Cat Eye Syndrome Research Articles

Clinical and molecular cytogenetic findings of cat eye syndrome and a 2-year-old patient with congenital aural atresia and hearing loss

BackgroundCat eye syndrome (CES) is a rare congenital disease frequently caused by a partial tetrasomy of the proximal long (q) arm of chromosome 22, due to a small supernumerary marker chromosome (sSMC). CES patients show remarkable phenotypic variability. Despite the progress of molecular cytogenetic technology, the cause of phenotypic variability and the genotype–phenotype correlations remain unknown.MethodsWe analyzed clinical and genetic data of a new patient with CES together with 27 previously reported ones with a confirmed genomic gain in the PubMed database between 2012 and 2023.ResultsWe reported a boy with CES carrying a 22q11.1-q11.21 duplication of 1.76 Mb tetrasomy (16888900_18644241, hg19) who presented currently rare or unreported clinical findings such as congenital aural atresia, hearing loss, PLSVC, and IVC. The results of the whole exome sequencing (WES) showed a heterozygous mutation of the GJB2 gene (NM_004004.6: exon2: c.109G > A). In addition, the results of our literature review showed that the presence of a classical sSMC was the most frequent cytogenetic abnormality in CES (82%). 63% of cases were in a homogenous state and 37% of cases were in a mosaic state. 72% of cases had a 1–2 Mb duplication. In the majority of CES patients the breakpoints in chromosome 22 are localized to a 50 kb region (18610000_18660000 bp). The CES critical region (CESCR) may be further delimited to a 0.3 Mb region (17799398_18111588 bp). Within this region CECR2, SLC25A18, ATP6V1E1, and BCL2L13 are strong candidate genes for causing the main CES phenotype. The ear anomalies are the most frequent features in CES patients (89%) and hearing loss was present in 36% of CES patients.ConclusionsThe phenotypic features in CES are highly variable. Our findings expand the symptom spectrum of CES and lay the foundation for better delineating the clinical phenotype, molecular cytogenetic features associated with CES and genotype–phenotype correlations. We recommend performing WES to rule out the involvement of other genetic factors in the patient’s phenotype. In addition, our findings also highlight the need for genetic counseling and recurrence risk assessment.

Mortality in Patients with 22q11.2 Rearrangements.

The 22q11.2 region is highly susceptible to genomic rearrangements leading to multiple genomic disorders, including 22q11.2 microdeletion syndrome (22q11.2 DS) (MIM# 188400), 22q11.2 microduplication syndrome (MIM# 608363), supernumerary der(22)t(11;22) syndrome (also known as Emanuel Syndrome; MIM# 609029), and Cat Eye Syndrome (MIM# 115470). In this study, we present data on causes of mortality, average age of death, and the existing associated risk factors in patients with 22q11.2 rearrangements. Our cohort included 223 patients (120 males and 103 females) with confirmed diagnoses of 22q11.2 rearrangements diagnosed through molecular techniques (FISH, MLPA, and CMA). Relatives from patients who have been molecularly confirmed with 22q11.2 rearrangements have also been added to the study, regardless of the presence or absence of symptoms. Of these 223 individuals, 21 (9.4%) died. Deceased patients' rearrangements include 19 microdeletions, 1 microduplication, and 1 patient with a marker chromosome. The median age of death was 3 months and 18 days (ranging from 3 days to 34 years). There were 17 patients who died at pediatric age (80.95%), 3 died at adult age (14.28%), and for 1 of whom, the age of death is unknown (4.76%). Eighteen patients were White Mediterranean (European non-Finnish) (85.71%) whereas three were Amerindian (South American) (14.28%). Mortality from cardiac causes accounted for 71.42%. The second most frequent cause of death was sepsis in two patients (9.52%). One patient died from respiratory failure (4.76%) and one from renal failure (4.76%). Information regarding the cause of death was not available in two patients (9.52%). Most patients who died were diagnosed within the first week of life, the majority on the first day. This study adds additional information on mortality in one of the largest cohorts of patients with 22q11.2 rearrangements in more than 30 years of follow-up.

Prenatal diagnosis and genetic analysis of small supernumerary marker chromosomes in the eastern chinese han population: A retrospective study of 36 cases.

