Transient myeloproliferative disorder as the presenting feature for mosaic trisomy 21.

Trisomy 21 is a common congenital disorder with well-documented clinical manifestations, including an increased risk for the transient myeloproliferative disorder as a neonate and leukemia in childhood and adolescence. Transient myeloproliferative disorder is only known to occur in hematopoietic cells with trisomy 21. Children with mosaic trisomy 21 also have a risk for hematological malignancies. We present a nondysmorphic neonate, with a negative noninvasive prenatal screening of maternal blood for trisomy 21, who came to medical attention because of ruddy skin. He was found to have mild polycythemia, thrombocytopenia, and developed peripheral blasts. His clinical presentation was consistent with transient myeloproliferative disorder, which is only seen with trisomy 21. Cytogenetic studies of peripheral blood are positive for mosaic trisomy 21.

Spontaneous intracranial hypotension secondary to congenital spinal dural ectasia and genetic mosaicism for tetrasomy 10p: illustrative case.

BACKGROUND: Spontaneous intracranial hypotension has historically been a poorly understood pathology that is often unrecognized and undertreated. Even more rarely has it been described in pediatric patients with an otherwise benign past medical history. OBSERVATIONS: Herein the authors describe one of the youngest patients ever reported, a 2-year-old girl who developed severe headaches, nausea, and vomiting and experienced headache relief after lying down. Imaging revealed tonsillar herniation 14 mm below the foramen magnum, presumed to be a Chiari malformation, along with extensive dural cysts starting from thoracic level T2 down to the sacrum. She was found to have streaky skin pigmentary variation starting from the trunk down to her feet. Genetic analysis of skin biopsies revealed mosaicism for an isodicentric marker chromosome (10p15.3-10q11.2 tetrasomy) in 27%-50% of cells. After undergoing a suboccipital and cervical decompression at an outside institution, she continued to be symptomatic. She was referred to the authors' hospital, where she was diagnosed with spontaneous intracranial hypotension. LESSONS: After receiving a series of epidural blood patches, the patient experienced almost complete relief of her symptoms. To the authors' knowledge, this is the first time this chromosomal anomaly has ever been reported in a living child, and this may represent a new genetic association with dural ectasia.

Comparison of Large, Medium, and Small Solid Tumor Gene Panels for Detection of Clinically Actionable Mutations in Cancer.

BACKGROUND: Next-generation sequencing of gene panels has supplanted single-gene testing for cancer molecular diagnostics in many laboratories. Considerations for the optimal number of genes to assess in a panel depend on the purpose of the testing. OBJECTIVE: To address the optimal size for the identification of clinically actionable variants in different-sized solid tumor sequencing panels. PATIENTS AND METHODS: Sequencing results from 480 patients with a large, 315 gene, panel were compared against coverage of a medium, 161 gene, and small, 50 gene, panel. RESULTS: The large panel detected a total of 2072 sequence variants in 480 patient specimens; 61 (12.7%) contained variants for which there is therapy approved by the US Food and Drug Administration, 89 (18.5%) had variants associated with an off-label therapy, and 312 (65.0%) contained variants eligible for a genomically matched clinical trial. The small panel covered only 737 of the 2072 variants (35.5%) and somewhat fewer therapy-related variants (on-label 88.5%, off-label 60.7%). The medium-size panel included 1354 of the 2072 (65.3%) variants reported by the large panel. All 318 patients with a clinically actionable variant would have been identified by the medium panel. CONCLUSIONS: The results demonstrate that a carefully designed medium size gene panel is as effective as a large panel for the detection of clinically actionable variants and can be run by most molecular pathology laboratories.

Congenital malignant melanoma: a case report with cytogenetic studies.

