A novel aberration of COL1A1-PDGFB fusion as an insertion in chromosome 15 in one case of dermatofibrosarcoma protuberans involving a rare location.

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin arising from the dermis. Its location is most commonly presented on the trunk of middle-aged adults and rarely on the face. The characteristic genetic aberration in the form of a reciprocal translocation t(17;22)(q21;q13) or a ring fusing the COL1A1 and PDGFB genes is found in 90% of DFSP. We present a case of a 42-year-old man who presented with a DFSP on the left cheek with foci of myxoid-fibrosarcomatous transformation. A conventional chromosomal analysis revealed a complex karyotype without a supernumerary ring chromosome or a linear translocation t(17;22). Comparative genome hybridization and fluorescence in-situ hybridization revealed the fusion of COL1A1 and PDGFB probes inserted in chromosome 15. This is a unique case of DFSP characterized by a rare body location, unique histopathological features, and novel chromosome COL1A1-PDGFB insertion, and may help guide future diagnostic and patient care modalities.

A novel translocation t(10;17)(p13;q11.2) harboring two cryptic deletions identified by array-CGH and characterized by SUZ12 overexpression in a patient with chronic thrombocytosis.

No specific translocation is associated with myeloproliferative neoplasms (MPNs). However, an interstitial deletion involving subband 17q11.2 which includes the NF1 gene, although rare, is a recurrent aberration in several myeloid disorders including MPNs. For the first time, we report an acquired novel translocation involving 10p13 and 17q11.2 in a 62-year-old Caucasian female which was referred for investigation of chronic and persistent unexplained thrombocytosis. The patient had no history of hematological sequelae and genomic testing for JAK2, CALR, and MPL mutations were negative. She was subsequently diagnosed with a triple negative essential thrombocythemia. Array-CGH analysis noted that the translocation harbored two cryptic deletions, one of which involved 17q11.2 encompassing the NF1 gene. One of the junction breakpoints involved the SUZ12 gene. Immunohistochemical assessment of the marrow trephine showed increased megakaryocytic expression of the SUZ12 protein, as well as EZH2 and Ki67; biochemical abnormalities suggestive of excess megakaryocytic hyperplasia. This novel translocation may affect the expression of SUZ12 and its downstream targets, and may represent a unique pathogenomic etiology which drives chronic thrombocytosis in essential thrombocythemia.

Narrowing down the Common Cytogenetic Deletion 14q to a 5.6-Mb Critical Region in 1p/19q Codeletion Oligodendroglioma-Relapsed Patients Points to Two Potential Relapse-Related Genes: SEL1L and STON2.

Based on a literature review and our database, we report on the smallest 14q deletion identified in a brain tumor characterized by 1p/19q codeletion low-grade oligodendroglioma. In 2013, array-comparative genomic hybridization of the brain tumor revealed 1p/19q codeletion as a sole abnormality. In 2019, the patient relapsed showing additional abnormalities including a 14q deletion of 16.5 Mb at 14q24.2q31.3. This region overlaps with 2 previously identified minimal regions, 14q21.2q24.3 and 14q31.3q32.1, based on 142 cases of glioma. The authors reported no correlation between these 2 regions and survival. By extracting these 2 regions from our patient's deletion and comparing it to 12 other cases of 1p/19q codeletion oligodendrogliomas reported in the literature, we narrowed down the 14q loss possible critical region to 5.6 Mb mapping at 14q31.1q31.2. This region contains 2 potential relapse-related genes: SEL1L and STON2.

A Novel Variant Rearrangement of the Rare Aberration dic(17;20)(p11.2;q11.2) Characterized by Array-CGH as an Insertion in a Patient with Myelodysplastic Syndrome of Multilineage Dysplasia (MDS-MLD).

We report on a novel variant of the dicentric chromosome 17;20 (dic (17;20)(p11.2;q11.2) in a patient with de novo myelodysplastic syndrome (MDS). Based on FISH and array-CGH, the variant turns out to be an insertion of chromosome 17 (17p11.2-telomere 17) into chromosome 20 with breakpoints at 20q11.22 and 20q13.33. Based on conventional chromosome analysis and G-banding patterns, the region 17p11.2-17q25 was directly inserted between 20q11.22 and 20q13.33. The breakpoint junctions occurred within KCNJ12 (17p11.2), UQCC1 (20q11.2), and CDH4 (20q13.3), leading to 5' deletions of all the genes and positioning the 3' of UQCC1 next to KCNJ12 at 17p11.2 and CDH4 next to an unknown gene at 17q25-20q13.3. In addition, the centromere of chromosome 17 was not active, transforming the primary constriction to a flat band. Therefore, the novel insertion variant is a pseudo dicentric derivative chromosome with one functional centromere: 45,XX,der(17;20)del(20)(q11.22q13.33)ins(20;17)(q11.2;p11.2q25). A review of the literature of all dic(17;20) cases is presented. For the first time, we report an array-CGH characterization of such rare variant that revealed to be an insertion.

