Hasle1, M Arico` 2, G Basso3, A Biondi4, A Cantu` Rajnoldi4, U Creutzig5, S Fenu6, C Fonatsch7, OA Haas8, J Harbott9, G Kardos10, G Kerndrup11, G Mann8, CM Niemeyer12, H Ptoszkova13, J Ritter5, R Slater14, J Stary´15, B Stollmann-Gibbels16, AM Testi6, ER van Wering17 and M Zimmermann5 for the European Working Group on MDS in Childhood (EWOG-MDS)

1Department of Pediatrics, Aarhus University Hospital, Denmark; 2Department of Pediatrics, University IRCCS S Matteo, Pavia, Italy; 3Department of Pediatrics, University of Padova, Italy; 4Department of Pediatrics, University of Milan, Italy; 5Department of Pediatrics, University of Mu¨nster, Germany; 6La Sapienza, Rome, Italy; 7Institute of Medical Biology, University of Vienna, Austria; 8St Anna Children’s Hospital, Vienna, Austria; 9Oncogenetic Laboratory, Children’s Hospital, Giessen, Germany; 10Department of Pediatrics, Free University of Amsterdam, The Netherlands; 11Department of Pathology, Odense University Hospital, Denmark; 12Department of Pediatrics, University of Freiburg, Germany; 13Department of Pediatrics, Ostrava, Czech Republic; 14Netherlands Working Party on Cancer Genetics and Cytogenetics, Rotterdam, The Netherlands; 152nd Department of Pediatrics, Prague, Czech Republic; 16Department of Pediatrics, University of Essen, Germany; 17Dutch Childhood Leukemia Study Group, The Hague, The Netherlands

We reviewed the clinical features, treatment, and outcome of The most conflicting area in the classification of childhood 100 children with myelodysplastic syndrome (MDS), juvenile MDS has been the pediatric equivalent of what the FAB group myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (−7) or deletion termed CMML. These children have most often been referred of the long arm of chromosome 7 (7q−). Patients with therapy- to as juvenile chronic myeloid leukemia (JCML) in the British induced disease were excluded. The morphologic diagnoses and American literature,7,8 whereas others have favored the according to modified FAB criteria were: MDS in 72 (refractory FAB term CMML.4,9–11 An International Working Group con- anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, cluded that the different terminology did not reflect the exist- RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML ence of different disorders and proposed the term juvenile in 28. The median age at presentation was 2.8 years (range 2 myelomonocytic leukemia (JMML). The term has attained months to 15 years), being lowest in JMML (1.1 year). Loss of 6,12–14 chromosome 7 as the sole cytogenetic abnormality was international acceptance and will be used throughout observed in 75% of those with MDS compared with 32% of this paper. Although we acknowledge that JMML often shows those with AML. Predisposing conditions (including familial myeloproliferative features different from other MDS types, we MDS/AML) were found in 20%. Three-year survival was 82% in have included JMML in the group of childhood MDS in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEB- accordance with the practice by other cooperative groups. T. Children with −7 alone had a superior survival than those Loss of chromosome 7 material, either as complete mono- with other cytogenetic abnormalities: this was solely due to a − − better survival in MDS (3-year survival 56 vs 24%). The reverse somy 7 ( 7) or as deletion of the long arm (7q ), is the most was found in AML (3-year survival 13% in −7 alone vs 44% in common cytogenetic abnormality in childhood MDS seen in other cytogenetic groups). Stable disease for several years was approximately 30% of cases.4,5,15 Only 4–5% of childhood documented in more than half the patients with RA or RAEB. AML cases show −7/7q−.16–19 AML patients with −7/7q− have Patients with RA, RAEB or JMML treated with bone marrow a very poor prognosis,16,17,19 but due to the infrequency of the transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest association there are very few data on the clinical character- prognostic factor. Only patients with a diagnosis of JMML fitted istics of these patients. what has previously been referred to as the monosomy 7 syn- Children with MDS and −7 have often been considered a drome. Our data give no support to the concept of monosomy distinct hematologic disorder described as the monosomy 7 7 as a distinct syndrome. syndrome, characterized by young age, male predominance, Keywords: myelodysplastic syndrome (MDS); acute myeloid leu- hepatosplenomegaly, and leukocytosis.20–23 The monosomy 7 kemia (AML); children; monosomy 7 syndrome has many similarities with JMML and the distinction between the two nosological entities has not been clear-cut. In a previous study we did not find any major clinical differences Introduction between JMML in children with and without −7.11 Further- more, −7 has been considered to represent a late event or an Myelodysplastic syndrome (MDS) comprises a heterogeneous opportunistic cytogenetic abnormality.24 Therefore, it may be group of clonal stem cell disorders characterized by ineffec- questioned whether a classification solely based on the loss tive hematopoiesis often with prominent morphologic abnor- of chromosome 7 is of clinical relevance. malities. MDS is rare in childhood with an annual incidence The aim of the present study was to describe the clinical 1 of only four/million. The French–American–British (FAB) characteristics, the predisposing conditions, survival and group proposed a classification of MDS comprising five sub- response to treatment of a large number of children with groups: refractory anemia (RA), RA with ringed sideroblasts −7/7q−. (RARS), RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia 2,3 (CMML). The FAB classification has become widely Materials and methods accepted for MDS in adults. The classification of childhood 4–6 MDS has remained rather controversial and inconsistent. Data on children with −7/7q− and myeloid malignancies were collected retrospectively through members of the European Correspondence: H Hasle, Department of Pediatrics, Aarhus Univer- Working Group on MDS in Childhood (EWOG-MDS). Patients sity Hospital Skejby, 8200 Aarhus N, Denmark; Fax: 45 8949 6023 previously exposed to chemotherapy or radiation, as well as Received 13 July 1998; accepted 20 November 1998 patients with Fanconi anemia or congenital granulocytopenia Monosomy 7 and myeloid leukemia H Hasle et al 377 were excluded. The study group consisted of 100 children Results from Austria (n = 5), Czech Republic (n = 8), Denmark (n = 20), Germany (n = 40), Italy (n = 15) and the Netherlands (n = Clinical characteristics 12). Data on 28 of the patients have been included in previous studies from EWOG-MDS.11,25 RA was diagnosed in 11 patients, RAEB in eight, RAEB-T in Inclusion required a diagnosis of MDS or AML and bone 10, JMML in 43 and AML in 28 (MO two, M1 four, M2 12, marrow (BM) or peripheral blood (PB) karyotype by standard M4 two, M5 one, M6 three, M7 two, unclassified two). The technique showing at least three cells with loss of a whole clinical characteristics according to morphologic diagnosis chromosome 7 or at least two cells with identical structural are shown in Table 1. The median age at presentation was abnormalities leading to loss of chromosome 7q material. 