Ring Chromosome Research Articles

Application of optical genome mapping technology for the detection of chromosomal structural variations

To assess the value of optical genome mapping (OGM) for the detection of chromosomal structural abnormalities including ring chromosomes, balanced translocations, and insertional translocations. Clinical data of four patients who underwent pre-implantation genetic testing concurrently with OGM and chromosomal microarray analysis at the Center of Reproductive Medicine of the Sixth Affiliated Hospital of Sun Yat-sen University from January to October 2022 due to chromosomal structural abnormalities were selected as the study subjects. Some of the results were verified by multi-color fluorescence in situ hybridization. The OGM has successfully detected a balanced translocation and fine mapped the breakpoints in a patient. Among two patients with insertional translocations, OGM has provided more refined breakpoint locations than karyotyping analysis in a patient who had chromosome 3 inserted into chromosome 6 and determined the direction of the inserted fragment. However, OGM has failed to detect the chromosomal abnormality in a patient with chromosome 8 inserted into the Y chromosome. It has also failed to detect circular signals in a patient with ring chromosome mosaicism. OGM has successfully detected chromosomal structural variations in the four patients and provided assistance for their diagnosis.

Mosaic Potocki-Lupski Syndrome Due to a Supernumerary Marker Chromosome Containing <i>RAI1</i>

Potocki-Lupski syndrome<strong> </strong>(PTLS) is a recurrent microduplication syndrome characterized by developmental delay, behavioral abnormalities, mildly dysmorphic facial features, hypotonia, and sleep disorders. We report here a 3-year-old girl diagnosed with mosaic PTLS harboring a supernumerary marker chromosome containing the <em>RAI1</em> (retinoic acid induced 1) gene. Cytogenetic testing, including chromosomal microarray, karyotype, and FISH analysis, identified a ring chromosome containing portions of chromosomes 14 and 17 in 85% of cells. Clinical features of this individual included atypical facies with frontal bossing, bitemporal narrowing, prominent cupped ears, and mild speech delay. Presented here is a novel case of PTLS associated with mosaic gains of chromosomes 14 and 17. As small supernumerary marker chromosomes (sSMCs) involving non-acrocentric chromosomes are rare, this case contributes to our understanding of phenotypic spectrum associated with sSMC(17).

Hematological and Cytogenetic Effects of X-rays in Cardiac Unit Workers and Catheterization Patients.

Introduction X-rays are widely used in medicine for diagnosis and treatment. Such beneficial uses may cause potentially hazardous situations for patients andworkers in the cardiac catheterization laboratory. The present study aims to estimate the radiation dose scattered in different parts of the catheterization units and doses absorbed by workers in thisunit, and patients who underwent cardiac catheterization procedures to evaluate all changes in hematological parameters and damaged cells (the cells that contain a number of chromosomal aberrations) after exposure to radiation at Azadi Teaching Hospital in the Duhok City of Iraq. Methodology Thestudy was conducted in one year and involved 19 male workers chronically exposed to X-ray machines in the cardiac catheterization laboratory, and 45 patients, 20 males and 25 females, who have been exposed to lower doses of X-ray during the cardiac catheterization process. There were 32 healthy individuals, 19 males and 13 females, as a control. Scattered radiation was calculated using an area monitoring detector.Optically Stimulated Luminescence (OSL) dosimeter andFlat Panel Detector (FPD)were used to calculate absorbed doses by workers and patients, respectively. Twelve hematological parameters before and after radiation were examined between study groups; the cytogenetic effects, damagedcells, and chromosomal aberrations of the white blood cells of workers, patientsin the catheterization unit, and individuals of the control group were analyzed. Results The results showed that the scattered X-rays in the catheterization unit after one year of continuous detection did not change significantly compared to the data before the start of the trial. The results of all blood parameters looked to be significantly different (p<0.05) compared to the controls but within the normal range.There is no significant difference (p>0.05) in corpuscular hemoglobin, white blood cells, red distribution width, and neutrophilvalues for workers after one year of exposure as compared with the control. Also, there was no significant difference (p>0.05) in white blood cells, neutrophils, and monocyte values for patients after the operation. The current study showed the damaged cells in workerswere significantlydifferent compared to the control. At the same time, the differences were non-significant for all workers (p=0.0962) after one year of exposure.The differences in damaged cells in patients were highly significant after the operation (p=0.0003). The present study demonstrated that the inductions of dicentrics, acentric, chromosome break, and ring chromosomes in human lymphocytes were intimately related to the irradiation dose. Conclusions The presentstudy found that the scattered X-rays in the catheterization unit after the end of the experiment did not change significantly. The current study also revealed that the exposure to X-rays had no significant effects on the blood indicators of workers and patients in the catheterization unit, whereas the damaged cells in patients did not change significantly compared with the control group at the beginning of the experiment.In patients, these cells were increased after the operation but were present at a high level in the workers, as compared with controls.The damaged cells in workers remained constant from the beginning of the experiment till the end.Finally, patients had increased damaged cells after the end of the trial period compared to workers.

