Working towards risk stratification for ascending aortic dilatation in pediatric Turner syndrome patients: results of a longitudinal echocardiographical observation.

This study aimed to longitudinally evaluate aortic root dimensions and elasticity in pediatric Turner syndrome (TS) in relation to known cardiac implications such as coarctation of the aorta (CoA) and bicuspid aortic valves (BAV) in order to create an improved risk profile for the presumed underlying vessel pathology in childhood. We report on the longitudinal findings of our pediatric TS outpatient clinic over a period of up to 7.6 years. Forty-nine TS patients (median age at baseline 9.7 ± 5.9 years, range 0-19.8) were followed-up for on average 2.9 ± 1.1 examinations and a median time of 3.4 ± 1.6 years. Aortic root (AoR) diameters and corresponding Z-scores were determined echocardiographically, and elasticity parameters as well as annual progression rates were calculated. At baseline, 16.3% of patients showed Z-scores > 2 at one or more levels of the AoR (35.7% of patients with BAV, odds ratio of 4.2). There was net progression to be noted at all measuring levels, leading to 28.6% of patients (50% of patients with BAV) exhibiting aortic dilatation at the end of follow-up. Progression correlated with the presence of BAV, non-mosaic monosomy, and age. A levelling-off of progression was seen with the onset of adolescence. CONCLUSIONS: Marked progression of aortic diameters leading to the development of dilatation can be observed in TS patients during childhood and stresses the importance of close surveillance during childhood. Main risk factors are BAV and complete monosomy 45X0. A beneficial influence of estrogen substitution can be suspected but needs further investigation. WHAT IS KNOWN: • Patients with Turner syndrome are at an increased risk for aortic dilatation and dissection. • The presence of BAV and complete monosomy 45X are additional risk factors. WHAT IS NEW: • Aortic dilatation can be detected in pediatric patients with Turner syndrome. • Relevant progression in childhood is possible in at-risk individuals and warrants close surveillance.

Systems approaches identify the consequences of monosomy in somatic human cells.

Chromosome loss that results in monosomy is detrimental to viability, yet it is frequently observed in cancers. How cancers survive with monosomy is unknown. Using p53-deficient monosomic cell lines, we find that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis demonstrates reduced expression of genes encoded on the monosomes, which is partially compensated in some cases. Monosomy also induces global changes in gene expression. Pathway enrichment analysis reveals that genes involved in ribosome biogenesis and translation are downregulated in all monosomic cells analyzed. Consistently, monosomies display defects in protein synthesis and ribosome assembly. We further show that monosomies are incompatible with p53 expression, likely due to defects in ribosome biogenesis. Accordingly, impaired ribosome biogenesis and p53 inactivation are associated with monosomy in cancer. Our systematic study of monosomy in human cells explains why monosomy is so detrimental and reveals the importance of p53 for monosomy occurrence in cancer.

Clinical phenotype and management of individuals with mosaic monosomy X with Y chromosome material stratified by genital phenotype.

Individuals mosaic for monosomy X and a cell line with Y chromosome material can have genitalia that appear phenotypical female, male, or ambiguous. Those with this karyotype and typical female genitalia are diagnosed with Turner syndrome; however, this definition specifically excludes those with genitalia other than typical female. There is limited information on whether medical and neurodevelopmental risks are similar among individuals with monosomy X and Y chromosome material across genital phenotypes. This multicenter retrospective study compared comorbidities and clinical management in individuals with monosomy X and Y material and male/ambiguous genitalia to those with typical female genitalia. Electronic medical records for all patients with monosomy X and Y material (n = 76) at two large U.S. pediatric centers were abstracted for predetermined data and outcomes. Logistic regression was used to compare the two phenotypic groups adjusting for site and duration of follow-up. The male/ambiguous genitalia group was just as likely to have congenital heart disease (RR 1.0, 95%CI [0.5-1.9]), autoimmune disease (RR 0.6 [0.2-1.3]), and neurodevelopmental disorders (RR 1.4 [0.8-1.2]) as those with female genitalia. Despite similar risks, they were less likely to receive screening and counseling. In conclusion, individuals with monosomy X and Y chromosome material have similar medical and neurodevelopmental risks relative to individuals with Turner syndrome regardless of genitalia, but there are notable differences in clinical management.

