Balkan Journal of Medical Genetics

ACUTE PRE-B LYMPHOBLASTIC LEUKEMIA AND CONGENITAL ANOMALIES IN A CHILD WITH A DE NOVO 22q11.1q11.22 DUPLICATION
Vaisvilas M, Dirse V, Aleksiuniene B, Tamuliene I, Cimbalistiene L, Utkus A, Rascon J
*Corresponding Author: Jelena Rascon, M.D., Ph.D., Center for Pediatric Oncology and Hematology, Children’s Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos, Santariskiu St. 4, LT 08406 Vilnius, Lithuania. Tel: +3705-232- 8703. Fax: +3705-272-0368. E-mail: jelena.rascon@santa.lt
page: 87

MATERIALS AND METHODS

Cytogenetic Analyses. Conventional chromosome analysis was carried out using G-banding techniques on stimulated peripheral blood lymphocytes according to standard laboratory protocols. A total 100 metaphases were analyzed. The karyotype was described according to the guidelines of the International System for Human Cytogenetic Nomenclature [3]. Chromosomal Microarray Analyses. The analysis was performed using the Infinium HD whole-genome genotyping assay with the HumanCytoSNP-12 BeadChip (Illumina Inc., San Diego, CA, USA) that was done according to standard protocol provided by the manufacturer. This array platform contains 299,140 SNPs distributed across the human genome with an average resolution of 31 kb. Genotypes were called by GenomeStudio Genotyping Module v2.0 (Illumina Inc.). Log R ratio and B allele frequency (BAF) values were extracted from GenomeStudio software and used in further copy number variation (CNV) analyses and breakpoint mapping with Hidden Markov Model-based QuantiSNP software (v1.1) [4]. Constitutional copy number polymorphisms were excluded based on comparison with the Database of Genomic Variants (http://projects.tcag.ca/variation). Case Report. A male patient, the first child of Caucasian non consanguineous parents, was born in the 40th gestational week. Weight at birth was 3900 g (75th percentile) and height was 59 cm (97th percentile). Shortly after birth, he was diagnosed with total anomalous pulmonary venous drainage, atrial septal defect and patent arterial duct that required urgent surgical care to repair this hemodynamically significant congenital heart defect. From the age of 6 months, the boy experienced episodes of periodic vomiting and abdominal cramps. Thorough investigations revealed duodenogastric reflux with multiple esophageal erosions and the intestinal malrotation. At 3 years of age, the boy was examined by a clinical geneticist. The patient’s weight, height and head circumference corresponded to the 50th percentile. His facial features appeared slightly dysmorphic with widely spaced eyes, superior placement of the eyebrows, down slanted palpebral fissures, mild ptosis, broad flat nose, opened mouth (Figure 1). His psychomotor development was borderline normal. A later review at age 5, after treatment of ALL, showed good progress and a normal development. One year later at the age of 4, the boy experienced an acute attack of diffuse abdominal pain and distention and was therefore rushed to the emergency department. A thorough investigation revealed an acute bowel obstruction due to malrotation of the intestines. During the next year, the patient was readmitted to the hospital several times for symptoms of infectious colitis and pancytopenia, until acute leukemia was diagnosed at the age of 4. Thirty percent of blast cells were present in peripheral blood. A bone marrow smear revealed hypercellular bone marrow with 83.5% of blasts and a DNA index of 1.2. Flow cytometry of the malignant clone in the bone marrow revealed the lymphoid origin of the blast cells with the following phenotype: CD45+, CD10+, CD38+, TdT+, CD19+, CD22+, cCD22+bl, cCD79a+, CD58+, CD66c+, CD123+, CD13-, CD15-, CD20-, CD33-, CD34-, cCD3-, cMPO-. Hence, pre-B ALLwas diagnosed. The patient was treated according to NOPHO ALL- 2008 clinical trial protocol. To date, the boy is on maintenance therapy and is in remission 2 years after diagnosis. Conventional chromosome analysis in peripheral blood cells revealed a mosaic karyotype 47,XY,+mar[85]/46, XY[15] (Figure 2). For further determination of the chromosomal origin of the marker chromosome, a whole-genome SNP array was carried out. The SNP array analysis revealed a 6.6 Mb duplication in the 22q11.1q11.22 (hg[19]: chr22:16079545-22701051) region (Figure 3) and delineated the marker chromosome. Parental SNP array analysis revealed a de novo origin of the 22q11.1q11.22 duplication in the proband. Duplication 22q11.1q11.22 was identified and assessed as clinically significant. A year later for the pre-B ALL determination SNP array analysis of the leukemic bone marrow revealed the following aberrations: trisomies of chromosomes 6, 11, 14, 17, 18, duplication of the 22q region and four signals in the 21q region (RUNX1 gene were not included into this region). These size and the breakpoints of the 22q duplication was the same as in the primary sample. According to SNP array data, the final karyotype was determined as hyperdiploidic with 51 chromosomes and additional 22q and 21q aberrations. Conventional chromosome analysis of leukemic bone marrow was unsuccessful because of poor growth of cells.

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