2.8 years (range 2 months to 15 years), being lowest in JMML Confirmatory fluorescence in situ hybridization (FISH) studies (1.1 year) (P Ͻ 0.001). JMML predominated among the young- were performed in a few cases, but the classification of the est children accounting for 83% of the 23 cases occurring in patients relied solely on standard cytogenetics. The first infants below 1 year of age (Figure 1). Boys dominated in all reported abnormal karyotype involving chromosome 7 was MDS subgroups with an overall boy/girl ratio of 2.4. In con- used to classify the patients as −7 alone, −7 plus other abnor- trast, a predominance of girls with AML resulted in a boy/girl malities (−7 + other), 7q− alone, or 7q− plus other abnormali- ratio of 0.75 (P Ͻ 0.01). ties (7q−+other). Karyotypes were described according to the At presentation 49 patients had fever Ͼ38°C, an active International System for Human Cytogenetic Nomenclature infection was documented in 34 children. Hepatosplenome- 1995.26 galy and lymphadenopathy were associated with JMML. Of All cases were categorized according to the FAB classi- the seven children with JMML who did not present with fication of MDS and AML, with the following two modifi- splenomegaly, five developed splenomegaly during the clini- cations: for a diagnosis of JMML up to 20% myeloblasts in the cal course. Skin rash was described in 16 children, nine of blood was accepted.11,27,28 AML was diagnosed when these had JMML. Blasts in the cerebrospinal fluid at presen- myeloblasts in PB were Ͼ30%, regardless of the number of tation were noticed in five patients, all with AML. Diabetes myeloblast in BM.29 insipidus was present in two patients, both had JMML with − White blood cell count (WBC) was corrected for the pres- 7. Chloroma occurred in five children with JMML, two with ence of nucleated red blood cells in PB. Reference values for RAEB-T, and two with AML. corpuscular volume (MCV) were taken from Dallman and Siimes30 and for hemoglobin F (HbF) from Huehns and Beaven.31 Due to the retrospective nature of the study some Hematologic findings data could not be retrieved. The number of patients with eval- = = Hematologic characteristics at diagnosis are given in Table uable data was: hemoglobin (n 99), MCV (n 68), HbF (n Ͻ = 41), WBC (n = 100), platelets (n = 99), complete PB differen- 2. Anemia (hemoglobin 11 g/dl) was present in 89% of the tial count (n = 97), complete BM differential count (n = 96), patients. Hemoglobin at presentation was highest among those with RA of whom two had a hemoglobin within normal spleen size (n = 100). reference for age; both showed macrocytosis, neutropenia, The date of diagnosis was defined as the date of first BM and thrombocytopenia. Macrocytosis was observed in seven examination suggesting a diagnosis of MDS or AML, also in of eight evaluable RA patients, but in only 27 of 60 non-RA patients in whom −7/7q− was detected only later. Date of patients (P Ͻ 0.05). HbF was elevated for age in 23 of 41 diagnosis ranged from November 1976 to March 1997. evaluable patients, but in only six of them did HbF exceed Patients 26 and 88 were lost to follow-up at 115 and 59 10%; one each with RA (HbF = 12%), RAEB (HbF = 47%), months, respectively. They were censored at the date of last RAEB-T (HbF = 70%) and two with JMML (HbF = 28% and follow-up. 70%). The latter was a 2-month-old boy with HbF of 70%, ␹2 The test was used to test statistical significance in contin- which is just above the upper normal limit for age. gency tables. Fisher’s exact test was applied when appropriate The presenting WBC was low in RA, RAEB and RAEB-T; for small sample size. Age distribution was compared using none of these patients presented with a WBC above 15 × Wilcoxon rank sum test. Survival was calculated from the date 109/l. Absolute monocytosis (Ͼ1 × 109/l) was observed in all of diagnosis to the date of death of any cause or last follow- patients with JMML, in one with RAEB-T and in five with AML up. The Kaplan–Meier method was used to estimate survival Neutropenia (Ͻ1.5 × 109/l) was seen in 43% of the patients 32 rates with comparisons based on the two-sided log-rank test. and thrombocytopenia (Ͻ150 × 109/l) in 83%. Standard errors (s.e.) were calculated using Greenwood’s for- Seven of 10 RAEB-T patients had BM blasts Ͻ20%, but mula. Prognostic factors were analyzed using Cox regression were classified as RAEB-T due to PB blasts Ͼ5%. Auer rods 33,34 and the method of recursive partition. The following vari- were present in four cases, all diagnosed as AML due to BM ables were included in the analyses: sex, age, hemoglobin, blasts Ͼ30%. BM erythropoiesis dominated in RA and RAEB WBC, platelets, morphologic diagnosis (RA, RAEB, RAEB-T, with a median myeloid:erythroid ratio of 1.0 and 0.9, respect- JMML, AML) and karyotype (−7, −7 +other, 7q−,7q−+other). ively, compared with 2.7 in RAEB-T and JMML and 11.2 in The recursive partition was performed according to the AML. method used by Trueworthy et al.35 Quantitative variables were categorized using the cutpoint which resulted in the highest risk-ratio in univariate Cox regression. The classi- Cytogenetic findings fication was repeated for each subgroup. The variable chosen for partition was the one with the largest estimated hazard Clinical characteristics according to karyotype are shown in ratio meeting the criterion of a P value Ͻ5%. Partitioning was Table 3. In MDS 75% of the patients had −7 as the sole abnor- restricted to splits which resulted in subgroups including more mality; this was found in only 32% of the AML cases (P Ͻ than 10 patients. 0.0001). 7q− was observed in 11% of those with MDS, but in Monosomy 7 and myeloid leukemia H Hasle et al 378 Table 1 Presenting features, treatment and survival in 100 children with complete or partial monosomy 7 according to diagnosis