Fluorescence in situ hybridization detection of chromosome 22 monosomy in pleural effusion cytology for the diagnosis of mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is characterized by mutations in several genes, including cyclin-dependent kinase-inhibitor 2A/p16 in the 9p21 locus, BRCA1-associated protein 1 (BAP1), and neurofibromatosis type 2 (NF2) in the 22q12 locus. Recent studies indicate that fluorescence in situ hybridization (FISH) detects hemizygous loss of NF2 in tissue specimens of MPM. The authors investigated whether NF2 FISH, either alone or in combination with other diagnostic assays (9p21 FISH, methylthioadenosine phosphorylase [MTAP] immunohistochemistry [IHC], and BAP1 IHC), effectively distinguishes MPM cells from reactive mesothelial cells (RMCs) in cell blocks prepared from pleural effusions. METHODS: FISH assays were used to examine the deletion status of NF2 and 9p21, and IHC was used to determine the expression of MTAP and BAP1 in cell blocks from 54 cases with MPM and 18 cases with RMCs. RESULTS: Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) showed 51.9% sensitivity (48.1% for chromosome 22 monosomy and 3.7% for hemizygous deletion) and 100% specificity in differentiating MPM cells from RMCs. Combinations of NF2 FISH, 9p21 FISH, and BAP1 IHC assays yielded greater sensitivity (98.1%) than any assay alone (9p21 FISH, 61.1%; MTAP IHC, 52.8%; or BAP1 IHC, 60.4%). The level of hemizygous NF2 loss in cell blocks positively correlated with that in corresponding tissues. Furthermore, to overcome cytologic specimen-specific challenges, FISH combined with cytokeratin AE1/AE3 immunofluorescence was necessary in 25.9% of MPM cases for FISH assessment of predominantly scattered MPM cells. CONCLUSIONS: NF2 FISH alone or in combination with other diagnostic assays effectively differentiates MPM cells from RMCs in cell blocks prepared from pleural effusions.

Premature ovarian insufficiency in the XO female mouse on the C57BL/6J genetic background.

In humans, all but 1% of monosomy 45.X embryos die in utero and those who reach term suffer from congenital abnormalities and infertility termed Turner's syndrome (TS). By contrast, XO female mice on various genetic backgrounds show much milder physical defects and normal fertility, diminishing their value as an animal model for studying the infertility of TS patients. In this article, we report that XO mice on the C57BL/6J (B6) genetic background showed early oocyte loss, infertility or subfertility and high embryonic lethality, suggesting that the effect of monosomy X in the female germline may be shared between mice and humans. First, we generated XO mice on either a mixed N2(C3H.B6) or B6 genetic background and compared the number of oocytes in neonatal ovaries; N2.XO females retained 45% of the number of oocytes in N2.XX females, whereas B6.XO females retained only 15% of that in B6.XX females. Second, while N2.XO females were as fertile as N2.XX females, both the frequency of delivery and the total number of pups delivered by B6.XO females were significantly lower than those by B6.XX females. Third, after mating with B6 males, both N2.XO and B6.XO females rarely produced XO pups carrying paternal X chromosomes, although a larger percentage of embryos was found to be XO before implantation. Furthermore, B6.XO females delivered 20% XO pups among female progeny after mating with C3H males. We conclude that the impact of monosomy X on female mouse fertility depends on the genetic background.

The Potential Role of Selected miRNA in Uveal Melanoma Primary Tumors as Early Biomarkers of Disease Progression.