Small supernumerary marker chromosomes (sSMCs) are additional chromosomes with unclear structures and origins, and their correlations with clinical fetal phenotypes remain incompletely understood, which reduces the accuracy of genetic counseling. We conducted a retrospective analysis of a cohort of 36 cases of sSMCs diagnosed in our center. We performed G-banding and chromosomal microarray analysis (CMA). The resulting karyotypes were compared with case reports in the literature and various databases including OMIM, DECIPHER, ClinVar, ClinGen, ISCA, DGV, and PubMed. Karyotype analysis data revealed that 19 out of 36 fetuses were mosaic. Copy number variants (CNVs) analysis results showed that 27 out of 36 fetuses harbored pathogenic/likely pathogenic variants. Among these 27 cases, 11 fetuses carried sex chromosome-related CNVs, including 4 female cases exhibiting Turner syndrome phenotypes and 7 cases showing Y chromosome deletions. In the remaining 16 fetuses with autosomal CNVs, 9 fetuses carried variants associated with Cat eye syndrome, Emanuel syndrome, Tetrasomy 18p, and 15q11-q13 duplication syndrome. Among these, 22 fetuses were terminated, and the remaining 5 fetuses were delivered and developed normally. Additionally, we identified a few variants with unclear pathogenicity. Cytogenetic analysis is essential for identifying the pathogenicity of sSMCs and increasing the accuracy of genetic counseling.

CD138 as a Specific CSF Biomarker of Multiple Sclerosis.

The aim of this study was to identify novel biomarkers for multiple sclerosis (MS) diagnosis and prognosis, addressing the critical need for specific and prognostically valuable markers in the field. We conducted an extensive proteomic investigation, combining analysis of (1) CSF proteome from symptomatic controls, fast and slow converters after clinically isolated syndromes, and patients with relapsing-remitting MS (n = 10 per group) using label-free quantitative proteomics and (2) oligodendrocyte secretome changes under proinflammatory or proapoptotic conditions using stable isotope labeling by amino acids in cell culture. Proteins exhibiting differential abundance in both proteomic analyses were combined with other putative MS biomarkers, yielding a comprehensive list of 87 proteins that underwent quantification through parallel reaction monitoring (PRM) in a novel cohort, comprising symptomatic controls, inflammatory neurologic disease controls, and patients with MS at various disease stages (n = 10 per group). The 11 proteins that passed this qualification step were subjected to a new PRM assay within an expanded cohort comprising 158 patients with either MS at different disease stages or other inflammatory or noninflammatory neurologic disease controls. This study unveiled a promising biomarker signature for MS, including previously established candidates, such as chitinase 3-like protein 1, chitinase 3-like protein 2, chitotriosidase, immunoglobulin kappa chain region C, neutrophil gelatinase-associated lipocalin, and CD27. In addition, we identified novel markers, namely cat eye syndrome critical region protein 1 (adenosine deaminase 2, a therapeutic target in multiple sclerosis) and syndecan-1, a proteoglycan, also known as plasma cell surface marker CD138 and acting as chitinase 3-like protein 1 receptor implicated in inflammation and cancer signaling. CD138 exhibited good diagnostic accuracy in distinguishing MS from inflammatory neurologic disorders (area under the curve [AUC] = 0.85, CI 0.75-0.95). CD138 immunostaining was also observed in the brains of patients with MS and cultured oligodendrocyte precursor cells but was absent in astrocytes. These findings identify CD138 as a specific CSF biomarker for MS and suggest the selective activation of the chitinase 3-like protein 1/CD138 pathway within the oligodendrocyte lineage in MS. They offer promising prospects for improving MS diagnosis and prognosis by providing much-needed specificity and clinical utility. This study provides Class II evidence that CD138 distinguishes multiple sclerosis from other inflammatory neurologic disorders with an AUC of 0.85 (95% CI 0.75-0.95).

Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer immunotherapy

The crosstalk between breast cancer cells and tumor associated macrophages (TAMs) greatly contributes to tumor progression and immunosuppression. In this work, cat eye syndrome chromosome region candidate 2 (CECR2) is identified to overexpress in breast cancer patients, which can recognize v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and activate nuclear factor κB (NF-κB) to release colony stimulating factor-1 (CSF-1). Pharmacological inhibition of CECR2 by the bromodomain competitor (Bromosporine, Bro) can downregulate CSF-1 to inhibit M2 type TAMs. To amplify the immunotherapeutic effect, a chimeric peptide-based and optical controlled CECR2 competitor (designated as N-PB) is constructed to enhance the nuclear targeted delivery of Bro and initiate an immunogenic cell death (ICD). In vivo results indicate a favorable breast cancer targeting ability and primary tumor suppression effect of N-PB under optical irradiation. Importantly, N-PB downregulates CSF-1 by competitive inhibition of CECR2 and NF-κB(RelA) interactions, thus inhibiting immunosuppressive M2-like TAMs while improving the antitumorigenic M1-like phenotype. Ultimately, the systemic anti-tumor immunity is activated to suppress the metastatic breast cancer in an optical controlled manner. This study provides a promising therapeutic target and reliable strategy for metastatic breast cancer treatment by interrupting immunosuppressive crosstalk between tumor cells and macrophages.