RA RAEB RAEB-T JMML AML n = 11 n = 8n= 10 n = 43 n = 28

Boys/girls 7/4 6/2 7/3 31/12 12/16 Age at presentation (years) median 4.5 3.7 6.5 1.1 2.8 range 1.9–12.5 0.5–13.7 2.4–15.7 0.2–11.4 0.6–15.1 Hepatomegaly (%) 0 (0) 4 (50) 5 (50) 38 (88) 18 (64) Splenomegaly (%) 0 (0) 2 (25) 4 (40) 36 (83) 15 (54) Lymphadenopathy (%) 2 (18) 4 (50) 3 (30) 27 (63) 12 (43) Neuroﬁbromatosis 4 Down syndrome 2 Treatment None or low-dose 4 2 1 15 2 AML-like 2 3 3 12 23 AML like + BMT21583 BMT alone 3 2 1 8 0 3-year survival (%) 82 63 8 45 34

32% of those with AML (P Ͻ 0.05). A striking sex-difference was observed with male sex being associated with −7 as the sole cytogenetic abnormality (boy/girl ratio 3.2). In contrast, girls dominated among those with 7q− and in those with additional cytogenetic abnormalities (boy/girl ratio 0.7) (P Ͻ 0.001). Loss of chromosome 7 with additional cytogenetic abnormalities or 7q− occurred in 37 patients (Table 4). All those with AML and 7q− had simple deletions, which was seen in only one with MDS (P Ͻ 0.001). The remaining MDS patients had more complex abnormalities, add(7) (n = 2), der(7) (n = 4), ring(7) (n = 1). Trisomy 8 was the most common additional aberration noted in eight patients (two RAEB, one RAEB-T, ﬁve AML). Of the eight patients with trisomy 8 one had constitutional trisomy 21, three acquired trisomy 21, and one acquired pentasomy 21q. A total of seven had acquired additional copies of chromosome 21 (one RA, two RAEB, two RAEB-T, two AML) one with tetrasomy 21 and another with pentasomy 21q. In patient 421 with Down syndrome the acquired extra chromosome 21 was present in a separate clone to the −7. Six of the patients with −7 and other cytogenetic abnormalities had marker chromosomes. An interstitial deletion of 7q was demonstrated in patient 128 by standard cytogenetics and by FISH analysis in patient 79. The commonly deleted seg- ments of 7q located at 7q22 and 7q32–3336 were deleted in 11 and 13 of the 15 evaluable patients with 7q−, respectively. Only patients 121 and 312 had deletions outside the commonly deleted regions. Serial cytogenetic examinations were performed in 49 patients. In seven children a normal karyotype preceded the detection of −7/7q−. One patient with RAEB and a patient with JMML had −7 documented at follow-up without morphologic evolution. In four patients −7/7q− was detected at progression. In one patient with JMML −7 was documented only at relapse following BMT. Eight patients presenting with −7 showed clonal evolution (data not shown).

Associated conditions

Four children were known to have neuroﬁbromatosis type 1 Figure 1 Age distribution according to diagnosis. (NF1) and two had Down syndrome. One of the patients with NF1 and two additional JMML patients without NF1 had Monosomy 7 and myeloid leukemia H Hasle et al 379 Table 2 Hematologic characteristics at diagnosis given as median and range

RA RAEB RAEB-T JMML AML

Hemoglobin (g/dl) 10.5 (7.6–12.5) 7.4 (1.8–10.5) 7.8 (5.6–10.9) 9.2(3.5–12.4) 68 (3.2–15.4) MCV elevated for age (% of 7 (88) 3 (60) 3 (60) 13 (38) 8 (50) evaluable) HbF elevated for age (% of 4 (100) 3 (75) 2 (100) 12 (41) 2 (100) evaluable) WBC (109/l)a 3.8 (1.5–8.6) 4.4 (1.5–10.8) 4.9 (1.4–14.4) 21.1 (3.1–259) 13.6 (1.8–109) Platelets (109/l) 64 (6–211) 76 (6–140) 48 (10–390) 58 (10–496) 45 (7–324) aWBC corrected for the presence of nucleated red blood cells.

Table 3 Presenting features, treatment and survival in the 100 children according to karyotype

−7 −7 + other 7q− 7q + other n = 63 n = 20 n = 4n= 13

Boys/girls 48/15 9/11 0/4 6/7 Age at presentation (years) median 2.6 5.3 1.6 2.5 range 0.2–15.7 0.7–14.1 0.5–3.2 0.4–15.0 Diagnosis RA8201 RAEB 5102 RAEB-T 5500 JMML 36 2 3 2 AML 9 10 1 8 Hepatomegaly (%) 41 (65) 12 (60) 4 (100) 8 (62) Splenomegaly (%) 39 (62) 9 (45) 3 (75) 6 (46) Lymphadenopathy (%) 29 (46) 8 (40) 3 (75) 8 (62) Neuroﬁbromatosis 4 Down syndrome 2 Familial cases 6 3 1 Treatment None or low-dose 19 1 1 3 AML-like 19 14 1 9 AML-like + BMT 12 4 2 1 BMT alone 13 1 0 0 3-year survival (%) 50 42 0 35

xanthogranuloma. One patient had a constitutional detected in four of six cytogenetically evaluated family mem- inv(9)(p12q12). One child had been treated with anti-thymo- bers. JMML was diagnosed in one pair of homozygous twins, cyte globulin and corticosteroid for aplastic anemia 6 years both children presenting at the age of 6 months with prior to the diagnosis of MDS. Another child had received 45,XX,−7. The sister of patient 229 was evaluated as possible treatment with corticosteroid and androgens since infancy for bone marrow donor and showed leukopenia and dysplastic Diamond–Blackfan anemia. None of the children had granulocytopoiesis. Initial karyotype was normal, but follow- received G-CSF. up 2 years later showed 47,XX,add(7)(q22), +mar. Those with A variety of associated non-hematological abnormalities affected family members presented at a higher age (6.4 vs 2.7 were reported; Silver–Russel syndrome, Rothmund-Thomson years, P Ͻ 0.05), but did not show any significant differences syndrome (described in details elsewhere),37 macrocephalus, from the non-familial cases concerning sex, cytogenetics, hydrocephalus, facial dysmorphia (n = 3), mental retardation and survival. (n = 2), deafness, blindness, ptosis (n = 3), vermis cerebelli agenesis, atrial septal defect, and an undefined bleeding disorder in a pair of twins. The child with Silver–Russel syndrome Treatment and survival presented at 8 months of age with synchronous AML and Wilms tumor. Univariate analysis showed low platelet count, high WBC, RAEB-T, and 7q− to be significantly poor prognostic factors (Table 6). Cox regression analysis proved morphologic diag- Familial cases nosis to be the strongest prognostic factor (Table 6). Survival was superior in RA vs other subgroups (P = 0.02) with a 3- MDS or AML in siblings was identified in eight families (Table year survival of 82% (s.e. = 0.09) in RA, 63% (s.e. = 0.17) in 5). Furthermore, leukemia was found in second or third degree RAEB, 45% (s.e. = 0.08) in JMML, 34% (s.e. = 0.10) in AML, relatives in two additional families, resulting in a total of 10 and only 8% (s.e. = 0.11) in RAEB-T (Figure 2). affected families (10%). Information on the type of leukemia Children with −7 alone had a 3-year survival of 50% (s.e. in the family members was often incomplete, −7/7q− was = 0.06) vs 42% (s.e. = 0.12) in −7 other, 0% in 7q−, and 35% Monosomy 7 and myeloid leukemia H Hasle et al 380 Table 4 Karyotypes in the 37 patients with abnormalities other that complete monosomy 7 alone