Uveal melanoma (UM) is the most common primary tumor of the eye diagnosed in adults, associated with a high risk of metastasis and thereby, poor prognosis. Among known risk factors for the development of metastatic disease is the loss of BAP1 expression and chromosome 3 monosomy in the primary tumor. However, the expression levels of specific micro RNAs (miRNA) in tumor tissue may also serve as a valuable marker for determining the risk of metastatic disease in patients with primary uveal melanoma. In our study, we analyzed the miRNA expression data of cases selected from The Cancer Genome Atlas study on uveal melanoma, and determined a panel of 15 miRNAs differentially expressed between patients with primary and metastatic disease. Next, 6 miRNAs were validated on a group of 46 tumor samples from primary and metastatic patients. We have shown, that expression of hsa-miR-592, hsa-miR-346, and hsa-miR-1247 was significantly increased, while hsa-miR-506 and hsa-miR-513c were decreased in the tumors of patients with metastatic disease. Hsa-miR-196b expression did not differ between the two subgroups, however, we showed significant correlation with BAP1 expression. Moreover, hsa-miR-592 also showed correlation with monosomy 3 tumors. Gene ontology analysis revealed involvement of those miRNAs with cellular processes mediating the metastatic process. Our results showed that miRNAs play an important role in the deregulation of several oncogenic pathways in UM and can, thereby, promote metastatic spread to distant organs. Moreover, differentially expressed miRNAs may be used as an interesting biomarker for the assessment of metastatic risk in uveal melanoma patients.

ATR-16 syndrome: mechanisms linking monosomy to phenotype.

BACKGROUND: Deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual's clinical phenotype is challenging. METHODS: Here, as an example of this common phenomenon, we analysed 41 patients with simple deletions of ~177 to ~2000 kb affecting one allele of the well-characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised deletion extents and screened for genetic background effects, telomere position effect and compensatory upregulation of hemizygous genes. RESULTS: We find the risk of developmental and neurological abnormalities arises from much smaller distal chromosome 16 deletions (~400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes; however, genetic background effects substantially modify phenotypic abnormalities. CONCLUSIONS: Using ATR-16 as a general model of disorders caused by CNVs, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.

Monosomy 18p is a risk factor for facioscapulohumeral dystrophy.

BACKGROUND: 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2). OBJECTIVES: Since 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD. METHODS: To test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination. RESULTS: Primary fibroblasts hemizygous for SMCHD1 have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD. CONCLUSIONS: 18p deletions leading to haploinsufficiency of SMCHD1, together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD.

Comprehensive chromosome screening and gene expression analysis from the same biopsy in human preimplantation embryos.

