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Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98(NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11fusion gene (4.0%). The most frequent NUP98fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3ITD, WT1, CEBPA, NBPF14, BCRand ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.

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Polymicrogyria PMG is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12yearold girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplicationdeletion and bacterial artificial chromosomes BACsarray also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACsarray in detecting complex rearrangements. © 2009 WileyLiss, Inc.

Genosensor Array 300 Abbott is a multiplex platform for arraybased comparative genomic hybridization that detects unbalanced genomic aberrations including whole chromosome gainslosses, microdeletions, duplications and unbalanced subtelomeric rearrangements. A series of 30 patients with unexplained mental retardation, dysmorphic features, congenital abnormalities and normal high resolution karyotype and FISH subtelomeric studies were analyzed using Genosensor Array 300 arrayCGH. We identified a chromosomal aberration in one patient with an interstitial 1p31.1 deletion. FISH analysis with BACs specific probes of the 1p region confirmed the interstitial 1p22.2p31.1 deletion. The patient was a 20yearold man with short stature, facial dysmorphism including asymmetry, scoliosis, severe psychomotor delay and an epibulbar dermoid cyst. The phenotype was compatible with Goldenhar syndrome despite the absence of asymmetric ears. This observation is of interest since it could be a clue in the search for the genes responsible for Goldenhar syndrome. This study demonstrates the utility of the arrayCGH technology in detecting interstitial deletions. © 2008 WileyLiss, Inc.

Constitutional interstitial deletions of 5q are relatively rare and most are poorly characterized cytogenetically. Consequently a definite karyotype–phenotype correlation is difficult to establish. We report on a new case of a girl presenting with an abnormal cry, upslanting palpebral fissures, hypertelorism, anteverted nostrils, microretrognathia, growth retardation, and an adenoid cyst at the base of the tongue. The first suspected diagnosis was cri‐du‐chat syndrome because of the mewing cry. Standard cytogenetic analyses were interpreted as normal, but FISH studies using the probe of cri‐du‐chat syndrome with the control probe EGR1 (5q31.2)/D5S23 (Abbott) revealed a 5q31.2 microdeletion which was then confirmed by CGH‐array (Abbott). FISH studies using PACs and BACs clones (Rocchi, Italia) enabled us to characterize the breakpoints of the deleted region. Cytogenetic analysis with FISH studies revealed a normal karyotype with normal 5q31 region in both parents. This case is compared with the other cases reported in the literature. © 2007 Wiley‐Liss, Inc.

We report on a 4‐year‐old female presenting with intrauterine growth retardation, facial dysmorphic features, major feeding difficulties with severe diarrhea and vomiting, mental retardation with abnormal behavior and hypertonia. Feeding difficulties were the most invalidating features with absent oral intake requiring persistent enteral feeding. Standard cytogenetic studies were normal, but high‐resolution chromosome analyses revealed a small de novo interstitial deletion of the long arm of chromosome 20, 46,XX,del(20)(q11.21q12). The deletion was confirmed using metaphase comparative genomic hybridization (CGH) and multicolor high resolution banding (mBAND). The deletion breakpoints were characterized using FISH analyses with YACs, PACs, and BACs clones located in the deleted and adjacent regions. A 6.6‐Mb deleted region between markers D20S815 (20q11.22) and D20S435 (20q12) could be delineated. None of the nine previously reported cases with interstitial 20q deletion found in the literature involve the same breakpoints. This report further emphasizes the indication of high‐resolution chromosome analyses in children with syndromic mental retardation. The description of additional cases would be useful in order to better characterize the phenotype of patients with proximal interstitial 20q deletion. © 2006 Wiley‐Liss, Inc.

The phenotype of mosaic variegated aneuploidy (MVA) syndrome is characterized by severe microcephaly, growth deficiency, mental retardation, and mild physical anomalies. The MVA syndrome is associated with mosaicism for several different aneuploidies involving many different chromosomes with or without premature centromere division (PCD). To date 28 cases of MVA syndrome have been reported. We report the first case of MVA syndrome without microcephaly. The clinical features in our patient included craniofacial dysmorphic features, growth retardation, and developmental delay. Cytogenetics analyses and FISH studies showed multiple aneuploidy with trisomy 18, 19, and 8, respectively in blood lymphocyte and fibroblastes without PCD. This case is compared with the other of MVA syndrome previously reported in literature. From this case report, we suggest that microcephaly is not mandatory for the diagnosis of MVA syndrome. © 2005 Wiley‐Liss, Inc.

A common feature of T cell acute lymphoblastic leukemias (T-ALLs) is the presence of structural alteration of the 5' part of the tal-1 locus, localized on chromosomal band 1p32. These alterations consist of either a t(1;14)(p32;q11) chromosomal translocation (3% of T-ALLs) or tald submicroscopic deletion (12-25% additional T-ALLs). We have characterized a case of T-ALL with t(1;14)(p32;q11) in which, unlike the majority of t(1;14), the recombination with the T cell receptor delta elements affected the 3' side of the tal-1 locus. In this case, tal-1 transcription is initiated from a promoter located within the fourth exon similarly to the DU 528 cell line. In a T-ALL bearing a t(1;14) affecting the 5' part of tal-1, two types of tal-1 transcripts were observed, namely those probably initiated from the D delta region juxtaposed to tal-1 by the translocation, and those from the exon 4 promoter. It is interesting that this exon 4 promotion was also found in leukemic T cell lines and T-ALL samples without apparent tal-1 genomic alteration. In contrast, no transcript initiated from the exon 4 promoter was found in T-ALL with tald1 or tald2 deletion. In these cells, tal-1 is expressed via SIL-tal-1 fused transcripts. Finally, this exon 4 initiation was detected neither in normal bone marrow, nor in malignant cells from the erythroid/megakaryocytic lineages. Taken as a whole, these data suggest that the exon 4 promoter is specifically active in T cell lineage.