EWOG No. Diagnosis Karyotype

Complete monosomy 7 with other aberrations (−7 + other) 119 RA 47,XX,+21/46,XX,−7,+21 229 RA 45,XX,add(2)(q32),−7,add(13)(q32) 605 RAEB 46,XX,del(3)(q?),−7,+21/45,XX,del(3)(p?),−7 117 RAEB-T 46,XY,−6,−7,+2mar 118 RAEB-T 47,XY,−7,+11,del(12)(q?),add(18)(p?),+21c 250 RAEB-T 47,XY,−7,+21,+21 421 RAEB-T 46,XX,add(5)(p?),−7,+21c/47,XX,idem,+8/ 49,XX,t(4;4),(q3?1;q3?5),+8,+21c,+21 602 RAEB-T 45,XY,−7,inv(9)(p12q12)c/near tetraploid 92 JMML 45,XY,inv(2)(p23q13),−7 104 JMML 45,XX,−7,i(17)(q10) 244 AML 44–47,XX,−6,del(6)(q21),−7,add(9)(q33),−10,−11,−16,−19,−2mar[cp12] 235 AML M0 45,XY,del(1)(q?),−7,add(11)(q?),−12,−14,add(17)(q?),+mar,+r/46,idem,+22 88 AML M1 47,XX,−7,der(11)(q?),+r,+mar 241 AML M1 46,XX,−7,+10 71 AML M2 46,XX,−7,+22 114 AML M2 46,XX,−7,+10 422 AML M2 48,XX,−7,+8,−12,+18,+19,+mar/49,XX,−7,+11,−12,+18,+19,+22,+mar 717 AML M2 46,XY,der(6)(?),−7,+8,der(11)(?),der(12)(?),−17,+2mar[cp8] 131 AML M4 47,XY,−7,i(21)(q10),+i(21)(q10),+mar/48,idem,+8 91 AML M6 45,XY,−7,add(12)(p?) Deletion 7q (7q−) 312 JMML 46,XX,add(7)(q36) 406 JMML 46,XX,add(7)(q22) 606 JMML 46,XX,del(7)(q?) 79 AML M0 46,XX,del(7)(q22),ish del(7)(q22q36) Deletion 7q with other aberrations (7q−+other) 248 RA 46,XY,+1,der(1;7)(q10;p10) 120 RAEB 47,XX,+8/46,XX,+1,der(1;7)(q10;p10) 719 RAEB 48,XY,r(7),+8,+21 15 JMML 46,XY,der(7)t(7;20)(q11;q11),del(20)(q11) 107 JMML 46,XY,t(1;3)(p13;p21),der(7)t(7;12)(q21;q13) 121 AML M1 46,XY,del(7)(q35),del(16)(q22) 72 AML M2 51,XX,+X,del(7)(q32),+8,+20,+21,+22 73 AML M2 46,XX,add(1)(p3?),add(5)(p15.1),del(5)(q22),del(7)(q22) 74 AML M2 47,XX,del(7)(q22),+8 75 AML M4 46,XY,t(6;8)(q?:q?),del(7)(q33),inv(16)(p13q22) 122 AML M5 46,XX,del(7)(q22),add(9)(p?23),del(12)(p11) 128 AML M7 45,XX,−5,der(7)del(7)(p21)del(7)(q22q33),−9,der(9)t(5;9)(q22;q34),dup(13)(q12q14),+mar 720 AML M7 46,XX,t(8;16)(p11;q13),add(9)(q34.3)/46,XX,del(7)(q22),t(8;16)(p11;q13)

Table 5 Hematological disorders in relatives

EWOG No. Sex/Age Diagnosis Cytogenetics Relative Age Diagnosis Cytogenetics

70 M/4yr AML −7 Grandmother ND Leukemia (NS) ND 79 F/6mo AML 7q− Twin sister 5mo AML ND 80 M/15yr RAEB-T −7 Sister ND AML ND 91 M/13yr AML −7 +other Cousin ND Leukemia (NS) ND 226 M/12yr RAEB-T −7 Sister ND Leukemia (NS) ND 229 F/12yr RA −7 +other Sister 17yr RA add(7)(q22) 250 M/7yr RAEB-T −7 + other Sister 6mo Leukemia (NS) ND 419 M/4yr RA −7 Sister 11yr Granulocytopenia Normal Father ND Granulocytopenia Normal Aunt 7yr AML ND Uncle 14yr AML ND Half-aunt 39yr AML ND Half-cousin 13yr RAEB −7 714 M/3mo JMML −7 Brother ND Died of bleeding, no diagnosis −7 715 F/6mo JMML −7 Mono-Twin 6mo JMML −7 = pt No. 716

ND, no data; NS, not speciﬁed. Monosomy 7 and myeloid leukemia H Hasle et al 381 Table 6 Analyses of prognostic factors

Factor P (log-rank test)

Univariate analysis Sex 0.73 Platelets Ͻ100 × 109/l 0.005 WBC Ͼ60 × 109/l 0.007 Age Ͻ2 years 0.28 Age Ͻ3 years 0.35 Age Ͻ4 years 0.21 RA 0.07 RAEB 0.64 RAEB-T 0.005 AML 0.74 −7 + other 0.25 7q− 0.007 7q−+other 0.91 Cox regression analysis ␹2 P Risk ratio Platelets Ͻ100 × 109/l 6.8 0.0092 2.4 WBC Ͼ60 × 109/l 5.3 0.0212 2.4 RAEB-T 9.9 0.0017 3.7

Figure 3 Survival in −7 alone vs other chromosome 7 abnormalities. (a) MDS; (b) AML.