STUDY QUESTION: Can simultaneous comprehensive chromosome screening (CCS) and gene expression analysis be performed on the same biopsy of preimplantation human embryos? SUMMARY ANSWER: For the first time, CCS and reliable gene expression analysis have been performed on the same human preimplantation embryo biopsy. WHAT IS KNOWN ALREADY: A single trophectoderm (TE) biopsy is routinely used for many IVF programs offering CCS for selection of only chromosomally normal embryos for transfer. Although the gene expression profiling of human preimplantation embryos has been described, to date no protocol allows for simultaneous CCS and gene expression profiling from a single TE biopsy. STUDY DESIGN, SIZE AND DURATION: This is a proof of concept and validation study structured in two phases. In Phase 1, cell lines were subjected to a novel protocol for combined CCS and gene expression analysis so as to validate the accuracy and reliability of the proposed protocol. In Phase 2, 20 donated human blastocysts were biopsied and processed with the proposed protocol in order to obtain an accurate CCS result and characterize their gene expression profiles using the same starting material. PARTICIPANTS/MATERIALS, SETTING AND METHOD: A novel protocol coupling quantitative real-time PCR-based CCS and gene expression analysis using RT-PCR was designed for this study. Phase 1: six-cell aliquots of well-characterized fibroblast cell lines (GM00323, 46,XY and GM04435, 48,XY,+16,+21) were subjected to the proposed protocol. CCS results were compared with the known karyotypes for consistency, and gene expression levels were compared with levels of purified RNA from same cell lines for validation of reliable gene expression profiling. Phase 2: four biopsies were performed on 20 frozen human blastocysts previously diagnosed as trisomy 21 (10 embryos) and monosomy 21 (10 embryos) by CCS. All samples were processed with the proposed protocol and re-evaluated for concordance with the original CCS result. Their gene expression profiles were characterized and differential gene expression among embryos and early embryonic cell lineages was also evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: CCS results from cell lines showed 100% consistency with their known karyotypes. ΔΔCt values of differential gene expression of four selected target genes from the cell lines GM4435 and GM0323 were comparable between six-cell aliquots and purified RNA (Collagen type I alpha-1 (COL1A1), P = 0.54; Fibroblast growth factor-5 (FGF5), P = 0.11; Laminin subunit beta-1 (LAMB1), P = 1.00 and Atlastin-1 (ATL1), P = 0.23). With respect to human blastocysts, 92% consistency was reported after comparing embryonic CCS results with previous diagnosis. A total of 30 genes from a human stem cell pluripotency panel were selected to evaluate gene expression in human embryos. Correlation coefficients of expression profiles from biopsies of the same embryo (r = 0.96 ± 0.03 (standard deviation), n = 45) were significantly higher than when biopsies from unrelated embryos were evaluated (r = 0.93 ± 0.03, n = 945) (P < 0.0001). Growth differentiation factor 3 (GDF3) was found to be significantly up-regulated in the inner cell mass (ICM), whereas Caudal type homebox protein-2 (CDX2), Laminin subunit alpha-1 (LAMA1) and DNA methyltransferase 3-beta (DNMT3B) showed down-regulation in ICM compared with TE. Trisomy 21 embryos showed significant up-regulation of markers of cell differentiation (Cadherin-5 (CDH5) and Laminin subunit gamma-1 (LAMC1)), whereas monosomy 21 blastocysts showed higher expression of genes reported to be expressed in undifferentiated cells (Gamma-Aminobutyric Acid Type-A Receptor Beta3 Subunit (GABRB3) and GDF3). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Gene expression profiles of chromosomally normal embryos were not assessed due to restrictive access to euploid embryos for research. Nonetheless, the profile of blastocysts with single aneuploidies was characterized and compared. Only 30 target genes were analyzed for gene expression in this study. Increasing the number of target genes will provide a more comprehensive transcriptomic signature and reveal potential pathways paramount for embryonic competence and correct development. WIDER IMPLICATIONS OF THE FINDINGS: This is the first time that CCS and gene expression analysis have been performed on the same human preimplantation embryo biopsy. Further optimization of this protocol with other CCS platforms and inclusion of more target genes will provide innumerable research and clinical applications, such as discovery of biomarkers for embryonic reproductive potential and characterization of the transcriptomic signatures of embryos, potentially allowing for further embryo selection prior to embryo transfer and therefore improving outcomes. STUDY FUNDING AND COMPETING INTERESTS: This study was funded by the Foundation for Embryonic Competence, Basking Ridge, NJ, USA. No conflicts of interests declared.

Hypomethylation and Genetic Instability in Monosomy Blastocysts May Contribute to Decreased Implantation Potential.

DNA methylation is a key epigenetic mechanism responsible for gene regulation, chromatin remodeling, and genome stability, playing a fundamental role during embryonic development. The aim of this study was to determine if these epigenetic marks are associated with chromosomal aneuploidy in human blastocysts. Surplus, cryopreserved blastocysts that were donated to research with IRB consent were chosen with varying chromosomal aneuploidies and respective implantation potential: monosomies and trisomies 7, 11, 15, 21, and 22. DNA methylation analysis was performed using the Illumina Infinium HumanMethylation450 BeadChip (~485,000 CpG sites). The methylation profiles of these human blastocysts were found to be similar across all samples, independent of chromosome constitution; however, more detailed examination identified significant hypomethylation in the chromosome involved in the monosomy. Real-time PCR was also performed to determine if downstream messenger RNA (mRNA) was affected for genes on the monosomy chromosome. Gene dysregulation was observed for monosomy blastocysts within significant regions of hypo-methylation (AVEN, CYFIP1, FAM189A1, MYO9A, ADM2, PACSIN2, PARVB, and PIWIL3) (P < 0.05). Additional analysis was performed to examine the gene expression profiles of associated methylation regulators including: DNA methyltransferases (DNMT1, DNMT3A, DNMT3B, DNMT3L), chromatin modifying regulators (CSNK1E, KDM1, PRKCA), and a post-translational modifier (PRMT5). Decreased RNA transcription was confirmed for each DNMT, and the regulators that impact DNMT activity, for only monosomy blastocysts (P < 0.05). In summary, monosomy blastocysts displayed hypomethylation for the chromosome involved in the error, as well as transcription alterations of associated developmental genes. Together, these modifications may be contributing to genetic instability and therefore be responsible for the limited implantation potential observed for full monosomy blastocysts.

