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Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. Methods A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. Results Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. Conclusion There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses. © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. Methods A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. Results The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. Conclusion This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate. © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.Leukemia (2009) 23, 85–94; doi:10.1038/leu.2008.257; published online 25 September 2008 [ABSTRACT FROM AUTHOR]

Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1–5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.Leukemia (2009) 23, 125–133; doi:10.1038/leu.2008.278; published online 16 October 2008 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which is about t-positive B-cell malignancy in atypical chronic lymphocytic leukemia.

Thirty cases of acute myeloid leukaemia (AML) with MYST histone acetyltransferase 3 (MYST3) rearrangement were collected in a retrospective study from 14 centres in France and Belgium. The mean age at diagnosis was 59.4 years and 67% of the patients were females. Most cases (77%) were secondary to solid cancer (57%), haematological malignancy (35%) or both (8%), and appeared 25 months after the primary disease. Clinically, cutaneous localization and disseminated intravascular coagulation were present in 30 and 40% of the cases, respectively. AMLs were myelomonocytic (7%) or monocytic (93%), with erythrophagocytosis (75%) and cytoplasmic vacuoles (75%). Immunophenotype showed no particularity compared with monocytic leukaemia without MYST3 abnormality. Twenty-eight cases carried t(8;16)(p11;p13) with MYST3-CREBBP fusion, one case carried a variant t(8;22)(p11;q13) and one case carried a t(8;19)(p11;q13). Type I (MYST3 exon 16-CREBBP exon 3) was the most frequent MYST3-CREBBP fusion transcript (65%). MYST3 rearrangement was associated with a poor prognosis, as 50% of patients deceased during the first 10 months. All those particular clinical, cytologic, cytogenetic, molecular and prognostic characteristics of AML with MYST3 rearrangement may have allowed an individualization into the World Health Organization classification.Leukemia (2008) 22, 1567–1575; doi:10.1038/leu.2008.128; published online 5 June 2008 [ABSTRACT FROM AUTHOR]

A series of 38 patients with acute myeloblastic leukemia (AML) with 49 or more chromosomes and without structural abnormalities was selected within the Groupe Francophone de Cytogénétique Hématologique (GFCH) to better define their characteristics. The median age of the patients was 65 years, and all FAB subtypes were represented. Although all chromosomes were gained, some seems to prevail: chromosome 8 (68%), 21 (47%), 19 (37%), and 13 and 14 (34% each). Since MLL rearrangement leads patients in a group with an unfavorable prognosis, search for cryptic rearrangements of MLL was performed in 34 patients and showed abnormalities in 5 (15%). When we applied the most frequent definition of complex karyotypes (three or more abnormalities), all patients with high hyperdiploid AML fall in the unfavorable category. Among the 18 patients without MLL rearrangement receiving an induction therapy, 16 (89%) reached CR and 6 (33%) were still alive after a 31-month median follow-up (14-61 months). Although this study was retrospective, these results suggest that high hyperdiploid AML without chromosome rearrangement seems to be a subgroup of uncommon AML (less than 1%), and may be better classified in the intermediate prognostic group. [ABSTRACT FROM AUTHOR]

Occipital encephalocele belongs to the family of neural tube defects, which occur in one among 2000 to 5000 live births. Syndromic encephaloceles include Meckel-Gruber syndrome and various chromosomal abnormalities. We report on a fetal case (13 WG) with bilateral cleft lip and palate, choanal atresia, occipital encephalocele, bilateral club feet, bilateral multicystic kidneys, enlarged bladder and urethral atresia. The fetal chromosome analysis showed a maternally inherited unbalanced translocation between the short arm of chromosome 1 and the long arm of chromosome 14, resulting in 1p35-pter deletion and 14q32-qter duplication (46,XY,der(1),t(1;14)(p35;q32)). Since the chromosomal breakpoints have not previously been implicated in syndromic encephalocele, this observation is of interest for the identification of other genes responsible for occipital encephalocele. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRβ) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRβ-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRβ-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRβ-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRβ-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRβ-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRβ-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.Leukemia (2007) 21, 121–128. doi:10.1038/sj.leu.2404410; published online 12 October 2006 [ABSTRACT FROM AUTHOR]