RA and RAEB: Four of the six patients who did not receive any treatment showed stable disease during a median follow- up of 42 months (range 33–74). Of the eight patients treated Figure 2 Survival according to diagnosis. with AML regimens, three were treated within 3 months without signs of progression, five received AML therapy after progression following a median interval of 28 months. Five (s.e. = 0.14) in 7q−+other. The superior survival in −7 was received BMT following a median period of observation of 18 solely due to a better survival in MDS (3-year survival 56% months. None of them showed signs of progression. (s.e. = 0.07) vs 24% (s.e. = 0.11) (P = 0.0003). Figure 3a). The None of the five patients treated with intensive chemo- reverse was found in AML, with a 3-year survival of only 13% therapy not followed by BMT survives. However, a 2-year-old (s.e. = 0.12) in −7 vs 44% (s.e. = 0.12) in other cytogenetic boy with RAEB and −7 received AML therapy and remained groups (P = 0.26) (Figure 3b). The difference was not statisti- in remission for 7 years. He then relapsed with acute lym- cally significant. phoblastic leukemia with complex cytogenetic abnormalities, A prognostic score for childhood MDS proposed by the Brit- but without any detectable abnormalities of chromosome 7. ish group5 assigned one point each for HbF Ͼ10%, platelets Death from infection during therapy-induced cytopenia Ͻ40 × 109/l, and two or more cytogenetic abnormalities. occurred in two of eight patients receiving AML-like therapy. Application of the scoring system was hampered by HbF being BMT without prior chemotherapy was given to five children, evaluable in only 39 of the MDS patients and therefore not two of them are surviving. included in the regression analyses. The 3-year survival was 63% in those with score zero (n = 19), 35% in those with score 1 (n = 13), and 17% when score Ͼ1(n = 6) (P Ͻ 0.01). JMML: Fifteen patients received no or only low-dose ther- Survival and treatment were both associated with diagnosis apy. These patients had more favorable prognostic factors11 (Table 1). Treatment is therefore presented separately accord- by presenting at a lower median age (9 months) and only three ing to diagnosis. We did not find any difference in survival showing platelets Ͻ33 × 109/l. Six of the patients receiving no between RA and RAEB and the two groups are presented intensive therapy are alive. Patients 417 and 704 have shown together. It should be noted than only one of the RAEB stable disease for 110 and 28 months, respectively. Four patients had BM blasts Ͼ15%. patients (26, 714, 715, 716) had a normal karyotype at latest Monosomy 7 and myeloid leukemia H Hasle et al 382 follow-up, despite persistent hematologic abnormalities and Discussion organomegaly in the latter three patients. These three children presented below 6 months of age, two were monozygotic twin Loss of chromosome 7 material occurs in 30% of childhood brothers and the third had an affected brother. The evolution MDS4,5,15 and in 4–5% of childhood AML.16–19 The annual was considered to represent spontaneous cytogenetic incidence of childhood AML is 5.4/million vs 4.0 for MDS.1 remission since the patients received supportive therapy only, Thus, the ratio of MDS vs AML should, accepting the Danish except splenectomy in patient 26. The latter patient has been population-based figures, be 4.9. In the present series the ratio described previously.38 was 2.6, which may indicate a selection bias towards rela- None of the 12 patients treated with intensive chemo- tively more AML cases. However, there may also have been therapy not followed by BMT and only two of the eight a positive selection bias for JMML, due to recruitment of cases patients receiving AML therapy followed by BMT survive. for the foregoing EWOG-MDS study on JMML.11 RARS does Death from complications of the therapy-induced cytopenia occur in children, but is very rare4 and was not found in our occurred in six of the 20 patients receiving AML-like therapy. series. RARS has previously been reported in one patient with BMT without prior chemotherapy was performed in eight chil- −7.39 We found fewer cases with AML M4 and M5 and more dren at a median of 7 months (range 1–15) from diagnosis, with M2 and M6 than in unselected series of AML.18 six of these children survive. JMML occurred almost exclusively in young children below 4 years of age. The age at presentation in JMML was only 13 months, in accordance with previous studies including mainly 9,11 RAEB-T: The median survival was only 11 months (Figure JMML patients with normal karyotype. No age peak was 2). Only two of the 10 patients survive (250 and 316). Both observed for the other MDS types. AML showed a peak in patients received AML therapy followed by BMT and have infants below 2 years of age. The age distribution appears − − 1,40 remained in continued remission 4 and 18 months post BMT. similar to what is found in MDS and AML without 7/7q . There was a strong male predominance in MDS, whereas girls dominated in AML. A female predominance has previously been reported among children below 2 years of age with AML: Almost all patients received AML therapy (Table 1). AML.41 However, in the present study the male predominance The overall survival at 3 and 5 years was 34%, being consider- in MDS and female predominance in AML was observed ably lower, although not statistically significant, in those with − − − among both infants and older children. Male sex was strongly 7 alone (Figure 3b). Four children (one 7q , three 7) associated with −7 alone and female sex with additional cyto- received autologous BMT, three died of relapse, patient 422 genetic abnormalities. . has remained in complete remission 4 year post autologous Qualitative defects of the neutrophils have been docu- BMT. mented in patients with −7.20,21,42 Fever at presentation was noted in 49% of our patients and infection in 34%, comparable to what was found in a larger series of JMML mainly with Monosomy 7 syndrome? normal karyotype.11 Our previous study showed a similar pro- portion of patients with fever or infection at diagnosis in JMML The ‘infantile monosomy 7 syndrome’ has been defined as −7 with or without −7.11 In addition, the risk of infection-related in a child under 4 years of age with any type of MDS.5 Of the death following intensive chemotherapy in MDS seems to be 63 children with −7, 35 were below 4 years of age and had comparable in patients with and without −7.43 the following diagnoses according to the modified FAB cri- HbF was increased above 10% in five patients. Increased teria: RA (n = 4), RAEB (n = 3) and JMML (n = 28). Male sex HbF has been one of the hallmarks of JMML. Only two of our dominated (boy/girl ratio 4.0) in all morphologic subgroups. JMML cases had HbF Ͼ10%, one of them had 7q− and in the The patients with JMML below 4 years of age frequently had other it was just above the normal limit for age. This is in hepatomegaly (93%), splenomegaly (89%) and lymphadeno- accordance with our previous study,11 showing that signifi- pathy (58%). Splenomegaly was not found in any of those cantly increased HbF is very uncommon in JMML associated with RA or RAEB. Two of three with RAEB had modest hepato- with −7. megaly and lymphadenopathy. Increased WBC was associa- Seven patients showed −7/7q− at follow-up investigations ted with JMML (median 21 × 109/l, range 5.2–135), in