COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia.

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2-8, Δ3-8 or Δ4-8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.

[Mosaic isochromosome Xq and microduplication 17p13.3p13.2 in a patient with Turner syndrome and congenital cataract]. / Isocromosoma Xq en mosaico y microduplicación 17pl3.3pl3.2 en una paciente con síndrome de Turner y catarata congénita.

The combination of Turner syndrome with other genetic disorders such as congenital cataract has been reported, but its association with a congenital form with autosomal dominant inheritance and incomplete penetrance has not been previously reported in the literature. There are no reports on its presentations with rearrangements on chromosome 17. We report the exceptional case of a 20 months old girl with a constellation of major and minor anomalies, diagnosed with mosaic Turner syndrome by isochromosome Xq associated with a microduplication 17p13.3p13.2, who also had bilateral congenital nuclear cataract autosomal dominant with incomplete penetrance. We reviewed in the literature the origin and cause of these genetic alterations and we provided an approach to the hypothesis of the pathogenesis of the association of two of these genetic disorders in the same patient.

Case report of isochromosome 17q in acute myeloid leukemia with myelodysplasia-related changes after treatment with a hypomethylating agent.

Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation. We present a case of chronic myelomonocytic leukemia with normal cytogenetics at diagnosis treated with decitabine (with good response); however, the patient evolved to acute myeloid leukemia with i(17q) shortly after suspending treatment. To the best of our knowledge, this is the first report of acute myeloid leukemia with myelodysplasia-related changes with i(17q) after the use of a hypomethylating agent.

Isocromosoma 18q en mosaico: caso clínico / Mosaic Isochromosome 18q: case-report

Background: The Isochromosome 18q and chromosome 18 short arm deletion (18p-) constitute structural anomalies that are reported with certain frequency in the literature. However, the association of both abnormalities in a patient is very uncommon. Objective: Description of a clinical case of Isochromosome 18 with emphasys in the few phenotypic manifestations. Case-report: Female infant 18 months-old, with short stature, minor dysmorphic features and a slight psychomotor developmental delay, whose chromosomal study in peripheral blood showed a chromosomal mosaicism with two cell lines: chromosome 18 long arm isochromosome and deletion of chromosome 18 short arm. The chromosomal analysis of both parents did not show numerical neither morphological alterations. Discussion: This case illustrates the importance of requesting a karyotype in patients with small stature, dysmorphic features and/or malformations. The patient clinical features are compared with other similar cases described in the literature. The coexistence of both structural abnormalities (mosaicism) is extremely uncommon.

Introducción: El Isocromoma 18q y la deleción del brazo corto del cromosoma 18 (18p-), son anomalías estructurales que se reportan con cierta frecuencia en la literatura. Sin embargo, la asociación de ambas alteraciones en una misma paciente es muy infrecuente. Objetivo: Descripción de un caso clínico de Isocromosoma 18 con énfasis en la escasas manifestaciones fenotípicas. Caso Clínico: Lactante femenino de 18 meses de edad portador de talla baja, dismorfias menores y un leve retraso del desarrollo sicomotor, cuyo estudio cromosómico en sangre periférica mostró un mosaico compuesto por un isocromosoma del brazo largo del cromosoma 18 y otro cromosoma 18 con deleción del brazo p. El análisis cromosómico de ambos padres no mostró alteraciones numéricas ni morfológicas. Discusión: Este caso ilustra la importancia de solicitar un cariograma en pacientes con talla baja, dismorfias y/o malformaciones. Se describen las malformaciones encontradas y se compara con otros casos similares descritos en la literatura. La alteración estructural en mosaico reportada es sumamente infrecuente.

FISH, PCR and cytogenetic characterization in a girl with ambiguous genitalia and karyotype mos46,X,iso(Y)(qter-->p11.3::p11.3-->qter)[80]/45,X[17]/46,X,+mar[3].

A cytogenetic study was carried out in a girl with virilized external genitalia, who showed a karyotype containing a Y isochromosome in mosaic form: mos46,X,iso(Y)(qter-->p11.3::p11.3-->qter)[80]/45,X[17]/46,X,+mar[3]. The chromosome aberrations were confirmed by fluorescence in situ hybridization analysis, with both whole chromosome paint Y probe and centromeric X chromosome probe. The molecular analyses by PCR detected the presence of the SRY, DAZ and AMGY genes, confirming the presence of the whole long arm and almost whole short arm of the Y chromosome. We suggest that the structural alteration of the Y chromosome was a new mutation, which occurred in the initial mitotic divisions of the embryo, originally 46,XY. The breakpoints occurred on the distal extremity of the short arm with later fusion of its extremities producing a Y isochromosome. The later numerical alteration occurred as a consequence of chromosomal instability. Although almost all cells (80%) in peripheral blood belonged to the iso(Y) line with a duplicated SRY gene, this did not determine male sexual differentiation in the patient. The result of accurate evaluation provides correct sex assignment and the prevention of the neoplastic degeneration of a dysgenetic gonad.

Sympatric occurrence of three cytotypes and four morphological types of B chromosomes of Astyanax scabripinnis (Pisces, Characiformes) in the River Ivaí Basin, state of Paraná, Brazil.

Chromosomes of Astyanax scabripinnis from the Tatupeba stream, Ivaí Basin (state of Paraná, Brazil), were analyzed. Astyanax scabripinnis population presents 3 different diploid numbers (2n = 46, 48 and 50) and B chromosomes in each cytotype. Eighty per cent of the females among individuals of cytotype I (2n = 50) has a metacentric B macrochromosome, whereas three different types of B chromosomes were identified in individuals of cytotype II (2n = 48). Cytotype III (2n = 46) showed two B chromosomes of different morphologic types (metacentric macrochromosomes and acrocentric) in all specimens and cells analyzed. Constitutive heterochromatin pattern for the three cytotypes showed weak markings in centromeric regions and conspicuous blocks in the telomere regions of ST and A chromosomes. Whereas C-banding showed that B chromosomes were totally or partially heterochromatic, a discussion on their behavior and origin was also undertaken.

Sindrome de Pallister Killian ou tetrassomia do braco curto do cromossomo 12 em mosaico : relato de dois casos diagnosticados pela hibridizacao in situ por fluorescencia (FISH) / Pallister Killian syndrome or tetrasomy of the short arm of the chromosome 12 mosaicism : report on two cases diagnosed by fluorescense in situ hybridization

A sindrome de Pallister Killian (SPK) e uma doenca rara caracterizada por multiplas malformacoes, retardo mental profundo e presenca de um isocromossomo...