Unclassified renal cell carcinoma with tubulopapillary architecture, clear cell phenotype, and chromosome 8 monosomy: a new kid on the block.

Accurate subtyping of renal cell carcinomas (RCCs) has become clinically important for therapy and prognostication. RCC subtypes are defined by distinct morphologic and immunohistochemical profiles, and in some instances recurrent cytogenetic and molecular properties. However, some tumors exhibit overlapping morphologic and immunophenotypic features, frequent enough to pose diagnostic dilemmas. This report concerns six histologically unusual RCCs that showed tubulopapillary architecture, clear cell phenotype, and non-diagnostic immunohistochemical profiles. Further investigation of these tumors utilized a single nucleotide polymorphism (SNP) microarray platform (OncoScan®, Affymetrix) that employed molecular inversion probe (MIP) technology to investigate genome-wide chromosomal copy number changes and loss of heterozygosity in formalin-fixed paraffin-embedded sections. The six tumors were assayed in parallel with and in comparison to RCC with typical morphologic or immunohistochemical features for a specific subtype (clear cell, clear cell papillary, and microphthalmia transcription factor (MiT) family translocation RCC). Three of the unusual RCCs showed a molecular signature of clear cell RCC and one of papillary RCC. The remaining two showed monosomy of chromosome 8. Those two cases were tested via next-generation sequencing, and no pathogenic variants were detected, including those in the genes VHL, PBRM1, SETD2, KDM5C, or BAP1. The addition of molecular investigations such as reported here as applied to histologically and immunohistochemically unusual RCC may help to define additional subtypes and contribute to the development of targeted therapy for renal cancer.

Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT.

Despite the overall benefit from allogeneic hematopoietic stem cell transplantation observed in patients with poor cytogenetic risk acute myeloid leukemia in first complete remission, the precise effect of this procedure for different poor-risk subtypes has not been fully analyzed. This retrospective analysis was performed to investigate whether allogeneic hematopoietic stem cell transplantation performed in first complete remission in patients with monosomal karyotype can overcome the adverse prognosis associated with these patients. Of the 4635 patients included in the study, 189 (4%) harbored a monosomal karyotype. The presence of a monosomal karyotype was associated with a worse outcome, with an inferior leukemia-free survival and overall survival (5-year leukemia-free survival and overall survival: 24 ± 3% and 26 ± 3% vs. 53 ± 1% and 57 ± 1% in monosomal-karyotype and non-monosomal-karyotype, respectively; P<0.0001) and higher relapse risk after transplantation (cumulative incidence of relapse at 5 years: 56 ± 4% in monosomal-karyotype vs. 28 ± 1% in non-monosomal-karyotype; P<0.0001). The adverse negative impact of monosomal karyotype cytogenetics was confirmed in the entire cohort in a multivariate analysis [Hazard Ratio (HR): 1.88, 95% Confidence Interval (CI):1.29-2.73, P=0.001 for relapse incidence; HR:1.71, 95%CI:1.27-2.32, P<0.0001 for leukemia-free survival; HR:1.81, 95%CI:1.32-2.48, P=0.0002 for overall survival], and was independent of the presence of other poor-risk cytogenetic subtypes. In summary, monosomal karyotype arises as a strong negative prognostic feature in acute myeloid leukemia also in patients who undergo allogeneic hematopoietic stem cell transplantation in first complete remission, stressing the need to develop additional pre- and post-transplantation strategies aimed at improving overall results. Nonetheless, allogeneic hematopoietic stem cell transplantation in early phase is currently the best therapy for this very poor-risk acute myeloid leukemia subtype.

Single monosomy as a relatively better survival factor in acute myeloid leukemia patients with monosomal karyotype.