Rare Association of Cat Eye Syndrome and Mullerian Agenesis: Third Reported Case

Introduction: Cat-eye syndrome is a rare genetic disease with extremely diverse phenotypes. Its most common manifestations include ocular coloboma, anal atresia, preauricular skin tags and pits. Case report: We report the third case of Cat-eye syndrome associated to Mullerian agenesis in a 28 years-old female, to highlight the possibility of a link between partial trisomy or tetrasomy of chromosome 22 (specifically of the region 22q11) and Müllerian agenesis. Discussion and Conclusion: In patients with CES, the short arm (p) and a small part of the long arm (q) of chromosome 22 are present three or four (trisomy or tetrasomy) times rather than twice in every cell of the organism. Schinzel et al, described in 1981 the first case of Cat eye syndrome associated to Mullerian agenesis in their series of 11 patients with CES. The second case of Müllerian agenesis in a patient with CES was reported by AlSubaihin et al. This rare association is suggesting that there may be genes in or near the 22q11 CES critical region that are important for normal mullerian development. Keywords: Cat-eye syndrome – Mullerian agenesis – Malformations – Genetic analysis

Cat eye syndrome: Clinical, cytogenetics and familial findings in a large cohort of 43 patients highlighting the importance of congenital heart disease and inherited cases.

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.

Cat eye syndrome caused by 22q11.1q11.21 duplication: case report in a Chinese family

Purpose This paper presents a report on two uncommon instances of cat eye syndrome in a Chinese family.Case presentationThe proband, a 23-year-old female, exhibited a diminutive cornea and complete blindness in her right eye, and the uncorrected distance visual acuity of her left eye was 0.7 LogMAR. Peripheral blood chromosome karyotyping reveal a karyotype of 47, XX, + mar. Subsequent analysis of chromosome copy number variation unveiled a 1.5 Mb duplication in the 22q11.1q11.21 region of the proband. The proband's mother,aged 49, displayed small eyes, wide-set eyes, downward slanting eyelids, and congenital heart disease. Chromosome copy number variation analysis also showed a 1.55 Mb duplication in the 22q11.1q11.21 region of chromosome 22 in the proband's mother. Ultimately, both members of this family were diagnosed with cat eye syndrome.Conclusion Cat eye syndrome is a rare genetic disorder that greatly affects patients' lives and requires personalized treatment. This study provides new evidence for a better understanding of the diagnosis of cat eye syndrome and emphasizes the importance of genetic counseling and supervision.

LncRNA CECR7 boosts hepatocellular carcinoma progression by recruiting RNA binding protein U2AF2 to enhance the stability of EXO1 mRNA

ObjectiveAs an important factor tumor regulator，long non-coding RNAs (lncRNAs) have aroused extensive attention via the diverse functional mechanisms that were associated with the pathological and physiological processes of HCC. Here, the main purpose of this study was to provide a clear understanding about the expression, functions and potential mechanism of lncRNA CECR7 (Cat Eye Syndrome Chromosome Region, Candidate 7) in HCC. MethodsRT-qPCR analysis and TCGA database analysis were applied to investigate the expression of CECR7 in HCC cell lines and tissues. Chi-squared Test was employed to explore the correlation between CECR7 expression and HCC clinicopathological features. Besides, Kaplan-Meier curves were constructed to test the effects of CECR7 expression on the prognosis of HCC patients. Transwell assays, MTT assay EdU assay and animal experiments were applied to explore the effects of CECR7 expression on HCC cells migration, invasion, and growth. Furthermore, RNA-seq analysis, luciferase reporter assay and mRNA decay rates assessment were utilized to investigate the mechanism whereby CECR7 regulated EXO1 mRNA. And, rescue experiments were used to determine whether EXO1 was an essential mediator for CECR7 to accelerate HCC cells migration, invasion, and growth. ResultsCECR7 was determined to be significantly overexpressed in HCC cell lines and tissues. CECR7 expression was closely correlated with the tumor size, venous infiltration, TNM stage, 5-year overall survival and disease-free survival of HCC. And, CECR7 played a catalytic role in HCC cells migration, invasion, and growth. Furthermore, CECR7 enhanced the stability of EXO1 mRNA by recruiting RNA binding protein U2AF2. And, EXO1 was determined to be an essential mediator for CECR7 to accelerate HCC cells migration, invasion, and growth. ConclusionIn a word, our findings demonstrates that the cancer-promoting gene lncRNA CECR7 motivates HCC metastasis and growth through enhanced mRNA stability of EXO1 mediated by U2AF2, proposing a new insight for targeted therapy of HCC.

