Mutations Are Rare and Diverse in Myelodysplastic Syndromes: Case Series and Review of the Literature.

Objectives: To investigate and characterize mutations in myelodysplastic syndrome (MDS), we present three cases with diverse mutations and review the literature.

Methods: The institutional SoftPath software was used to find MDS cases between January 2020 and April 2022. The cases with a diagnosis of a myelodysplastic/myeloproliferative overlap syndrome including MDS/MPN with ring sideroblasts and thrombocytosis were excluded.

Cytogenetically cryptic PML::RARA fusion in acute promyelocytic leukemia: Testing strategies in the modern era.

Acute promyelocytic leukemia (APL) is a unique leukemia that is characterized by the fusion. This fusion is often detected by conventional karyotype and fluorescence in situ hybridization (FISH); however, rare cases are cryptic and require molecular techniques to identify the fusion. Furthermore, as the incidence of these cases is rare, analysis by a targeted next-generation sequencing (NGS) panel of myeloid associated genes has never been reported.

A high-grade glioma with amplification.

The molecular alterations underlying progression of low-grade glial/glioneuronal tumors remain to be elucidated. We present a case of a 56-year-old male with an enhancing left temporal lobe tumor. Histology revealed a high-grade glioma adjacent to a low-grade glioneuronal component with abundant Rosenthal fibers, focal eosinophilic granular bodies, and CD34-positive neurons.

Copy number alterations and copy-neutral loss of heterozygosity in Ukrainian patients with primary myelofibrosis.

Aim: To examine frequencies and spectrum of genomic alterations in Ukrainian patients diagnosed with primary myelofibrosis (PMF).

Materials And Methods: We enrolled 30 Ukrainian patients diagnosed with PMF who were previously tested for usual mutations in mye-loproliferative neoplasms driver genes (JAK2, MPL and CALR). Genomic DNA samples were obtained from peripheral blood leukocytes of these patients.

Assessing copy number aberrations and copy neutral loss of heterozygosity across the genome as best practice: An evidence based review of clinical utility from the cancer genomics consortium (CGC) working group for myelodysplastic syndrome, myelodysplastic/myeloproliferative and myeloproliferative neoplasms.

Multiple studies have demonstrated the utility of chromosomal microarray (CMA) testing to identify clinically significant copy number alterations (CNAs) and copy-neutral loss-of-heterozygosity (CN-LOH) in myeloid malignancies. However, guidelines for integrating CMA as a standard practice for diagnostic evaluation, assessment of prognosis and predicting treatment response are still lacking. CMA has not been recommended for clinical work-up of myeloid malignancies by the WHO 2016 or the NCCN 2017 guidelines but is a suggested test by the European LeukaemiaNet 2013 for the diagnosis of primary myelodysplastic syndrome (MDS).

Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group.

Structural genomic abnormalities, including balanced chromosomal rearrangements, copy number gains and losses and copy-neutral loss-of-heterozygosity (CN-LOH) represent an important category of diagnostic, prognostic and therapeutic markers in acute myeloid leukemia (AML). Genome-wide evaluation for copy number abnormalities (CNAs) is at present performed by karyotype analysis which has low resolution and is unobtainable in a subset of cases. Furthermore, examination for possible CN-LOH in leukemia cells is at present not routinely performed in the clinical setting.

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident.

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL, and CALR genes; however, 10%-15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in primary myelofibrosis patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients.

EBV-positive, HHV8-negative large B-cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient.

Clinicopathologic and cytogenetic findings of an unusual EBV+ve, HHV8-ve germinotropic lymphoma, with a nongerminal center immunophenotype occurring in an immunocompetent individual, are presented. A comprehensive literature search revealed a single report of three similar cases. These may represent a unique subset of EBV-positive large B-cell lymphomas in immunocompetent individuals.

Possible reactivation of chromosomally integrated human herpesvirus 6 after treatment with histone deacetylase inhibitor.