Utility of genetic testing in the pre-surgical evaluation of children with drug-resistant epilepsy.

We evaluated the utility of genetic testing in the pre-surgical evaluation of pediatric patients with drug-resistant focal epilepsy. This single-center retrospective study reviewed the charts of all pediatric patients referred for epilepsy surgery evaluation over a 5-year period. We extracted and analyzed results of genetic testing as well as clinical, EEG, and neuroimaging data. Of 125 patients referred for epilepsy surgical evaluation, 86 (69%) had some form of genetic testing. Of these, 18 (21%) had a pathogenic or likely pathogenic variant identified. Genes affected included NPRL3 (3 patients, all related), TSC2 (3 patients), KCNH1, CHRNA4, SPTAN1, DEPDC5, SCN2A, ARX, SCN1A, DLG4, and ST5. One patient had ring chromosome 20, one a 7.17p12 duplication, and one a 15q13 deletion. In six patients, suspected epileptogenic lesions were identified on brain MRI that were thought to be unrelated to the genetic finding. A specific medical therapy choice was allowed due to genetic diagnosis in three patients who did not undergo surgery. Obtaining a molecular diagnosis may dramatically alter management in pediatric patients with drug-resistant focal epilepsy. Genetic testing should be incorporated as part of standard investigations in the pre-surgical work-up of pediatric patients with drug-resistant focal epilepsy.

A combination of long- and short-read genomics reveals frequent p-arm breakpoints within chromosome 21 complex genomic rearrangements

PurposeAlthough chromosome 21 is the smallest human chromosome, it is highly relevant in the pathogenicity of both cancer and congenital diseases, including Alzheimer disease and trisomy 21 (Down syndrome). In addition, cases with rare structural variants (SVs) of chromosome 21 have been reported. These events vary in size and include large chromosomal events, such as ring chromosomes and small partial aneuploidies. The p-arm of the acrocentric chromosome 21 was devoid of reference genomic sequence in GRCh37 and GRCh38, which hampered our ability to solve genomic rearrangements and find the mechanism of formation of disease-causing SVs. We hypothesize that conserved satellite structures and segmental duplications located on the p-arm play an important role in the formation of complex SVs involving chromosome 21. MethodsThree cases with complex chromosome 21 rearrangements were studied with a combination of short-read and long-read genome sequencing, as well as optical genome mapping. The data were aligned to the T2T-CHM13 assembly. ResultsWe were able to resolve all 3 complex chromosome 21 rearrangements in which 15, 8, and 26 breakpoints were identified, respectively. By comparing the identified SV breakpoints, we were able to pinpoint a region between 21p13 and 21p12 that appears to be frequently involved in chromosome 21 rearrangements. Importantly, we observed acrocentric satellite DNA at several breakpoint junctions suggesting an important role for those elements in the formation of complex SVs. ConclusionTaken together, our results provide further insights into the architecture and underlying mechanisms of complex rearrangements on acrocentric chromosomes.

Gene amplification in neoplasia: A cytogenetic survey of 80 131 cases.

