A multicenter analysis of individuals with a 47,XXY/46,XX karyotype.

PURPOSE: Klinefelter syndrome, a sex chromosome aneuploidy (SCA), is associated with a 47,XXY chromosomal complement and is diagnosed in ∼1:600 live male births. Individuals with a 46,XX cell line, in addition to 47,XXY, are less common with a limited number of published case reports. METHODOLOGY: To better understand the implications of a 47,XXY/46,XX karyotype, we conducted a retrospective, multicenter analysis of the cytogenetic findings and associated clinical records of 34 patients diagnosed with this SCA across 14 institutions. RESULTS: Presence of the XX cell line ranged from 5% to 98% in patient specimens. Phenotypes also exhibited significant heterogeneity with some reporting a single reason for referral and others presenting with a constellation of symptoms, including ambiguous genitalia and ovotestes. Ovotestes were present in 12% of individuals in this cohort, who had a significantly higher percentage of XX cells. Notably, 2 patients were assigned female sex at birth. CONCLUSION: These findings highlight the variability of the clinical phenotypes associated with this SCA, as well as the challenges of clinical management for this population. Karyotype or fluorescence in situ hybridization analysis, which offer single-cell resolution, rather than chromosomal microarray or molecular testing, is the ideal test strategy in these instances as mosaicism can occur at low levels.

Discordant Prenatal Cell-Free DNA Screening vs. Diagnostic Results of Sex Chromosome Aneuploidies: Implications for Newborn Screening and Genetic Counseling.

Sex chromosome aneuploidies (SCAs) collectively occur in 1 in 500 livebirths, and diagnoses in the neonatal period are increasing with advancements in prenatal and early genetic testing. Inevitably, SCA will be identified on either routine prenatal or newborn screening in the near future. Tetrasomy SCAs are rare, manifesting more significant phenotypes compared to trisomies. Prenatal cell-free DNA (cfDNA) screening has been demonstrated to have relatively poor positive predictive values (PPV) in SCAs, directing genetic counseling discussions towards false-positive likelihood rather than thoroughly addressing all possible outcomes and phenotypes, respectively. The eXtraordinarY Babies study is a natural history study of children prenatally identified with SCAs, and it developed a longitudinal data resource and common data elements with the Newborn Screening Translational Research Network (NBSTRN). A review of cfDNA and diagnostic reports from participants identified a higher than anticipated rate of discordance. The aims of this project are to (1) compare our findings to outcomes from a regional clinical cytogenetic laboratory and (2) describe discordant outcomes from both samples. Twenty-one (10%), and seven (8.3%) cases were found to be discordant between cfDNA (result or indication reported to lab) and diagnosis for the Babies Study and regional laboratory, respectively. Discordant results represented six distinct discordance categories when comparing cfDNA to diagnostic results, with the largest groups being Trisomy cfDNA vs. Tetrasomy diagnosis (66.7% of discordance in eXtraordinarY Babies study) and Mosaicism (57.1% in regional laboratory). Traditional genetic counseling for SCA-related cfDNA results is inadequate given a high degree of discordance that jeopardizes the accuracy of the information discussed and informed decision making following prenatal genetic counseling.

Near-tetraploidy/tetraploidy acute myeloid leukemia with clinical, pathologic and molecular characteristics.

Near-tetraploidy/tetraploidy (NT/T) is a cytogenetic alteration in acute myeloid leukemia (AML). In AML, specific chromosomal alterations are associated with clinical, morphological, and immunophenotypic features. The impact of cytogenetics on the prognosis of AML is well established. However, the prognostic implication of NT/T on AML remains unclear. Our aim is to further characterize the clinical, morphologic, immunophenotypic, molecular mutational, and prognostic features of NT/T AML. This retrospective chart review of NT/T AML cases showed NT/T AML was more common in older adult males, with predominately large blasts and myelodysplasia-related features. The most common lineage of dysplasia was dysgranulopoiesis in 77.8% of cases. Cases displayed multiple cytogenetic abnormalities, with only four showing NT/T as the sole abnormality. TP53 was the most common molecular mutation associated with NT/T AML (44.5%). Of the patients receiving treatment for NT/T AML, 80% achieved a CR. The median overall survival for the entire cohort was 4.5 months.

Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas. ALKALCL cases with concurrent MYC translocation are exceedingly rare and are more aggressive and chemoresistent compared with other ALKALCL. We report a patient who presented with ALKALCL possessing coexistent MYC rearrangement, massive tumor dissemination, and early widespread relapse. This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant.

21q22 amplification detection in three patients with acute myeloid leukemia: cytogenomic profiling and literature review.