HDAC inhibitors might induce ciHHV-6 reactivation. In ciHHV-6 HSCT recipients posttransplant viral load can estimate persistent host chimerism when the donor is ciHHV-6 negative.

Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAF.

Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAF represents the PTC hallmark and is targeted with selective inhibitors (e.g.

Chromothriptic cure of WHIM syndrome.

Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage.

Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia.

The basis for persistence of leukemic stem cells in the bone marrow microenvironment remains poorly understood. We present evidence that signaling cross-talk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in the acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl-positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl-positive CD34+progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations.

Clinical and molecular characterization of overlapping interstitial Xp21-p22 duplications in two unrelated individuals.

Development and implementation of high-density DNA arrays demonstrated the important role of copy number changes on the X chromosome in the etiology of developmental delay and mental retardation (MR). We describe two unrelated patients with developmental delay due to similar interstitial duplications at Xp21-p22. The first patient is a 6-month-old male with multiple affected family members including many females.

Myeloproliferative disorder with eosinophilia and ETV6-ABL gene rearrangement: efficacy of second-generation tyrosine kinase inhibitors.

ETV6/ABL is a rare gene rearrangement that has rarely been detected in Philadelphia-negative chronic myeloproliferative disorders (C-MPD) and found to have tyrosine kinase activity similar to the BCR/ABL fusion protein. We describe a case of a 61-year-old female with a C-MPD associated with an ETV6/ABL gene rearrangement. She achieved complete cytogenetic remission on imatinib 400mg daily for 17 months, but then developed morphologic and cytogenetic relapse.

Marfan syndrome type II: there is more to Marfan syndrome than fibrillin 1.

Marfan syndrome is a well-described autosomal dominant syndrome with widely variable clinical manifestations. Cardiovascular complications include mitral valve prolapse with or without associated mitral valve insufficiency, aortic root dilatation, and most importantly the occasional development of aortic aneurysms or rupture. Given the inconsistent phenotype along with the potentially life-threatening implications, clinicians are increasingly turning to genetic testing for definitive diagnostic confirmation.

Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.

The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop. Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.

Desbuquois syndrome: clinical, radiographic, and morphologic characterization.

To further characterize the clinical, radiographic and chondro-osseous morphologic changes in the Desbuquois syndrome, 7 patients from three sibships are described. They all had prenatal onset severe rhizomelic and mesomelic shortness with marked joint laxity and marked micrognathia. Radiographic changes were distinct, consisting of a supernumerary ossification center between the proximal phalanx of the index finger and the second metacarpal, and variable thumb changes.

Proboscis lateralis with associated orbital cyst: detailed MR and CT imaging and correlative embryopathy.

Proboscis lateralis is a rare craniofacial malformation. We present a case in a 1-week-old male infant, describe the clinical and imaging findings, and discuss the pertinent embryology. MR and CT proved to be complementary: CT provided anatomic detail in bone, defined the nasal cavity, and aided in determining the relationship of the proboscis and orbit; MR clarified the relationship of the proboscis to the orbit and skull base, and the relationships of normal brain to the dysplastic ethmoid centers.

Phenotypic, cytogenetic, and molecular studies of three patients with constitutional deletions of chromosome 5 in the region of the gene for familial adenomatous polyposis.

We have studied three patients, one with extensive polyposis of the colon, who have constitutional interstitial deletions of the long arm of chromosome 5. High-resolution banding studies indicated that the deletion in the patient with polyposis spans the region 5q21-q22, which includes APC, a gene involved in familial adenomatous polyposis and sporadic colon cancer. Molecular analysis with probes for sequences flanking APC confirmed this conclusion.

Cytogenetic and molecular characterization of marker chromosomes in patients with mosaic 45,X karyotypes.

Cytogenetic and molecular techniques were employed to determine the origin of marker chromosomes in five patients with mosaic 45,X karyotypes. The markers were shown to be derived from the X chromosome in three female patients and from the Y chromosome in one female and one male. One of the female patients, with a very small, X-derived ring chromosome, had additional phenotypic abnormalities not typically associated with Turner syndrome.