Gene amplification is a crucial process in cancer development, leading to the overexpression of oncogenes. It manifests cytogenetically as extrachromosomal double minutes (dmin), homogeneously staining regions (hsr), or ring chromosomes (r). This study investigates the prevalence and distribution of these amplification markers in a survey of 80 131 neoplasms spanning hematologic disorders, and benign and malignant solid tumors. The study reveals distinct variations in the frequency of dmin, hsr, and r among different tumor types. Rings were the most common (3.4%) sign of amplification, followed by dmin (1.3%), and hsr (0.8%). Rings were particularly frequent in malignant mesenchymal tumors, especially liposarcomas (47.5%) and osteosarcomas (23.4%), dmin were prevalent in neuroblastoma (30.9%) and pancreatic carcinoma (21.9%), and hsr frequencies were highest in head and neck carcinoma (14.0%) and neuroblastoma (9.0%). Combining all three amplification markers (dmin/hsr/r), malignant solid tumors consistently exhibited higher frequencies than hematologic disorders and benign solid tumors. The structural characteristics of these amplification markers and their potential role in tumorigenesis and tumor progression highlight the complex interplay between cancer-initiating gene-level alterations, for example, fusion genes, and subsequent amplification dynamics. Further research integrating cytogenetic and molecular approaches is warranted to better understand the underlying mechanisms of these amplifications, in particular, the enigmatic question of why certain malignancies display certain types of amplification. Comparing the present results with molecular genetic data proved challenging because of the diversity in definitions of amplification across studies. This study underscores the need for standardized definitions in future work.

CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells

ABSTRACT Cyclin-dependent Kinase 2 (CDK2) inhibition prevents supernumerary centrosome clustering. This causes multipolarity, anaphase catastrophe and apoptotic death of aneuploid cancers. This study elucidated how CDK2 antagonism affected centrosome stoichiometry. Focused ion beam scanning electron microscopy (FIB-SEM) and immunofluorescent imaging were used. Studies interrogated multipolar mitosis after pharmacologic or genetic repression of CDK2. CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering. This caused ring-like chromosomes or multipolar cancer cells to form before onset of cell death. Intriguingly, CDK2 inhibition caused a statistically significant increase in single centrioles rather than intact centrosomes with two centrioles in cancer cells having chromosome rings or multipolarity. Statistically significant alterations in centrosome stoichiometry were undetected in other mitotic cancer cells. To confirm this pharmacodynamic effect, CDK2 but not CDK9 siRNA-mediated knockdown augmented cancer cells with chromosome ring or multipolarity formation. Notably, engineered gain of CDK2, but not CDK9 expression, reversed emergence of cancer cells with chromosome rings or multipolarity, despite CYC065-treatment. In marked contrast, CDK2 inhibition of primary human alveolar epithelial cells did not confer statistically significant increases of cells with ring-like chromosomes or multipolarity. Hence, CDK2 antagonism caused differential effects in malignant versus normal alveolar epithelial cells. Translational relevance was confirmed by CYC065-treatment of syngeneic lung cancers in mice. Mitotic figures in tumors exhibited chromosome rings or multipolarity. Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

Whole genome sequencing provides evidence for Bacillus velezensis SH-1471 as a beneficial rhizosphere bacterium in plants

Bacillus is widely used in agriculture due to its diverse biological activities. We isolated a Bacillus velezensis SH-1471 from the rhizosphere soil of healthy tobacco, which has broad-spectrum antagonistic activity against a variety of plant pathogenic fungi such as Fusarium oxysporum, and can be colonized in the rhizosphere of a variety of plants. This study will further explore its mechanism by combining biological and molecular biology methods. SH-1471 contains a ring chromosome of 4,181,346 bp with a mean G + C content of 46.18%. We identified 14 homologous genes related to biosynthesis of resistant secondary metabolite, and three clusters encoded potential new antibacterial substances. It also contains a large number of genes from colonizing bacteria and genes related to plant bacterial interactions. It also contains genes related to environmental stress, as well as genes related to drug resistance. We also found that there are many metabolites in the strain that can inhibit the growth of pathogens. In addition, our indoor pot test found that SH-1471 has a good control effect on tomato wilt, and could significantly improve plant height, stem circumference, root length, root weight, and fresh weight and dry weight of the aboveground part of tomato seedlings. Therefore, SH-1471 is a potential biological control strain with important application value. The results of this study will help to further study the mechanism of SH-1471 in biological control of plant diseases and promote its application.