The NUP98 gene is fused with 19 different partner genes in various human hematopoietic malignancies. In order to gain additional clinico-hematological data and to identify new partners of NUP98, the Groupe Francophone de Cytogénétique Hématologique (GFCH) collected cases of hematological malignancies where a 11p15 rearrangement was detected. Fluorescence in situ hybridization (FISH) analysis showed that 35% of these patients (23/66) carried a rearrangement of the NUP98 locus. Genes of the HOXA cluster and the nuclear-receptor set domain (NSD) genes were frequently fused to NUP98, mainly in de novo myeloid malignancies whereas the DDX10 and TOP1 genes were equally rearranged in de novo and in therapy-related myeloid proliferations. Involvement of ADD3 and C6ORF80 genes were detected, respectively, in myeloid disorders and in T-cell acute lymphoblastic leukemia (T-ALL), whereas the RAP1GDS1 gene was fused to NUP98 in T-ALL. Three new chromosomal breakpoints: 3q22.1, 7p15 (in a localization distinct from the HOXA locus) and Xq28 were detected in rearrangements with the NUP98 gene locus. The present study as well as a review of the 73 cases previously reported in the literature allowed us to delineate some chromosomal, clinical and molecular features of patients carrying a NUP98 gene rearrangements.Leukemia (2006) 20, 696–706. doi:10.1038/sj.leu.2404130; published online 9 February 2006 [ABSTRACT FROM AUTHOR]

Imatinib mesylate (Gleevec®), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.Leukemia (2004) 18, 1340-1346. doi:10.1038/sj.leu.2403399 Published online 10 June 2004 [ABSTRACT FROM AUTHOR]

To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children ?15 years and 153 adults), and 67 (18.5%) [47 children (22.4%) and 20 adults (13.1%)] were shown to either harbor the t(5;14)q35;q32) translocation or express the HOX11L2 gene or both. Most of the common hematological parameters did not show significant differences within positive and negative populations, whereas the incidence of CD1a+/CD10+ and cytoplasmic CD3+ patients was significantly higher in positive than in negative children. Out of the 63 positive patients investigated by conventional cytogenetics, 32 exhibited normal karyotype, whereas the others 31 showed clonal chromosome abnormalities, which did not include classical T-ALL specific translocations. Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients. Our results also show that HOX11L2 expression essentially occurs as a result of a 5q35 rearrangement, but is not associated with another identified T-ALL specific recurrent genetic abnormality, such as SIL-TAL fusion or HOX11 expression.Leukemia (2003) 17, 1851-1857. doi:10.1038/sj.leu.2403061 [ABSTRACT FROM AUTHOR]

The MLL gene, located at 11q23, is frequently rearranged in acute leukaemia as either chimaeric fusion genes or partial tandem duplications. We report a series of 12 acute leukaemia cases with apparent amplification of the MLL gene ascertained using fluorescence in situ hybridisation (FISH). Seven cases showed intrachromosomal amplification of MLL, four cases showed extrachromosomal amplification as double minute chromosomes (dmin) and one case had separate subclones with dmin and homogenously staining region (hsr). Southern blot analysis of the MLL gene showed MLL gene rearrangement in three of the 10 successful cases. These cases do not naturally fall into either of the two recognised categories of MLL rearrangement and may represent a third variety of MLL gene abnormalities. [ABSTRACT FROM AUTHOR]