contrast only, underscoring the importance of repeated cytogenetic to a median WBC of 3.7 × 109/l (range 2.1–5.5) in RA and examination in children with MDS.15 Six of those with −7 and 4.8 × 109/l (range 3.9–5.5) in RAEB. Only one JMML patient additional aberrations had marker chromosomes. It is likely overlapped the WBC range found in RA/RAEB. Children with that some of the marker chromosomes contained chromosome RA or RAEB had a 3-year survival of 86 vs 54% in JMML (not 7 material.44,45 Most of the patients with 7q− had what on statistically significant). Of the nine patients receiving AML- standard cytogenetics appeared to be terminal deletions. like therapy all died, however, one survived 7 years in However, FISH studies in such patients frequently show inter- remission. stitial deletions or cryptic translocations,46 as documented in Morphologic diagnoses in the 19 children aged 4–15 years one of our patients. with MDS and −7 showed RA (n = 4), RAEB (n = 2), RAEB-T Four children had NF1, two Down syndrome, one aplastic (n = 5) and JMML (n = 8). With the exception of RAEB-T being anemia, and one Diamond–Blackfan anemia. Familial leuke- associated with age Ͼ4 years, no significant differences were mia occurred in 10 children. A variety of non-hematological observed between those below or above 4 years of age. Hepa- abnormalities were reported. If we include the two children tomegaly, splenomegaly and leukocytosis were also associa- with Silver–Russel syndrome and Rothmund–Thomson syn- ted with JMML in older children, although the median WBC drome a total of 20 patients had predisposing conditions (21% in JMML (14 × 109/l) was lower than in younger patients. The in MDS and 18% in AML). Predisposing conditions (including 3-year survival was 71% in RA, 50% in RAEB, 25% in JMML previous chemotherapy and Fanconi anemia, not included and 13% in RAEB-T. here) was found in 30% in an unselected series of MDS.1 In Monosomy 7 and myeloid leukemia H Hasle et al 383 contrast, only 4% of children with AML are known to have cular favorable prognosis, as was also shown in a series from predisposing genetic disorders.47 St Jude Children’s Hospital.39 Children with MDS and −7 Down syndrome with −7/7q− has only been reported in a alone had a significantly better survival than those with other few cases.48–50 As many as 20% of children with RA, RAEB cytogenetic abnormalities. AML patients with −7/7q− had a or RAEB-T have Down syndrome.1 Finding only two cases of poor prognosis as in previous studies.17,47 The present study Down syndrome in the present series further indicates that indicates that the inferior survival in AML may only be related −7/7q− is relatively uncommon in myeloid leukemias in chil- to those with −7 as the sole abnormality. The male predomi- dren with Down syndrome.51,52 MDS and AML have been nance and the poor survival in AML with −7 is comparable described in a few patients with Diamond–Blackfan anemia,53 to what is found in MDS. AML with −7 may represent an although not previously associated with −7/7q−. The develop- advanced stage (blast crisis) of MDS rather than truly de novo ment of AML with 7q− in a child with Silver–Russel syndrome AML. Due to the low number of patients AML studies have is interesting in light of recent data showing uniparental dis- traditionally lumped together −7 and 7q−.16–19,24 The present omy for the entire chromosome 7 in some of these patients.54 study suggests major differences in survival and biology and Familial occurrence of MDS with −7/7q− has been reported we recommend that −7 and 7q− be analyzed separately in in a number of cases10,24,55–57 and has been claimed to future studies. account for as many as one-third of the children with −7.55 Complete loss of chromosome 7 occurred in all morpho- We found MDS or AML in relatives of 10 patients. This fre- logic subgroups. The patients differed in clinical features at quency is in contrast to a population-based study58 and a sin- presentation and in outcome. Only those patients with a diag- gle institution study5 including a total of 28 children with −7 nosis of JMML fitted what has previously been referred to as showing no relatives with MDS/AML. Familial MDS does also the monosomy 7 syndrome. A previous EWOG-MDS study of occur without −7/7q−5,59 and it is uncertain whether −7 per children with JMML11 showed no major clinical differences se increases the risk for familiar cases. There were no con- between JMML in children with and without −7. Spontaneous spicuous clinical characteristics, except for higher age, as growth in vitro and GM hypersensitivity are characteristics of reported previously,24 of those with affected family members JMML and are observed regardless of whether −7 is present compared with the non-familial cases. Some data indicate that or not13 (P Emanuel, unpublished data). NF1 has served as the inherited predisposing locus in familial MDS or AML with a model for the understanding of the pathogenesis of JMML. −7/7q− is not located on chromosome 7.56 This is in accord- Mutation in the NF1 gene results in a lack of neurofibromin ance with the absence of leukemia cases in a cohort study of leading to a persistent activation of the Ras protein and hence 183 persons with constitutional aberrations of chromosome disturbed signal transduction as if the ras gene had been 7.60 mutated.67,68 Ras mutations are found in 15% of children Spontaneous regression of −7 has occasionally been without NF1 who have MDS associated with −7.67 The fact reported in the literature.38,39,61–63 We add three new cases, that −7 is seen at about the same frequency when JMML all presenting with JMML, to this very unusual phenomenon. develops in NF1 as when it occurs in children without predis- It has been suggested that spontaneous remission occurs when posing conditions11 is further evidence that monosomy 7 MDS is a polyclonal expression of a multiorgan disease.64 Our should not be considered a discrete entity. It may be more cases with spontaneous cytogenetic remission had clonal appropriate to consider children with clinical features of hematopoiesis and no signs of associated systemic disease, JMML as one disorder regardless of the presence of −7. Loss although patient 714 had atrial septal defect and the twins of chromosome 7 occurs in a heterogeneous group of myeloid Nos 715 and 716 had an undefined bleeding disorder. disorders and our data give no support to the concept of None of the 20 children with MDS treated with AML-like monosomy 7 as a distinct syndrome. chemotherapy not followed by BMT is surviving, although one patient remained in remission for 7 years until secondary malignancy occurred. Eight of 28 patients with RA. RAEB or Acknowledgements JMML receiving AML-like therapy died during therapy- induced cytopenia. Previous studies5,39,43 showed similar poor Alexandra Fischer, Department of Pediatrics, University of outcome following intensive chemotherapy, although one Freiburg, Germany is greatly appreciated for excellent man- study reported favorable outcome following intensive chemo- agement of the database. We are indebted to the many doctors therapy in RAEB and RAEB-T.65 As the overall remission rate who generously contributed data to the study. and survival in childhood MDS is low −7 may not be an inde- pendent prognostic factor.43 In patients with RA or RAEB −7 alone may indicate a fair chance for a long stable period