Ring Chromosomes in Hematological Malignancies Are Associated with TP53 Gene Mutations and Characteristic Copy Number Variants.

Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs-90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.

Ring chromosome 13 and sexual ambiguity: Case report

Background: Ring chromosome 13 is a rare chromosomal disorder. Patients with this disorder may present with various clinical features depending on the deleted segments. Methods/Observation: Herein, we report a 3-years old boy with severe symptoms including a global development delay and sexual ambiguity. Karyotype analysis showed 46,XY,r(13). Conclusion: The patient is likely carrying 13q31-34 segments loss which could explain the observed phenotype. Keywords: Chromosome 13, deletion, ring chromosome, development delay, sexual disorder.

The Presence of Ring Chromosomes in Patients with Myeloid Neoplasms Is Predictive of a Poor Outcome

Cytogenomic analysis is an important tool in the risk stratification of patients with hematologic malignancies. Complex chromosomal alterations are associated with a poor prognosis (Döhner et al., Blood 2022). Ring chromosomes (RC) are circular chromosomal structures associated with loss or gain/amplification of genetic material and are associated with poor prognosis in acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) (Rosenbaum et al., Human Path 2017). Due to their rarity, the impact of RC on response to therapy has not yet been well characterized. We further examined the significance of RC in AML, MDS and myeloproliferative neoplasms (MPN) by retrospectively analyzing records of patients identified to have RC and myeloid neoplasms at our institution between 2017 and 2023 and collected demographic, diagnostic, treatment, molecular, cytogenomic, and outcomes data. We identified 27 cases with RC with clinical data available for 25. Demographic and treatment details are described in Table 1. The most common chromosomes involved were r(11) and r(7), 6 and 4 cases respectively, followed by r(6) and r(19) with 2 cases each. The most frequently observed diagnosis was AML in 12 patients (48%) followed by MDS with 9 cases (36%) and MPN in 4 cases (16%). In 17 cases (68%) the RC was cytogenetically detected at diagnosis and was not observed in the context of prior therapy. Remarkably, mutations in TP53 were present in 14 cases (56%) and accompanied by loss of 17p (bi-allelic) in 7 cases (28%). The next most commonly observed gene mutations were in DNMT3A (7 cases), TET2 (4 cases) and ASXL1 (3 cases). In 11 cases (44%) the alterations in TP53 were not associated with prior therapy for other malignancies. The median time from prior chemotherapy to detection of the RC was 5.1 years (range 0.6 to 13.5 years). Chromothripsis (a single DNA catastrophic event resulting in extensive genomic rearrangements of one or a few chromosomes) as detected by CGH+SNP array and homogenous staining regions (autonomously replicating extra-chromosomal elements that are frequently associated with gene amplification) were observed in 3 patients each. RC were the sole genetic abnormality in 5 patients. A Kaplan-Meier analysis of median overall survival (mOS) in patients with AML and MDS with RC at diagnosis revealed that patients who received supportive care had significantly shorter mOS than patients who received hypomethylating agents (HMA), HMA/Venetoclax(VEN), or anthracycline-based chemotherapy (log rank test, p = 0.001). A significant difference in mOS between patients who received HMA alone versus HMA/VEN versus chemotherapy was not observed (11.4 vs 3.1 vs 7.3 months, p = 0.8) (Figure 1). Patients who received any of the therapies outlined above likewise demonstrated a significantly longer progression free survival (log rank test, p = 0.001). There was no effect on mOS for any of the other tested prognostic parameters, including the presence of a complex karyotype, TP53 allele status, or therapy-related neoplasm, nor for pair-wise interactions between those categories and first-line therapies (p &amp;gt; 0.05 for all tested associations). These data represent a large single-institution cohort of patients with RC and is the first to investigate the impact of therapy and molecular profiles in this population. We observed a high prevalence of TP53 mutations and loss of 17p, however we lacked longitudinal data to make causal inferences regarding the relationship between these abnormalities and ring formation. Of note, 68% of patients did not have prior exposure to therapy, and 36% of all patients lacked TP53 mutations or chromosomal p53 loss, indicating a high rate of de novo ring formation. This is a novel finding perhaps suggesting that inherent chromosomal instability characterizes these patients. Comparing response to type of therapy and outcomes of patients, we conclude that the mOS in patients with RC without therapy is significantly shortened compared with any of the therapeutic options described above, and that the addition of VEN to HMA did not positively influence mOS or PFS compared to HMA alone or chemotherapy in our cohort. Furthermore, the presence of a complex karyotype or a mutation and/or deletion of TP53 with a RC was not independently associated with inferior mOS, suggesting that the presence of a ring chromosome alone may be an important adverse risk factor in myeloid malignancies.