Therapy-related leukemia associated with chemotherapy, particularly alkylating agents and topoisomerase II inhibitors, are being reported with increasing frequency in the literature mainly after breast cancer. We also observed an increasing number of such leukemias in the data base of the specialized registry of hematological malignancies of the Côte d'Or department. Between 1980 and 1998, 156 AML and RAEB-t were registered in women in Côte d'Or. Among them, 12 occurred in women with breast cancer history (7.7%). Analysis by period of time shows a significant increase in the proportion of therapy-related leukemia secondary to breast cancer (P < 0.02). Chemotherapy including topoisomerase II inhibitors was used in 10 cases in which mitoxantrone was used in eight cases. In these eight cases, leukemia had clinical and biological characteristics usually described with topoisomerase II inhibitors but 44% were promyelocytic sub-type with the t(15;17) specific karyotypic abnormality. These data on a well-defined population demonstrate the increased proportion of therapy-related leukemia secondary to breast cancer, probably due to the use of mitoxantrone. [ABSTRACT FROM AUTHOR]

Two patients with Philadelphia-positive chronic myelogenous leukemia underwent allogeneic bone marrow transplantation from a related HLA mismatched donor (patient 1) or from an unrelated HLA-identical donor (patient 2). Following bone marrow transplantation partial engraftment (patient 1) or graft failure (patient 2) occurred followed by autologous Philadelphia negative hematopoietic recovery either spontaneously (patient 1) or after infusion of autologous bone marrow rescue (patient 2). Neither Philadelphia chromosome, nor ber-abl rearrangement was detectable by PCR analysis up to 7 years (patient 1) and 9 years (patient 2) post-transplantation. These two observations indicate that sustained engraftment of allogeneic bone marrow stem cells following a myeloablative regimen is not necessary to cure chronic myelogenous leukemia. It is hypothesized that the proliferative advantage of Philadelphia-negative progenitors and the anti-leukemic effect of lymphocytes in the graft have resulted in prolonged remission of the patients. [ABSTRACT FROM AUTHOR]

The MLL gene located at 11q23 has been described as a 'promiscuous' gene due its involvement with a large number of genetic partners. The EU Concerted Action Workshop on 11q23 provided 550 cases for study of which 82 showed abnormalities which did not involve the established translocations or deletion of 11q23. In these 'other' cases, which included inversions and duplications, 11q23 was found to be involved with 25 chromosome partners of which 10 had not been previously reported. These were 1q31, 4p11, 6q13, 8q21, 10q22, 10q25, 11q11, 11q21, 13q34 and 18q23. This study demonstrated the value of the Workshop, in confirming the diversity of chromosomal partner sites involved with 11q23 and in the identification of new partners. [ABSTRACT FROM AUTHOR]

This study prospectively analysed the relationships between immunophenotypic and cytogenetic features of blast cells in 432 acute non-lymphoblastic leukemias (ANLL) at presentation. An abnormal karyotype was detected in 232 cases (54%). These abnormalities were related to immunophenotypic markers as detected using a consensual panel of monoclonal antibodies allowing lineage assignment and investigation of myeloid marker expression on blast cells. In univariate analysis, CD9, CD10, CD15, CD34 and TdT expression appeared significantly associated with chromosomal anomalies. Multivariate analysis identified CD34 and CD9 expression as independently predictive of the presence of at least one cytogenetic abnormality (P < 10(-4) and P < 0.03, respectively). Significant associations between immunophenotypic and karyotypic features were observed both within individual FAB subgroups and independently from morphological criteria. Specific features were seen in five ANLL entities: M0 or M1/B lineage antigen positivity/t(9;22) or del(11)(q23); M2/CD13-/t(8;21); M4/CD13+, CD34+, CD36+/inv(16); M4 or M5/lack of B lineage antigen/del(11)(q23) or t(9;11). More practically, and although the relationships demonstrated only represent a fraction of homogeneous immunophenotypic subgroups, identification of such immunophenotypic features should prompt careful karyotypic examination, eventually using molecular biology analysis on non-growing cells. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias.

Presents a letter to the editor describing the case report of X-linked recessive ichthyosis in a girl.

Presents the case study of a person diagnosed with minimally differentiated acute myeloid leukemia at relapse. Treatment given to the patient during the initial diagnosis of leukemia; Relapse of acute leukemia in the patient after ten months of completion of treatment; Diagnosis of B III acute lymphoid leukemia on relapse.