Three Novel Aberrations Involving PLAG1 Leading to Lipoblastoma in Three Different Patients: High Amplification, Partial Deletion, and a Unique Complex Rearrangement.

Lipoblastoma is a rare benign neoplasm with overlapping histology with other lipomatous tumors. Genetic aberrations including translocations of 8q and splitting of the PLAG1 probe leading to "promoter swapping" and gains of chromosome 8 or PLAG1 foci have been described in lipoblastoma. Here, we report 3 lipoblastomas revealing novel genetic aberrations involving PLAG1: a high level of PLAG1 amplification up to 50 copies in a 4-year-old girl with recurrence of a right flank mass, a partial deletion of PLAG1 with the flanking junction breakpoints involving the 3'PLAG1 and 5'HAS2 genes in a 17-month-old boy with a retroperitoneal mass, and an insertion of 2q31 into 8q11.2 and translocation of 8q to 2q with the latter translocated onto 12q leading to separation of the PLAG1 FISH probe in a 5-year-old girl with a left back mass. Our novel cytogenetic findings further expand the mechanisms of PLAG1 transcriptional upregulation in lipoblastoma pathogenesis.

Novel TLE4-NTRK2 fusion in a ganglioglioma identified by array-CGH and confirmed by NGS: Potential for a gene targeted therapy.

Gangliogliomas are rare neoplasms of the central nervous system that mostly originate in the temporal lobe and are associated with seizures. Literature mentions that BRAF mutations are most commonly associated with gangliogliomas. We discuss a unique case of ganglioglioma originating in the posterior fossa that showed multiple losses and a unique interstitial deletion at 9q21 by an array-comparative genome hybridization (array-CGH). The deletion led to a novel molecular fusion (TLE4-NTRK2) which was confirmed by next generation sequencing and provides a potential for a gene-targeted therapy.

Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

Subcutaneous melanocytoma mimicking a lipoma: a rare presentation of a rare neoplasm with histological, immunohistochemical, cytogenetic and molecular characterization.

Melanocytoma are the melanocytic tumors originating from leptomeningeal melanocytes. Melanocytomas are commonly seen in the central nervous system (CNS) and are often associated with neurocutaneous melanosis (NCM). However, simultaneous presentation of intra-axial and extracranial melanocytoma is a very rare event. Here, we report a unique case of 21-year-old male with intermediate-grade subcutaneous (SC) melanocytoma, mimicking lipoma, occurred synchronously with an intracranial melanocytoma, not associated with NCM. A 21-year-old Caucasian male presented to the emergency department (ED) with severe vertigo and vomiting. A magnetic resonance imaging (MRI) of the brain was performed at the ED, which revealed an SC mass in the right occipital scalp and a right cerebellopontine angle (CPA) mass. Excision of the SC mass revealed a well-circumscribed highly pigmented melanocytic tumor. The SC mass tumor cells were positive for melanocytic lineage markers. The histopathological features were between benign melanocytomas and malignant melanomas. The Ki67 and PHH3 IHCs confirm the intermediate grade of the tumors. An array-CGH (comparative genome hybridization) and next-generation sequencing analysis of the tumor DNA extracted from the formalin-fixed paraffin-embedded tissue reveals chromosome 6p gain and p.Q209P mutation in the GNAQ gene, respectively, consistent with the diagnosis of intermediate-grade melanocytoma.

A unique case of a cutaneous lesion resembling mammary analog secretory carcinoma: a case report and review of the literature.

Mammary analog secretory carcinoma (MASC) is a rare type of salivary gland tumor named for its morphological and genetic similarity to secretory carcinoma of the breast. These tumors are most often found in the parotid gland but have been described in several other mucosal locations of the head and neck. In this case report, a cutaneous lesion most closely resembling MASC was found in a neck mass of a 64-year-old male patient without evidence of a primary salivary gland or oral tumor. The lesion was excised, and the patient remains disease free to date. This case depicts a rare tumor in the skin most closely mimicking MASC and brings additional awareness to dermatopathologists of this tumor.