A D e Novo Supernumerary Ring Chromosome 1 Causes B-Cell Acute Lymphoblastic Leukemia in Monozygotic Twins Due to Independent and Partially Convergent Evolutionary Trajectories

Introduction B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. In recent years, our understanding of B-ALL biology has benefited from genomic and transcriptomic analyses that identify driver alterations in 98% of patients. In addition, prior studies of monozygotic twins, who both developed B-ALL, have provided insight into the developmental timing and natural history of the disease, as well as the identification of novel mechanisms of leukemogenesis. Herein we study a case of monozygotic twins, who developed B-ALL (Table 1). We report the characterization of a de novo supernumerary ring chromosome 1 (SRC1) as an initiator event that followed independent but partially convergent clonal trajectories in each twin. Thus, SRC1 resulted in genomic rearrangements of MEF2D in both twins but targeted distinct fusion gene partners ( BCL9 versus ARNT). To our knowledge, this study represents the first description of MEF2D-ARNT as an event involved in B-ALL, and the association of SRC1 Syndrome with leukemia. Methods We performed integrative whole genome sequencing (WGS) and RNAseq analysis on B-ALL samples at diagnosis and compared this to WGS data from minimal residual disease negative bone marrow aspirates. Coverage levels for tumors and matched normals were: Twin A=104 &amp; 59; Twin B=81 &amp; 53. Tumor purity estimations were 0.80 in Twin A and 0.31 in Twin B. For RNAseq, expression profile efficiencies were 61% and 36% respectively. Comprehensive variant calling was performed using the Isabl platform (Medina et al, 2020) to map all putative somatic and germline events. ALLCatchR (Beder et. al, 2022) was used for molecular B-ALL subtype allocation in 26 samples from our pediatric cohort of patients including the twins (age range 1-23), and MutationTimeR (Gerstung et al, 2020) to calculate the relative timing of copy number gains. All research studies were approved by NYU and MSKCC Institutional Review Boards. Results The tumor mutational burdens for each leukemia sample were 0.86 for Twin A and 0.47 mutations/Mb for Twin B, and they showed independent alterations in oncogenic genes (Table 1). The only B-ALL driver that both twins had partially in common was an intrachromosomal translocation resulting in MEF2D fusions, but each with a distinct partner gene ( BCL9 versus ARNT) which was confirmed by RNAseq (supporting reads: Twin A=48, Twin B=107) and PCR assays (Fig. 1). Each sample demonstrated enhanced transcription levels of MEF2D compared to our reference B-ALL cohort (transcripts per million: Twin A=48.0, Twin B=77.4, median=27.7, sd=19.9), and were transcriptionally classified as MEF2D-subtype by the ALLCatchR classifier. These results functionally supported the role of MEF2D-ARNT as a new oncogenic event. Analysis of germline variants showed a tandem duplication flanking the pericentromeric region of chromosome 1 in both twins (1:120,163,074-157,714,717) where MEF2D BCL9and ARNT are localized, that had been previously identified as SRC1 in only one of them by constitutional genotyping (Table 1). Cell fractions in normal and tumor tissues were: Twin A=14.8% &amp; 50%, Twin B=8.6% &amp; 26.5%. PCR interrogation of parental germline DNA failed to identify SRC1, suggesting this to be a de novo event in the affected twins (Fig. 1). We compared the relative timepoint in which the SRC1 took place in each sample using MutationalTimeR, but we were only able to obtain results in Twin A due to a higher mutational burden (number of variants in SRC1: Twin A=44, Twin B=13). As expected, the tandem duplication that formed the SRC1 was identified as an early mutational event (confidence interval of relative time of appearance: 0-0.4). Conclusions Our results identify SRC1 as the common initiating genomic event leading to MEF2D fusion driven B-ALL in both twins. These findings support a model in which a tandem duplication around a pericentromeric area was an initiating event which caused the scission and circularization of DNA without the loss of genetic material. This led to a de novo acquisition of a SRC1, that after independent but partially convergent clonal trajectories gave rise to 2 distinct oncogenic MEF2D fusion driven leukemias in each twin . Moreover, ARNT is a novel partner gene to MEF2D which has not been previously described. This is the first report of B-ALL association with SRC1 Syndrome, which emphasises the utility of the study of monozygotic twins to identify novel alterations underlying B-ALL.