Monosomal karyotype (MK) defined by either ⩾2 autosomal monosomies or single monosomy with at least one additional structural chromosomal abnormality is associated with a dismal prognosis in patients with acute myeloid leukemia (AML). It was detected in 174 of 3041 AML patients in South Korean Registry. A total of 119 patients who had received induction therapy were finally analyzed to evaluate the predictive factors for a positive prognosis. On multivariate analysis, single monosomy, the absence of abn(17p), ⩾10% of cells with normal metaphase and the achievement of a complete remission (CR) after induction therapy were significant factors for more favorable outcomes. Especially, single monosomy remained as a significantly independent prognostic factor for superior survival in both patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR and who did not. Allo-HSCT in CR improved overall survival significantly only in patients with a single monosomy. Our results suggest that MK-AML may be biologically different according to the karyotypic subtype and that allo-HSCT in CR should be strongly recommended to patients with a single monosomy. For other patients, more prudent treatment strategies should be examined. Furthermore, the biological mechanism by which a single monosomy influences survival should be investigated.

Monosomy 1p36 - a multifaceted and still enigmatic syndrome: four clinically diverse cases with shared white matter abnormalities.

Monosomy 1p36 is the most common subtelomeric deletion syndrome seen in humans. Uniform features of the syndrome include early developmental delay and consequent intellectual disability, muscular hypotonia, and characteristic dysmorphic facial features. The gene-rich nature of the chromosomal band, inconsistent deletion sizes and overlapping clinical features have complicated relevant genotype-phenotype correlations. We describe four patients with isolated chromosome 1p36 deletions. All patients shared white matter abnormalities, allowing us to narrow the critical region for white matter involvement to the deletion size of up to 2.5 Mb from the telomere. We hypothesise that there might be a gene(s) responsible for myelin development in the 1p36 subtelomeric region. Other significant clinical findings were progressive spastic paraparesis, epileptic encephalopathy, various skeletal anomalies, Prader-Willi-like phenotype, neoplastic changes - a haemangioma and a benign skin tumour, and in one case, sleep myoclonus, a clinical entity not previously described in association with 1p36 monosomy. Combined with prior studies, our results suggest that the clinical features seen in monosomy 1p36 have more complex causes than a classical contiguous gene deletion syndrome.

Allogeneic hematopoietic cell transplantation may alleviate the negative prognostic impact of monosomal and complex karyotypes on patients with acute myeloid leukemia.

Monosomal karyotype (MK) and complex karyotype (CK) are well known to be associated with a very poor clinical outcome in patients with acute myeloid leukemia (AML). However, whether or not the prognostic impact of MK and CK remains relevant for patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT) is still unclear. We retrospectively analyzed the status of MK and CK, as well as other clinical laboratory features, in 148 allo-HCT AML patients at our institution and correlated with their event-free survival (EFS) and overall survival (OS) after transplantation. MK and CK were identified in 14 (9%) and 19 (13%) cases, respectively. On univariate analysis, only age (≥60 years) and WBC count (≥15 × 10(9)/L) were significant adverse predictors for EFS (P < .001 and P = .017, respectively) and OS (P = .002 and P = .021, respectively). MK, CK, and other relevant parameters analyzed did not affect the clinical outcome. Multivariable analysis confirmed that both older age and high WBC count were independent prognostic factors for a shorter OS (P = .001 and P = .003, respectively) and a shorter EFS (P < .001 and P = .001, respectively). Our results indicate that neither MK nor CK are high-risk factors in AML patients undergoing allo-HCT.

Partial trisomy 2p24-->pter and monosomy 18q22.1- qter resulting from parental translocation.

This is a report of a 6 month-old boy with a partial trisomy 2p24-->pter and monosomy 18q22-->qter. This is the first case presenting this unbalanced translocation with phenotypic features. The patient had growth and developmental retardation, facial dysmorphism, cleft palate, congenital cardiopathy, hypospadias, evantration of diaphragm and deafness. Cranial MRI showed mild ventricular dilatation. Cytogenetic analysis of the patient and his parents revealed a karyotype 46,XY, der(18), t(2;18)(p24;q22)mat in the patient. Subtelomeric FISH analysis confirmed the cytogenetic findings. Phenotypic features were consistent with either partial trisomy 2p or deletion 18q.

Partial trisomy 3p and partial monosomy 11q associated with double outlet right ventricle and septum pellucidum et vergae: a case report.