Data on myelodysplastic syndromes (MDS) are seldom collected by cancer registries and unbiased findings from population-based studies remain rare. We report detailed information on MDS in a well-defined French population in the period 1980-1990. The crude incidence rate was 3.2 per 100000 per year and no significant change in incidence was noted in the study period. The sex ratio was 1.9 and the male predominance was present in all age groups. We observed a rise in incidence after 60 years of age but no significant change in incidence of MDS as a whole was observed over the period studied. Refractory anaemia with excess of blasts (RAEB) was the most frequent subtype. Overall 5 year transformation rate of MDS was 31% (+/- 4%) but it was 100% in RAEB in transformation. The observed 5 year survival rate was 23% +/- 3% and the corresponding corrected rate was 33%. The prognosis of RAEB in transformation was worse than the prognosis of other subtypes (P < 0.01). Discrepancies with epidemiological data from other European countries are discussed.

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Since January 2004, the French Ministry of Health supports a multicentric study aimed at detecting biological prognostic markers in B-CLL at Binet stage A, able to identify those patients in early clinical disease stage who will progress to a more advanced disease requiring early therapy. These include: 1/ detection by FISH of prognostically relevant cytogenetic abnormalities [trisomy 12, deletions of the ATM and P53 genes, and deletions at chromosomal band 13q14], 2/ cytoplasmic expression of ZAP-70 and CD38 by flow cytometry, 3/ IgVH gene analysis, and 4/ serum concentration levels of sCD23 and thymidine kinase. 550 patients from 10 institutions are currently enrolled in this study, 331 men and 219 women, with a median age at the time of diagnosis of 66 years (ranged from 26 to 100). To date interphase cytogenetic analyses by FISH have been carried out in leukemic cells of 484 patients using commercially available probes. For deletions, results are scored as A, B or C depending on the % of deleted lymphocytes [A = <5 (negative), B = 5–20, C = >20–100)]. The distribution of the prognostically relevant cytogenetic abnormalities is as follows: 63.6 % (n = 308) 13q14 deletions, 12.6% (n = 61) trisomies 12, 11.1% (n = 54) ATM gene deletions, and 16.6 % (n = 81) P53 gene deletions, all equally shared between men and women subgroups. Conventional cytogenetics (CC) have been performed in 391 out of the 484 patients. Results of the two techniques (FISH/CC) are highly discordant for detection of 13q-, 11q-, and 17p- deletions, respectively observed in 8.8 %, 3.6%, 4.4% of our cases by CC, and quite similar for detection of trisomy 12 (9.8% by CC). Nevertheless, FISH/CC discordance disappears for 11q- and 17p- detections when only FISH results from the C group are taken into account (5.7%, 4.3% deleted cells, respectively, in C group), showing the power of FISH to detect minor 11q- and 17p- clones in B-CLL at Binet stage A. In addition, CC detect abnormal karyotypes in 38.6 % of cases, including recurrent numerical abnormalities [21% (n=32) involving chromosome X, 3.3% chromosome 19], and structural rearrangements (5.3% at 14q32, and 3.9% 6q deletion). 15.9% of abnormal karyotypes (n = 24) are complex. IgVH gene analyses have been performed in 301 patients. As expected, adverse prognostic genetic markers [ATM and P53 deletions, trisomy 12] are significantly more frequent in cases with unmutated IgVH sequences (n = 83) as compared to mutated cases (n = 218) [? 2 tests: P < 0.0001, P = 0.008, and P = 0.0004, respectively]. On the contrary, the prognostically favorable 13q14 deletion is more frequent in cases with mutated IgVH status [? 2 test: P = 0.0002]. Comparison with the ZAP-70 status, analyzed by flow cytometry, shows less clear distributions of ATM and P53 deletions, trisomy 12 and 13q deletion, between the ZAP-70 + (n = 112) and ZAP-70 - (n=209) subgroups [? 2 tests: P < 0.008, P = 0.32, P = 0.046, and P = 0.048, respectively]. By May 2006, this ongoing study designed for 700 patients should provide very helpful data on laboratory parameters important in the management of untreated B-CLL at Binet stage A.

Since January 2004, the French Ministry of Health supports a multicentric study aimed at detecting biological prognostic markers in B-CLL at Binet stage A, able to identify those patients in early clinical disease stage who will progress to a more advanced disease requiring early therapy. These include: 1/ detection by FISH of prognostically relevant cytogenetic abnormalities [trisomy 12, deletions of the ATMand P53genes, and deletions at chromosomal band 13q14], 2/ cytoplasmic expression of ZAP-70 and CD38 by flow cytometry, 3/ IgVHgene analysis, and 4/ serum concentration levels of sCD23 and thymidine kinase. 550 patients from 10 institutions are currently enrolled in this study, 331 men and 219 women, with a median age at the time of diagnosis of 66 years (ranged from 26 to 100).