Live-born autosomal ring chromosomes at the Johns Hopkins Hospital Cytogenomics Laboratory: Case series-Spanning 52 years of experience in a single center.

Ring chromosomes (RCs) are a structural aberration that can be tolerated better in acrocentric or gonosomal chromosomes. Complete RCs arise from telomere-telomere fusions. Alternatively, genomic imbalances corresponding to the ends of the chromosomal arms can be seen with RC formation. RCs are unstable in mitosis, result in mosaicism, and are associated with a "ring syndrome," which presents with growth and development phenotypes and differs from those features more frequently observed with pure terminal copy number changes. Due to variability in mosaicism, size, and genomic content, clear genotype-phenotype correlations may not always be possible. Given the rarity of RCs, this historical data is invaluable. We performed a retrospective review of individuals bearing RCs to investigate the incidence in our laboratory. This work details the methods and features seen in association with twenty-three autosomal RCs. In decreasing order, the most frequently seen autosomal RCs were 18, 22, 4, 13, 17, and 9. The additional cases detail clinical and cytogenomic events similar to those reported in RCs. As methodologies advance, insights may be gleaned from following up on these cases to improve genotype-phenotype correlations and understand the cryptic differences or other predisposing factors that lead to ring formation and development.

Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities.

Adipocytic neoplasms are frequently encountered in clinical practice. Atypical lipomatous tumor (ALT) is a locally aggressive but non-metastasizing adipocytic neoplasm that primarily occurs in the proximal extremities of middle-aged to older adults. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing and inflammatory subtypes. The sclerosing subtype is an unfavorable prognostic factor for local recurrence. ALT is characterized by supernumerary ring and/or giant rod chromosomes. These rings and giant markers invariably contain amplified sequences originating from the long arm of chromosome 12, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. Confidently differentiating deep-seated ALT from deep-seated ordinary lipoma is often difficult on imaging. Moreover, the sclerosing subtype may mimic a higher grade liposarcoma. Detection of MDM2 amplification by fluorescence in situ hybridization would be helpful diagnostically for ALT in more difficult cases. The standard treatment for deep-seated ALT is surgery. Although there is no consensus on the best surgical approach for deep-seated ALT of the extremities, the use of marginal resection is acceptable to preserve musculoskeletal function. This review provides an overview of the current knowledge on the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.

Molecular characterization of de novo ring chromosome 21 in a child with seizures, growth retardation, and multiple congenital anomalies

Molecular characterization of de novo ring chromosome 21 in a child with seizures, growth retardation, and multiple congenital anomalies

Clinical features and genetic analysis of two fetuses with ring chromosome 21 mosaicism

To investigate the perinatal clinical phenotype and genetic characteristics of two fetuses with ring chromosome 21 mosaicisms. Two fetuses who were diagnosed at the Xiamen Maternal and Child Health Care Hospital in November 2021 were selected as the study subjects. Clinical data of the two fetuses were collected. Conventional G-banded karyotyping and chromosomal microarray analysis (CMA) were carried out for the fetuses and their parents. Prenatal ultrasonography of fetus 1 has revealed absence of nasal bone, ventricular septal defect, persistent left superior vena cava, and mild tricuspid regurgitation. Chromosomal karyotyping was 46,X?,dic r(21;21)(p12q22;q22p12)[41]/45,X?,-21[9]. CMA has revealed a 30.00 Mb quadruplication at 21q11.2q22.3 and a 3.00 Mb deletion at 21q22.3. For fetus 2, ultrasonography has revealed pointed echo of the nasal bone. The fetus was found to have a karyotype of 46,X?,r(21)(p12q22)[83]/45,X?,-21[14]/46,X?,dic r(21;21)(p12q22;q22p12)[3]. CMA has revealed a 5.10 Mb quadruplication at 21q22.12q22.3 and a 2.30 Mb deletion at 21q22.3. The perinatal phenotype of the two fetuses with ring chromosome 21 mosaicisms is related to the duplication of chromosomal segments near the breakpoints of the chromosomal deletions. The combined chromosomal karyotyping and CMA has enabled prenatal diagnosis and genetic counseling for these families.