with- References out progression and a favorable outcome following BMT without prior chemotherapy. This is in contrast to MDS with 1 Hasle H, Kerndrup G, Jacobsen BB. Childhood myelodysplastic −7/7q− in adults, which is associated with a very poor prog- syndrome in Denmark: incidence and predisposing conditions. nosis.66 The survival in RA, RAEB, and JMML following BMT Leukemia 1995; 9: 1569–1572. without prior chemotherapy was superior to that of patients 2 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the classification of the myel- treated with AML therapy alone or AML therapy followed by odysplastic syndromes. Br J Haematol 1982; 51: 189–199. BMT. Although the comparison was hampered by the fact that 3 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, children who received AML-like regimens as first-line therapy Gralnick HR, Sultan C. Proposed revised criteria for the classi- may represent more aggressive disease, our data suggest that fication of acute myeloid leukemia. A report of the French–Amer- BMT is the treatment of choice for these patients. The indolent ican–British Cooperative Group. Ann Intern Med 1985; 103: nature of RA and RAEB often allows sufficient time searching 620–625. 4 Hasle H. Myelodysplastic syndromes in childhood. Classification, for an optimal donor. epidemiology, and treatment. Leuk Lymphoma 1994; 13: 11–26. Regression analyses showed morphologic diagnosis to be 5 Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ, Gib- the strongest prognostic factor. Children with RA had a parti- bons B, Reeves BR, Chessells JM. Pediatric myelodysplasia: a study Monosomy 7 and myeloid leukemia H Hasle et al 384 of 68 children and a new prognostic scoring system. Blood 1995; M, Zimmermann M. Allogeneic bone marrow transplantation for 85: 1742–1750. chronic myelomonocytic leukemia in childhood: a report from the 6 Haas OA, Gadner H. Pathogenesis, biology, and management of European Working Group on Myelodysplastic Syndrome in Child- myelodysplastic syndromes in children. Semin Hematol 1996; 33: hood. J Clin Oncol 1997; 15: 566–573. 225–235. 26 ISCN (1995). An International System for Human Cytogenetic 7 Freedman MH, Estrov Z, Chan HSL. Juvenile chronic myelogenous Nomenclature. Karger: Basel; 1995. leukemia. Am J Pediatr Hematol Oncol 1988; 10: 261–267. 27 Hasle H, Kerndrup G. Atypical chronic myeloid leukaemia and 8 Hann IM, Myelodysplastic syndromes. Arch Dis Child 1992; 67: chronic myelomonocytic leukaemia in children. Br J Haematol 962–966. 1995; 89: 428–429. 9 Castro-Malaspina H, Schaison G, Passe S, Pasquier A, Berger R, 28 Niemeyer CM, Fenu S, Hasle H, Mann G, Stary J, van Wering ER. Bayle-Weisgerber C, Miller D, Seligmann M, Bernard J. Subacute Differentiating juvenile myelomonocytic leukemia from infectious and chronic myelomonocytic leukemia in children (juvenile CML). disease. Blood 1998; 91: 365–367. Clinical and hematologic observations, and identification of prog- 29 Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, nostic factors. Cancer 1984; 54: 675–686. Bloomfield CD, Brunning R. Gale RP. Grever MR, Keating MJ, 10 Brandwein JM, Horsman DE, Eaves AC, Eaves CJ, Massing BG, Sawitsky A, Stass S, Weinstein H, Woods WG. Report of the Wadsworth LD, Rogers PC, Kalousek DK. Childhood myelodys- national cancer institute-sponsored workshop on definitions of plasia: suggested classification as myelodysplastic syndromes diagnosis and response in acute myeloid leukemia. J Clin Oncol based on laboratory and clinical findings. Am J Pediatr Hematol 1990; 8: 813–819. Oncol 1990; 12: 63–70. 30 Dallman PR, Siimes MA. Percentile curves for hemoglobin and red 11 Niemeyer CM, Arico` M, Basso G, Cantu`-Rajnoldi A, Creutzig U, cell volume in infancy and childhood. J Pediatr 1979; 94: 26–31. Haas OA, Harbott J, Hasle H, Kerndrup G, Locatelli F, Mann G, 31 Huehns ER, Beaven GH. Developmental changes in human hae- Stollmann-Gibbels B, van’t Veer Korthof ET, van Wering ER. Zim- moglobins. In: Benson P (ed). The biochemistry of Development. mermann M, and Members of the European Working Group on W Heineman Medical Books: London; 1971, pp 175–203. Myelodysplastic Syndromes in Childhood (EWOG-MDS). Chronic 32 Kaplan EL, Meier P. Nonparametric estimation from incomplete myelomonocytic leukemia in childhood: a retrospective analysis observations. J Am Stat Assoc 1958; 53: 457–481. of 110 cases. Blood 1997; 89: 3534–3543. 33 Cox DR. Regression models and life tables. J R Stat Soc B 1972; 12 Iversen PO, Rodwell RL, Pitcher L, Taylor KM, Lopez AF. Inhi- 34: 187–220. bition of proliferation and induction of apoptosis in juvenile myel- 34 Ciampi A, Hogg SA, Kates L. Stratification by stepwise regression, omonocytic leukemic cells by the granulocyte–macrophage col- correspondence analysis and recursive partition: a comparison of ony-stimulating factor analogue E21R. Blood 1996; 88: 2634– three methods of analysis for survival data with covariates. Com- 2639. putational Stat Data Analysis 1986; 4: 184–204. 13 Emanuel PD, Shannon KM, Castleberry RP. Juvenile myelomono- 35 Trueworthy R, Shuster J, Look T, Crist W, Borowitz MJ, Carroll A, cytic leukemia: molecular understanding and prospects for ther- Frankel L, Harris M, Wagner H, Haggard M, Mosijc´zuk AD, Pullen apy. Mol Med Today 1996; 2: 468–475. J, Steuber P, Land V. Ploidy of lymphoblasts is the strongest predic- 14 Arico` M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia. tor of treatment outcome in B-progenitor cell acute lymphoblastic Blood 1997; 90: 479–488. leukemia of childhood: a pediatric oncology group study. J Clin 15 Groupe Francais de Cytogeńe´tique He´matologique. Forty-four Oncol 1992: 10: 606–613. cases of childhood myelodysplasia with cytogenetics, docu- 36 Le Beau MM, Espinosa R, Davis EM, Eisenbart JD, Larson RA, mented by the Groupe Francais de Cytogeńe´tique He´matologique. Green ED. Cytogenetic and molecular delineation of a region of Leukemia 1997; 11: 1478–1485. chromosome 7 commonly deleted in malignant myeloid diseases. 16 Leverger G, Bernheim A, Daniel MT, Flandrin G, Schaison G, Blood 1996; 88: 1930–1935. Berger R. Cytogenetic study of 130 childhood acute nonlympho- 37 Rizzari C, Bacchiocchi D, Rovelli A, Biondi A, Cantu`-Rajnoldi A, cytic leukemias. Med Pediatr Oncol 1988; 16: 227–232. Uderzo C, Masera G. Myelodysplastic syndrome in a child with 17 Kalwinsky DK, Raimondi SC, Schell MJ, Mirro JJ, Santana VM, Rothmund–Thomson syndrome: a case report. J Pediatr Hematol Behm F, Dahl GV, Williams D. Prognostic importance of cytog- Oncol 1996; 18: 96–97. enetic subgroups in de novo pediatric acute nonlymphocytic leu- 38 Stollmann B. Fonatsch C, Havers W. Persistent Epstein–Barr virus kemia. J Clin Oncol 1990; 8: 75–83. infection associated with monosomy 7 or chromosome 3 abnor- 18 Creutzig U, Harbott J, Sperling C, Ritter J, Zimmermann M, Lo¨ffler mality in childhood myeloproliferative disorders. Br J Haematol H, Riehm H, Schellong G, Ludwig WD. Clinical significance of 1985: 60: 183–196. surface antigen expression in children with acute myeloid leuke- 39 Chan GCF, Wang W, Head D, Krance R, Chen G, Raimondi SC. mia: results of study AML-BFM-87. Blood 1995; 86: 3097–3108. Childhood monosomy 7: a clinical review of 25 cases in a single 19 Woods WG, Kobrinsky N, Buckley JD, Lee JW, Sanders J, Neudorf institution. Blood 1995; 86 (Suppl 1): 51a (Abstr.). S, Gold S, Barnard DR, DeSwarte J, Dusenbery K, Kalousek D, 40 Lie SO, Jonmundsson G, Mellander L, Siimes MA, Yssing M, Gus- Arthur DC, Lange BJ. Timed-sequential induction therapy tafsson G. A population-based study of 272 children with acute improves postremission outcome in acute myeloid leukemia: a myeloid leukaemia treated on two consecutive protocols with dif- report from the Children’s Cancer Group. Blood 1996; 87: ferent intensity: best outcome in girls, infants, and children with 4979–4989. Down’s syndrome. Nordic Society of Paediatric Haematology and 20 Sieff CA, Chessells JM, Harvey BA, Pickthall VJ, Lawler SD. Mono- Oncology (NOPHO).Br J Haematol 1996; 94: 82–88. somy 7 in childhood: a myeloproliferative disorder. Br J Haematol 41 Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer 1981; 49: 235–249. in children in the United States. Sex-, race, and 1-year age-specific 21 Gyger M, Bonny Y, Forest L. Childhood monosomy 7 syndrome. rates by histologic type. Cancer 1995; 75: 2186–2195. Am J Hematol 1982; 13: 329–334. 