Su Partial trisomy 3p and partial monosomy 11q are rare chromosomal disorders with a deletion of part of chromosome 11 combined with a duplication of part of chromosome 3. These are usually inherited from a parent who carries a balanced translocation involving chromosome 3, which can result in the unbalanced translocation trisomy 3p in a child. In this paper, we report a newborn who has dysmorphic facial features, double outlet right ventricle, hypotonia, hypospadias, neonatal thrombocytopenia, hydroureteronephrosis, talipes equinovarus and septum pellucidum et vergae. Cytogenetic investigation revealed 46,XY,der(11)t(3;11)(p22.2;q23.3) and the karyotype of his father showed a balanced translocation, 46XY,t(3;11)(p22.2;p23.3).

45,X/46,XX karyotype mitigates the aberrant craniofacial morphology in Turner syndrome.

The aim of this project was to study the impact on craniofacial morphology from Turner syndrome (TS) karyotype, number of intact X chromosomal p-arms, and age as well as to compare craniofacial morphology in TS with healthy females. Lateral radiographs from 108 females with TS, ranging from 5.4 to 61.6 years, were analysed. The TS females were divided into four karyotype groups: 1. monosomy (45,X), 2. mosaic (45,X/46,XX), 3. isochromosome, and 4. other, as well as according to the number of intact X chromosomal p-arms. The karyotype was found to have an impact on craniofacial growth, where the mosaic group, with presence of 46,XX cell lines, seems to exhibit less mandibular retrognathism as well as fewer statistically significant differences compared to the reference group than the 45,X karyotype. Isochromosomes had more significant differences versus the reference group than 45,X/46,XX but fewer than 45,X. To our knowledge, this is the first time the 45,X/46,XX and isochromosome karyotypes are divided into separate groups studying craniofacial morphology. Impact from p-arm was found on both maxillary and mandibular length. Compared to healthy females, TS expressed a shorter posterior and flattened cranial base, retrognathic, short and posteriorly rotated maxilla and mandible, increased height of ramus, and relatively shorter posterior facial height. The impact of age was found mainly on mandibular morphology since mandibular retrognathism and length were more discrepant in older TS females than younger.

White matter aberrations in prepubertal estrogen-naive girls with monosomic Turner syndrome.

Turner syndrome (TS) offers a unique opportunity to investigate associations among genes, the brain, and cognitive phenotypes. In this study, we used 3 complementary analyses of diffusion tensor imaging (DTI) data (whole brain, region of interest, and fiber tractography) and a whole brain volumetric imaging technique to investigate white matter (WM) structure in prepubertal, nonmosaic, estrogen-naive girls with TS compared with age and sex matched typically developing controls. The TS group demonstrated significant WM aberrations in brain regions implicated in visuospatial abilities, face processing, and sensorimotor and social abilities compared with controls. Extensive spatial overlap between regions of aberrant WM structure (from DTI) and regions of aberrant WM volume were observed in TS. Our findings indicate that complete absence of an X chromosome in young females (prior to receiving exogenous estrogen) is associated with WM aberrations in specific regions implicated in characteristic cognitive features of TS.

Persistence of a monosomic cell line in a fetus with mosaic trisomy 8.

We report on a fetus presenting with an increased nuchal translucency, in which chorionic villus sampling led to the diagnosis of mosaic trisomy 8. Ultrasound scan performed at 15(+6) weeks revealed bilateral cleft lip and palate, flat facial profile, and arrhinia. Pregnancy was terminated at 16(+6); postmortem examination showed additional findings including hypospadias, bilateral renal dysplasia, and focal portal fibrosis of the liver. In order to confirm the presence of trisomy 8, FISH analysis was performed in abnormal renal and hepatic tissue, which, unexpectedly, showed a higher fraction of cells with only one fluorescent probe signal (43% and 23%, respectively), if compared with normal fetal liver and kidney (3-10%). This finding is consistent with the survival in this fetus of a monosomic cell line after mitotic non-disjunction, which is in contrast with what is generally thought about mosaic trisomy genesis. We hypothesize that the possible persistence of the monosomic cell line, in addition to the variable distribution of aneuploid cells in the body tissues, could explain the high heterogeneity of mosaic trisomy 8 phenotype.