The Multifaceted Syndromic Primary Immunodeficiencies in Children.

Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs). This is a retrospective descriptive study of children aged 0-18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021. sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems. Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.

Response to growth hormone therapy in ring chromosome 15: Review and evidence from a new case on possible beneficial effect in neurodevelopment

Type 1 Insulin-like Growth Factor Receptor(IGF1R) plays a fundamental role in normal growth and development. Its disruption is usually characterized by severe intrauterine and postnatal growth retardation, microcephaly and neurodevelopmental delay.The efficacy of recombinant human growth hormone treatment remains a challenge for children with IGF1 resistance and pathogenic mutations of IGF1R, with limited data in patients carrying the most severe form of IGF1R defect, the ring chromosome 15. Subject and methodWe tested a high dose of rhGH in a new patient with ring chromosome 15, as confirmed by karyotype and CGH array. We performed a systematic review, and all published r(15) syndrome cases treated by growth hormone(GH) up to April 2023 were searched, and their response to GH therapy was recorded and summarized. ResultsTwelve patients with ring chromosome 15 received GH therapy according to a literature review. We expand the spectrum by the 13th case treated by GH, and we report an impressive improvement in intellectual performance and progressive catch-up growth after 5 and 20 months of follow-up. By introducing our new case in the analysis, the sex ratio was 3:10, and GH therapy was started at the age of 5.5 (3/9.4) (years) for an age of diagnosis of 4.75 (1.3/9.5) (years). The height before GH therapy was −5.1(−5.9/−4.1) SDS. The median duration of treatment was 1.7(0.9/2) (years), with a median height gain of 1(0.3/1.8) SDS and an improvement in growth velocity of 4.1(2.8/5.3) (cm/year). ConclusionGH seems to be effective for r(15) syndrome patients with short stature.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy

PurposeTo evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. MethodsIn this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. ResultsForty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were “responders” and 12 (29%) were “super-responders”. Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. ConclusionsIn this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.

Characteristics and mechanisms of mosaicism in prenatal diagnosis cases by application of SNP array

BackgroundWith the application of chromosome microarray, next-generation sequencing and other highly sensitive genetic techniques in disease diagnosis, the detection of mosaicism has become increasingly prevalent. This study involved a retrospective analysis of SNP array testing on 4512 prenatal diagnosis samples, wherein the characterization of mosaicism was explored and insights were gained into the underlying mechanisms thereof.ResultsUsing SNP array, a total of 44 cases of mosaicism were identified among 4512 prenatal diagnostic cases; resulting in a detection rate of approximately 1.0%. The prevalence of mosaicism was 4.1% for chorionic villus sample, 0.4% for amniotic fluid, and 1.3% for umbilical cord blood. Of these cases, 29 were mosaic aneuploidy and 15 were mosaic segmental duplication/deletion. Three cases of mosaic trisomy 16 and three cases of mosaic trisomy 22 were diagnosed in the CVS samples, while four cases of mosaic trisomy 21 were detected in amniotic fluid and umbilical cord blood samples. The distribution pattern of mosaicism suggested trisomy rescue as the underlying mechanism. Structurally rearranged chromosomes were observed, including three cases with supernumerary marker chromosomes, three cases with dicentric chromosomes, and one case with a ring chromosome. All mosaic segmental duplication/deletion cases were the result of mitotic non-disjunction, with the exception of one case involving mosaic11q segmental duplication.ConclusionImproved utilization of SNP arrays enables the characterization of mosaicism and facilitates the estimation of disease mechanisms and recurrence.