Instability of isochromosome 4p in a child with pure trisomy 4p syndrome features and entire 4q-arm translocation.

Constitutional chromosome instability so far has mainly been associated with ring formation. In addition, isochromosome formation involving the short arm with translocation of the entire long arm is rarely observed. This type of rearrangement has been reported for chromosomes 4, 5, 7, 9, 10, 12, and 20. Here, we present the third patient having an isochromosome 4p with 4q translocation, but showing for the first time chromosome instability detected by FISH following chromosome microarray analysis.

Combined immunodeficiency in a 3-year-old boy with 16p11.2 and 20p12.2-11.2 chromosomal duplications.

We report for the first time on a 3-year-old boy with paternally inherited 212.85 kb-16p11.2 and 7.8 Mb-20p12.2-11.23 interstitial microduplications associated with having congenital cardiac defect, dysmorphic facial features, and combined T-, B-, and NK cell immunodeficiency. In addition the 7.8 Mb-20p12.2-11.23 microduplication is unique showing novel breakpoints among all partial trisomy/duplication 20p reported to date, narrowing down the critical region for trisomy 20p syndrome.

An intragenic deletion of the gene MNAT1 in a family with pectus deformities.

Pectus carinatum and excavatum have multiple genetic associations. We report on a novel association of these deformities in a 34-month-old male and his father, likely due to a small intragenic deletion of MNAT1 (ménage a trois 1 gene). Both individuals share a deletion of MNAT1 located at 14q23.1 and an interstitial duplication of CHRNA7 located at 15q13.3. Deletion of MNAT1 has been associated with connective tissue abnormalities and is likely the etiology of the malformations, whereas the duplication of CHNRA7 is unlikely related due to the lack of association with any such connective tissue abnormalities.

Masked hypodiploidy in anaplastic meningiomas by duplication of the original clone found in atypical meningiomas: illustration of the evolution of genetic alterations.

Meningiomas are common, usually benign neoplasms of the central nervous system. Atypical and anaplastic meningiomas can be aggressive, show more rapid growth, and a greater propensity to recur following resection. General consensus believes that genetic abnormalities leading to anaplastic transformation are present at initial tumor presentation; however, this has not been demonstrated by array-comparative genome hybridization. We confirm the hypothesis by showing the evolution of genetic alterations in the transformation of an atypical meningioma to an anaplastic meningioma. Additionally, we provide potential genes responsible for malignant transformation of meningiomas, which, with further research, may provide diagnostic and therapeutic implications.

Oculo-auriculo-vertebral spectrum, cat eye, and distal 22q11 microdeletion syndromes: a unique double rearrangement.

An array-CGH on 19-year-old male showed a proximal 1.11 Mb duplication and a distal 1.7 Mb deletion of 22q11.2 regions flanking the Velocardiofacial/DiGeorge syndrome region that remained intact. FISH analyses revealed both abnormalities to be on the same homolog 22. This double rearrangement lead to the co-existence of two syndromes: Cat eye and distal 22q11.2 microdeletion syndromes with a rare associated phenotype of oculo-auriculo-vertebral spectrum (OAVS). A review of the literature indicates that this is the second report of a proximal duplication and the fifth report of a distal deletion and OAVS suggestive of a possible OAVS candidate gene in this region.

Neonatal pancytopenia associated with de novo 1q43-44 deletion and 10p15 duplication.

Deletion of 1q43-44 has been reported in >50 cases. Phenotype-genotype correlation of this deletion has recently been described based on 20 pure cases. This led to the definition of critical regions and candidate genes for microcephaly, corpus callosum abnormalities, and seizure disorders. Variable penetrance and expressivity are associated with 1q43-44 microdeletion syndrome, explaining the lack of correlation in rare cases. Despite variation in size of the deletion, most cases are characterized by typical dysmorphic features, but none have demonstrated neonatal pancytopenia. We report on a newborn with partial monosomy 1q43-44 and partial trisomy 10p15.1→10pter born with dysmorphic features and neonatal pancytopenia. Array-CGH analysis characterizes the deletion and the duplication as terminal with estimated sizes of 8 to 9 and 5 to 6 Mb, respectively. Conventional cytogenetic analysis showed the 10p duplication as unbalanced and translocated onto 1q. The deletion in the 1q43-44 region is the largest among the 20 cases reported most recently. The 10p partnership with the derivative 1q43-44 region is unique. We discuss the association of neonatal pancytopenia with 1q deletion and 10p duplication, in light of a recent published case of acute lymphoblastic leukemia in a constitutional case of 1q deletion and 1p duplication.