BACKGROUND: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized. CASE PRESENTATION: Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks. CONCLUSIONS: Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes.

Analysis of clinicopathological and cytogenetic differences between B-lymphoblastic lymphoma and B-lymphoblastic leukemia in childhood.

Although considered the same disease by 2016 WHO Classification, B-ALL and B-LBL show different clinicobiologic behavior, with B-ALL manifesting as disseminated disease and B-LBL as a localized mass. Distinction between the two is based on an arbitrary cutoff of 25% bone marrow involvement. We reviewed clinical, immunophenotypic, and cytogenetic data in B-lymphoblastic neoplasms of childhood to explain the differences. Performing a retrospective review of 126 cases of B-ALL and 18 cases of B-LBL in patients ≤18 years, revealed the following significant differences: younger age of presentation for leukemia; increased cytogenetic abnormalities in leukemia than lymphoma, specifically increased recurrent genetic abnormalities, with the exception of ploidy aberrancy; and the observation that unfavorable recurrent genetic abnormalities occurred in B-ALL and only favorable abnormalities in B-LBL. Down syndrome presented with leukemia only. Findings demonstrated that pediatric B-ALL and B-LBL exhibit dissimilar genomic profiles, suggesting possible differences in pathogenesis between the two closely-related neoplasms.

Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia: a multi-institutional study.

Acute lymphoblastic leukemia (ALL) in infants <1-year-old is biologically different from ALL in older children. Although KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL. In a multi-institutional review involving four medical institutions, 54 cases of infantile B-ALL were identified. Patients were divided into congenital and non-congenital groups with multiple age subgroups. Male predominance was seen in congenital cases compared to female in non-congenital cases. There were decreasing trends of hyperleukocytosis, central nervous system involvement, KMT2A rearrangements, lineage switch, and mortality, versus increasing trends of CD10 expression and non-KMT2A abnormalities. Statistically significant differences emerged at 3 and 9 months, the latter was not previously described. Poor-prognostic risk factors decreased with age, the last trimester of infantile B-ALL essentially merging with pediatric B-ALL.

Heterogeneity of Abnormal RUNX1 Leading to Clinicopathologic Variations in Childhood B-Lymphoblastic Leukemia.

OBJECTIVES: Abnormalities of the RUNX1 gene in childhood B-acute lymphoblastic leukemia (B-ALL) are manifested by ETV6-RUNX1 or RUNX1 amplification. A detailed comparison between the two regarding clinicopathologic features with genetic analysis has not been performed previously. This parallel study assessed how different RUNX1 abnormalities affect the clinicopathology of B-ALL. METHODS: We compared clinicopathologic factors, including age, sex, WBC count, cerebrospinal fluid (CSF) involvement, immunophenotype, and blast proliferation rate between B-ALL with RUNX1 amplification (10 cases) and B-ALL with ETV6-RUNX1 translocation (67 cases) in childhood B-ALL. RESULTS: CD7 was often expressed in RUNX1 amplification but not in ETV6-RUNX1 (44% vs 0%, P = .0001) and appeared to correlate with CSF involvement in the former group (3/4 [75%]). CD13 was often detected in ETV6-RUNX1 with additional RUNX1 gain (38%) with an even higher frequency in double ETV6-RUNX1 translocation (77%), but was not detected in RUNX1 amplification (0%, P < .05). Children with RUNX1 amplification were older and more often CSF positive, while those with ETV6-RUNX1 were younger, more frequently had hyperleukocytosis, and had higher blast proliferation rates. CONCLUSIONS: RUNX1 copy numbers seem to be proportional to the age of B-ALL onset and the frequency of CSF involvement, while RUNX1 amplification vs translocation causes aberrant expression of CD7 and CD13, respectively.

Rare double-hit with two translocations involving IGH both, with BCL2 and BCL3, in a monoclonal B-cell lymphoma/leukemia.

BACKGROUND: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus. CASE PRESENTATION: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum. CONCLUSIONS: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

Isochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder.

BACKGROUND: A small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder. RESULTS: Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms. CONCLUSIONS: We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features.

Primary high-grade B-cell lymphoma of the breast with concurrent IGH-BCL2 and MYC-IGL translocations in an adolescent patient.

BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients. As a result of limited clinician experience and the condition's rarity, it poses a great challenge to pediatric pathologists and oncologists in terms of making an accurate diagnosis and choosing better treatment regimens. In this article, we report a case of an adolescent patient who presented with high-grade breast lymphoma with concurrent BCL2-IGH and MYC-IGL translocations, and we review the clinical, pathological, and genetic features; management strategies; and outcomes associated with this unusual neoplasm.