42 Ruutu P, Ruutu T, Repo H, Vuopio P, Timonen T, Kosunen TU, 22 Weiss K, Stass S, Williams D, Kalwinsky D, Dahl GV, Wang W, de la Chapelle A. Defective neutrophil migration in monosomy 7. Johnson FL, Murphy SB, Dow LW. Childhood monosomy 7 syn- Blood 1981; 58: 739–745. drome: clinical and in vitro studies. Leukemia 1987; 1: 97–104. 43 Hasle H, Kerndrup G, Yssing M, Clausen N, Østergaard E, 23 Evans JP, Czepulkowski B, Gibbons B, Swansbury GJ, Chessells Jacobsen N, Jacobsen BB. Intensive chemotherapy in childhood JM, Childhood monosomy 7 revisited. Br J Haematol 1988; 69: myelodysplastic syndrome. A comparison with results in acute 41–45. myeloid leukemia. Leukemia 1996; 10: 1269–1273. 24 Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 44 Flactif M, Lai JL, Preudhomme C, Fenaux P. Fluorescence in situ 7: epidemiology, biology, and mechanistic implications. Blood hybridization improves the detection of monosomy 7 in myelod- 1995; 85: 1985–1999. ysplastic syndromes. Leukemia 1994; 8: 1012–1018. 25 Locatelli F, Niemeyer C, Angelucci E, Bender-Go¨tze C, Burdach 45 Viguie´ F, Prigent Y, Ramond S, Baumelou E, Cadiou M, Dreyfus S, Ebell W, Friedrich W, Hasle H, Hermann J, Jacobsen N, Klinge- F, Zittoun R. Fluorescence in situ hybridization analysis of minute biel T, Kremens B, Mann G, Pession A, Peters C, Schmid HJ, Stary marker chromosomes in leukemia with monosomy 7. Leukemia J, Suttorp M, Uderzo C, van’t Veer Korthof ET, Vossen J, Zecca 1995; 9: 1154–1158. Monosomy 7 and myeloid leukemia H Hasle et al 385 46 Tosi S. Harbott J. Haas OA, Douglas A, Hughes DM, Ross FM, Familial bone marrow monosomy 7. Evidence that the predispos- Biondi A, Scherer SW, Kearney L. Classification of deletions and ing locus is not on the long arm of chromosome 7. J Clin Invest identification of cryptic translocations involving 7q by fluor- 1989; 84: 984–989. escence in situ hybridization (FISH). Leukemia 1996; 10: 644– 57 Gilchrist DM, Friedman JM, Rogers PC, Creighton SP. Myelodys- 649. plasia and leukemia syndrome with monosomy 7: a genetic per- 47 Woods WG, Nesbit ME, Buckley J, Lampkin BC, McCreadie S, spective. Am J Med Genet 1990; 35: 437–441. Kim TH, Piomelli S, Kersey JH, Feig S, Bernstein I, Hammond D, 58 Hasle H, Olsen JH. Cancer in relatives of children with myelod- the Children’s Cancer Study Group. Correlation of chromosome ysplastic syndrome, acute and chronic myeloid leukaemia. Br J abnormalities with patient characteristics, histologic subtype, and Haematol 1997; 97: 127–131. induction success in children with acute nonlymphocytic leuke- 59 Mijovic A, Antunovic P, Pagliuca A, Mufti GJ. Familial myelod- mia. J Clin Oncol 1985; 3: 3–11. ysplastic syndromes: a key to understanding leukaemogenesis? 48 Groupe Francais de Cytogeńe´tique He´matologique. Cytogenetic Leukemia Res 1997; 21(Suppl. 1): S6 (Abstr.). findings in leukemic cells of 56 patients with constitutional chro- 60 Hasle H, Olsen JH, Hansen J, Friedrich U, Tommerup N. Occur- mosome abnormalities. Cancer Genet Cytogenet 1988; 35: rence of cancer in a cohort of 183 persons with constitutional 243–252. chromosome 7 abnormalities. Cancer Genet Cytogenet 1998; 105: 49 Bunin N, Nowell PC, Belasco J, Shah N, Willoughby M, Farber 39–42. PA, Lange B. Chromosome 7 abnormalities in children with Down 61 Scheurlen W, Borkhardt A, Ritterbach J, Huppertz HI. Spon- syndrome and preleukemia. Cancer Genet Cytogenet 1991; 54: taneous hematological remission in a boy with myelodysplastic 119–126. syndrome and monosomy 7. Leukemia 1994; 8: 1435–1438. 50 Zipursky A, Wang H, Brown EJ, Squire J. Interphase cytogenetic 62 Benaim E, Hvizdala EV, Papenhausen P, Moscinski LC. Spon- analysis of in vivo differentiation in the myelodysplasia of Down taneous remission in monosomy 7 myelodysplastic syndrome. Br J Haematol 1995; 89: 947–948. syndrome. Blood 1994; 84: 2278–2282. 63 Renneboog B, Hansen V, Heimann P, De Mulder A, Jannsen F, 51 Creutzig U, Ritter J, Vormoor J, Ludwig WD, Niemeyer C, Reinisch Ferster A. Spontaneous remission in a patient with therapy-related I, Stollmann Gibbels B, Zimmermann M, Harbott J. Myelodyspla- myelodysplastic syndrome (t-MDS) with monosomy 7. Br J sia and acute myelogenous leukemia in Down’s syndrome. A Haematol 1996; 92: 696–698. report of 40 children of the AML-BFM Study Group. Leukemia 64 Bader-Meunier B, Tchernia G, Mielot F, Fontaine JL. Thomas C, 1996; 10: 1677–1686. Lyonnet S, Lavergne JM, Dommergues JP. Occurrence of myelop- 52 Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, How- roliferative disorders in patients with Noonan syndrome. J Pediatr ells WB, Gold S, Sanders J, Neudorf S, Smith FO, Woods WG. 1997; 130: 885–889. Distinctive demography, biology, and outcome of acute myeloid 65 Creutzig U, Bender-Go¨tze C, Ritter J, Zimmermann M. Stollmann- leukemia and myelodysplastic syndrome in children with Down Gibbels B, Ko¨rholz D, Niemeyer C. The role of intensive AML- syndrome: children’s cancer group studies 2861 and 2891. Blood specific therapy in treatment of children with RAEB and RAEB-T. 1998; 91: 608–615. Leukemia 1998; 12: 652–659. 53 Mori PG, Haupt R, Fugazza G, Sessarego M, Corcione A, Strigini 66 Greenberg P, Cox C, Le Beau MM, Fenaux P, Morel P, Sanz G, P, Sansone R. Pentasomy 21 in leukemia complicating Diamond– Sanz M, Vallespi T. Hamblin T, Oscier D, Ohyashiki K, Toyama Blackfan anemia. Cancer Genet Cytogenet 1992; 63: 70–72. K, Aul C, Mufti G, Bennett J. International scoring system for eval- 54 Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyna uating prognosis in myelodysplastic syndromes. Blood 1997; 89: H, Mehes K, Hamel BCJ. Otten BJ, Hergerberg M, Werder E, Scho- 2079–2088. enle E, Schinzel A. Uniparental disomy 7 in Silver–Russel syn- 67 Kalra R, Paderanga DC, Olson K, Shannon KM. Genetic analysis is drome and primordial growth retardation. Hum Mol Genet 1995; consistent with the hypothesis that NF1 limits myeloid cell growth 4: 583–587. through p21ras. Blood 1994; 84: 3435–3439. 55 Carroll WL, Morgan R, Glader BE. Childhood bone marrow mono- 68 Shannon KM, O’Connell P, Martin GA, Paderanga D, Olson K, somy 7 syndrome: a familial disorder? J Pediatr 1985; 107: Dinndorf P, McCormick F. Loss of the normal NF1 allele from 578–580. the bone marrow of children with type 1 neurofibromatosis and 56 Shannon KM, Turhan AG, Chang SS, Bowcock AM, Rogers PC, malignant myeloid disorders. New Engl J Med 1994; 330: 597– Carroll WL, Cowan MJ, Glader BE, Eaves CJ, Eaves AC, Kan YW. 601.