A Novel t(10;22) Translocation Harboring an IGL Gene Deletion in a CLL Patient Transforming to B-PLL with 1q Gain.

OBJECTIVES: We report on a rare case of B-cell prolymphocytic leukemia (B-PLL) in a patient with a history of chronic lymphocytic leukemia (CLL) that showed a novel translocation t(10;22)(q21;q11.22) and an interstitial deletion of 11q14.1-q23.3 in 2017. The chromosome microarray analysis (CMA) confirmed the 11q22 deletion and revealed a small interstitial deletion of IGL gene. In 2018, the patient presented with worsening lymphocytosis, anemia and thrombocytopenia. The peripheral blood smear revealed an increased prolymphocyte population, which comprised 60.4% of lymphoid cells, establishing a diagnosis of B-cell prolymphocytic leukemia. The CMA and G-banded chromosome analysis showed one additional aberration in the form of 1q gain translocated onto the other homologue 22. These findings suggested clonal evolution of CLL to B-PLL. The most common translocation involving immunoglobulin lambda chain (IGL) in CLL is the t(18;22), followed by t(8;22) and (11;22). An evolution to B-PLL occurs in most cases without gaining additional aberrations. Here, we report for the first time a novel translocation involving IGL with chromosome 10q21 and one 1q gain occurring in a patient with CLL that transformed to B-PLL. Based on the disease progression and this newly developed cytogenetic aberration, our case supports the progressive nature of CLL in the presence of IGL deletion and suggests the pathological role of 1q gain in CLL transformation.

First-dose idarubicin cardiomyopathy: a case of new heart failure after induction chemotherapy for acute myeloid leukaemia.

Anthracyclines are an effective chemotherapy agent. However, very few cases of idarubicin-induced cardiomyopathy exist. Herein, we describe a case of first-dose idarubicin-related acute heart failure in a woman with a history of myelodysplastic syndrome converted to acute myeloid leukaemia.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with inv(16)(p13q22) as a sole genetic abnormality.

Inversion of chromosome 16, inv(16)(p13q22), juxtaposes the core binding factor beta (CBFB) and myosin heavy chain 11 (MYH11) genes, resulting in a myeloid leukemic disease phenotype characterized by increased bone marrow and peripheral blood blasts with myelomonocytic antigen expression and an accompanying eosinophilia. This cytogenetic abnormality has been reported in a variety of other neoplasms, in which it generally occurs as part of a complex karyotype, including rare B-lineage non-Hodgkin lymphomas. We report a case of clinically, morphologically, and immunologically typical lymphoplasmacytic lymphoma/Waldenström macroglobulinemia in which a majority of the malignant cells had an inv(16)(p13q22) as a sole abnormality. We review the literature and discuss the possible role of this genetic lesion in B-cell neoplasia.

Coexistence of neocentromeric marker 3q and trisomy 3 in two different tissues in a 3-year-old boy with peripheral T-cell lymphoma: support for a gene dosage effect hypothesis.

A very small supernumerary de novo marker chromosome was ascertained during cytogenetic diagnosis of a 3 1/2-year-old boy with peripheral T-cell lymphoma, unspecified. The marker, which was C-band and alpha-satellite DNA negative, was identified in the pleural effusion and involved cervical lymph node whereas the involved bone marrow cells had trisomy 3 as a clone. The neocentromere marker was characterized by multiple probes demonstrating an inversion duplication of the distal portion of chromosome 3q involving the BCL6 gene. Whole or partial trisomy 3q represents one of the most recurrent chromosomal abnormalities occurring in T-cell lymphomas, suggesting that the 3q contains a critical region for the pathogenesis of T-cell lymphoma. Our present case showed that the critical region may reside within the neocentromere marker 3q27~q29 in this case in particular and revealed a different mechanism in increasing gene dosage rather than gene disruption. In addition, this type of neocentromere is one most often reported in constitutional cases. Here, we report its presence in cancer for the first time.