Overlapping Spectrum of Craniofacial Microsomia Phenotype in Cat-Eye Syndrome.

This study reports three patients with Cat-eye Syndrome (CES), two of which present a previous clinical diagnosis of Craniofacial microsomia (CFM). Chromosomal microarray analysis (CMA) revealed a tetrasomy of 1,7 Mb at the 22q11.2q11.21 region, which is the typical region triplicated in the CES, in all patients. The most frequent craniofacial features found in individuals with CFM and CES are preauricular tags and/or pits and mandibular hypoplasia. We reinforce that the candidate genes for CFM features, particularly ear malformation, preauricular tags/pits, and facial asymmetry, can be in the proximal region of the 22q11.2 region.

Atresia de vias biliares em paciente com síndrome do olho do gato - relato de caso

Biliary atresia is a rare condition, of undefined etiology and with a potentially fatal evolution. The cat eye syndrome is a rare chromosomal disease that is associated with several malformations, biliary atresia being among the most rarely described. Male newborn with jaundice onset at 20 days of age, accompanied by fecal hypocholia. Laboratory tests, imaging and liver biopsy were suggestive of biliary atresia. The patient underwent Kasai surgery at 55 days of age. He also had several malformations, and the genetic team diagnosed cat eye syndrome. He presented with a favorable clinical evolution after surgery, maintaining follow-up with several specialties. This genetic syndrome has a variable phenotype and the early identification of associated malformations is essential for proper treatment, which can have a positive impact on both patient survival and quality of life.

Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype-Phenotype Correlation.

We conducted a retrospective study of 59 22q11.2SD cases, with the aim of highlighting phenotype-genotype correlations. All cases were tested using MLPA combined kits: SALSA MLPA KIT P245 and P250 (MRC Holland). most cases (76%) presented classic deletion LCR A-D with various severity and phenotypic findings. A total of 14 atypical new deletions were identified: 2 proximal deletions LCR A-B, 1 CES (Cat Eye Syndrome region) to LCR B deletion, 4 nested deletions LCR B-D and 1 LCR C-D, 3 LCR A-E deletions, 1 LCR D-E, and 2 small single gene deletions: delDGCR8 and delTOP3B. This study emphasizes the wide phenotypic variety and incomplete penetrance of 22q11.2DS. Our findings contribute to the genotype-phenotype data regarding different types of 22q11.2 deletions and illustrate the usefulness of MLPA combined kits in 22q11.2DS diagnosis.

Prenatal Diagnosis of Chromosome 22q11.21 Microduplication Syndrome in a Fetus with Congenital Malformation of the Cardiovascular System: Case Report

A clinical case of microduplication of chromosome 22q11.21 in a fetus with a malformation of the cardiovascular system (vascular ring) is presented. This anatomical variant of the vascular ring is extremely rare and is formed by the pathological circumflex retroesophageal left-sided cervical aortic arch with the left arterial ductus arteriosus. The anatomical features of the circumflex cervical aortic arch are the left-sided pathological curved aortic arch in combination with the right-sided descending aorta. This vascular pathology can cause compression of the trachea and esophagus. This variant of the vascular ring is extremely unfavorable for surgical correction. Chromosome 22q11.21 microduplication syndrome is associated with the clinical presentation of “cat eye syndrome”. The clinical case description shows unique data from instrumental and genetic studies. All stages of examination of a pregnant woman from primary to tertiary medical care are described. The features and importance of a multidisciplinary approach are also presented.&#x0D; Every case of congenital heart defect in fetus, confirmed by echocardiographic method in a specialized institution, requires medical and genetic counseling. Using of the highly sensitive specific molecular cytogenetic method, comparative genomic hybridization, in prenatal diagnosis allows for timely diagnosis of microstructural disorders of chromosomes in fetus. Follow-up of a pregnant woman with congenital heart defect in the fetus requires a multidisciplinary approach not only to improve diagnosis and treatment, but also to calculate genetic risk.