Although rare, congenital malignant melanoma (CMM) should be considered in the differential diagnosis of congenital skin lesions. We report a case of CMM in a 4-month-old infant presenting with an enlarging scalp mass, initially thought to be a hemangioma. Incisional biopsy of the lesion showed a compound congenital nevus with atypical cells suggestive of a proliferative nodule versus malignancy on histopathology. Subsequent excisional biopsy revealed malignant melanoma, and further workup confirmed extensive disease with distant metastases. Cytogenetic analysis of both the tumor sites showed highly abnormal karyotypes including pseudotetraploidy, telomere associations, and evidence of gene amplification, all consistent with malignancy. Fluorescence in situ hybridization demonstrated amplification of the MYC gene, with no copy number changes in CDKN2A (INK4/ARF), PTEN, or Cyclin D1. Our report details the cytogenetic and molecular studies of CMM, which provide insight into the biologic behavior of the lesions and may confirm diagnosis when histopathology is not determinant.

Single nucleotide polymorphism genomic arrays analysis of t(8;21) acute myeloid leukemia cells.

Translocation of chromosomes 8 and 21, t(8;21), resulting in the AML1-ETO fusion gene, is associated with acute myeloid leukemia. We searched for additional genomic abnormalities in this acute myeloid leukemia subtype by performing single nucleotide polymorphism genomic arrays (SNP-chip) analysis on 48 newly diagnosed cases. Thirty-two patients (67%) had a normal genome by SNP-chip analysis (Group A), and 16 patients (33%) had one or more genomic abnormalities including copy number changes or copy number neutral loss of heterozygosity (Group B). Two samples had copy number neutral loss of heterozygosity on chromosome 6p including the PIM1 gene; and one of these cases had E135K mutation of Pim1. Interestingly, 38% of Group B and only 13% of Group A samples had a KIT-D816 mutation, suggesting that genomic alterations are often associated with a KIT-D816 mutation. Importantly, prognostic analysis revealed that overall survival and event-free survival of individuals in Group B were significantly worse than those in Group A.

Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome?

CONTEXT: The clinical association between loss of the Y chromosome and acute myelogenous leukemia and myelodysplastic syndrome (AML/MDS) has been debated because both phenomena are related to aging. A prior publication suggests that loss of the Y chromosome in more than 75% of cells may indicate a clonal phenomenon that could be a marker for hematologic disease. OBJECTIVE: To evaluate the relationship between loss of the Y chromosome and AML/MDS. DESIGN: A retrospective review of cytogenetic reports of 2896 male patients ascertained from 1996 to 2007 was performed. Results were stratified based on the percentage of cells missing the Y chromosome and were correlated with patients' ages and bone marrow biopsy reports through logistic regression analysis with adjustment for age. RESULTS: Loss of the Y chromosome was found in 142 patients. Of these, 16 patients demonstrated myeloid disease, with 2 cases of AML and 14 cases of MDS. An increased incidence (P < .05) of AML/MDS was seen only in the group composed of 8 patients with complete loss of the Y chromosome in all karyotyped cells (1 case of AML and 7 cases of MDS). CONCLUSION: Loss of the Y chromosome appears to be primarily an age-related phenomenon. However, in individuals in which all cells on cytogenetic analysis showed loss of the Y chromosome, there was a statistically significant increase in AML/MDS, suggesting that the absence of any normal-dividing cells in a bone marrow analysis may be indicative of AML/MDS.

Rare t(1;11)(q23;p15) in therapy-related myelodysplastic syndrome evolving into acute myelomonocytic leukemia: a case report and review of the literature.

Balanced chromosome rearrangements are the hallmark of therapy-related leukemia that develops in patients treated with topoisomerase II inhibitors. Many of these rearrangements involve recurrent chromosomal sites and associated genes (11q23/MLL, 21q22.3/AML1, and 11p15/NUP98), which can interact with a variety of partner genes. One such rearrangement is the rare t(1;11)(q23;p15), which involves juxtaposition of the homeobox gene PMX1 (PRRX1) and NUP98. We report on an additional patient with t(1;11) who presented with myelodysplastic syndrome (MDS) subsequent to treatment for a pleomorphic liposarcoma. With time, the patient's disorder progressed to acute myelomonocytic leukemia with cytogenetic evidence of clonal evolution. To our knowledge, this is the first report of a patient presenting with a myelodysplastic syndrome with isolated t(1;11) (q23;p15), which evolved into therapy-related acute myeloid leukemia (t-AML). This patient is the third reported with this cytogenetic rearrangement and t-AML, and is compared with the other two reports of t(1;11)(q23;p15).