Congenital hypopituitarism and multiple midline defects in a newborn with non-familial Cat Eye syndrome

BackgroundCat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2).Case presentationWe report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis.ConclusionsCES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Chromosomal Abnormalities and Pregnancy Outcomes for Fetuses With Gastrointestinal Tract Obstructions

Fetal gastrointestinal tract obstruction (GITO) is the most frequently encountered gastrointestinal defect in the prenatal period. This study aimed to investigate the genetic disorders and pregnancy outcomes of fetal GITO. We reviewed data from 70 pregnancies that were referred for invasive prenatal testing because of fetal GITO. According to the level of obstruction, they were classified into esophageal atresia/stenosis, duodenal atresia/stenosis, jejunal or ileal atresia/stenosis, or anal atresia. Traditional karyotyping was performed on all the 70 pregnancies, and chromosomal microarray analysis (CMA) was performed on 32 of them in parallel. Traditional karyotyping revealed twelve (17.1%) chromosomal abnormalities, including 11 cases of trisomy 21 (Down syndrome), and one case of a supernumerary marker chromosome related to Cat eye syndrome. According to the absence or presence of other ultrasound anomalies, they were categorized into isolated GITO (n = 36) and non-isolated GITO (n = 34). The rate of chromosomal abnormalities in the non-isolated GITO pregnancies was significantly higher than that in the isolated GITO pregnancies (29.4 vs. 5.5%, p < 0.05); the survival rate in the isolated group was significantly higher than that in the non-isolated group (67.6 vs. 34.4%, p < 0.05). Among the 32 cases where CMA was performed, an additional one (3.1%) copy number variant with clinical significance was noted in a fetus with normal karyotype. The microduplication on 7q12 was considered to be the genetic etiology of duodenal stenosis, although it was inherited from a phenotypically normal mother. Our study supports the strong association between Down syndrome and fetal GITO, especially duodenal stenosis. Our findings suggested that the risk of chromosomal abnormalities was increased when GITO was accompanied by other ultrasound anomalies; thus, chromosomal abnormalities and fetal anatomy should be carefully evaluated for pregnancy management of fetal GITO.

Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold

Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.

EP413: Type II cat eye syndrome in a newborn with intrauterine growth retardation and echogenic intracardiac focus during pregnancy

The chromosome 22q11.2 region is vulnerable to chromosome rearrangements due to low-copy repeats (LCRs)-mediated nonallelic homologous recombination. It has long been implicated in human diseases, such as DiGeorge/Velocardiofacial syndromes (DGS/VCFS), the most frequently identified chromosomal disorder caused by deletion of the region (recurrent breakpoints BP-A to -D), and cat eye syndrome (CES), which is usually caused by the presence of a bisatellited supernumerary marker chromosome (SMC) resulting in tetrasomy of 22q11.1q11.21.

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.

Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, and cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.

Hepatoblastoma in an infant with cat eye syndrome

Introduction: Cat eye syndrome (CES) is a rare chromosomal disorder with highly variable clinical presentations involving multiple organs. The features mimic other syndromes such as CHARGE or VACTERL, and genetic testing is required to confirm the diagnosis. CES and malignancy were not reported until recently in a 3-year-old child. Case report: We report a case of CES with hepatoblastoma presenting in infancy, highlighting the need to be vigilant during the follow-up of these patients. Conclusion: Our case report has possibly identified an association of malignancy with CES in infancy. Further studies linking the association of malignancy with CES may highlight the need for careful monitoring, a high index of suspicion and a low threshold for an ultrasound scan and AFP to ensure timely diagnosis and treatment.

Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.

Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life. While this phenotypic signature may be broadly similar by the time of presentation, it is likely that this is only the final common pathway with a number of possible preceding causative factors and disparate pathogenic mechanisms—i.e., aetiological heterogeneity. Certainly, there are distinguishable variants which suggest a higher degree of aetiological homogeneity such as the syndromic variants of biliary atresia splenic malformation or cat-eye syndrome, which implicate an early developmental mechanism. In others, the presence of synchronous viral infection also make this plausible as an aetiological agent though it is likely that disease onset is from the perinatal period. In the majority of cases, currently termed isolated BA, there are still too few clues as to aetiology or indeed pathogenesis.