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Annual Review of Genomics and Human... 2008Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein... (Review)
Review
Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases.
Topics: Cell Cycle Proteins; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; De Lange Syndrome; Ectromelia; Female; Genotype; Humans; Male; Mental Retardation, X-Linked; Models, Genetic; Models, Molecular; Mutation; Phenotype; Transcriptional Activation; alpha-Thalassemia; Cohesins
PubMed: 18767966
DOI: 10.1146/annurev.genom.9.081307.164211 -
Canadian Medical Association Journal Nov 1963Data are presented on 115 children, including three sets of twins, born in Canada in 1961 and 1962 with congenital malformations associated with the use of thalidomide...
Data are presented on 115 children, including three sets of twins, born in Canada in 1961 and 1962 with congenital malformations associated with the use of thalidomide by their mothers in early pregnancy. The epidemiological method is described. Of the 115 children, 74 were alive at the time of reporting, 41 of these being severely handicapped; 8 had been stillborn; 33 had died. Limb involvement was usually bilateral, affecting the upper limbs alone in 42 cases, and the upper and lower limbs in 41. Of 112 mothers, only 60 had had the drug prescribed by the physician providing maternity care; 87 were estimated to have first taken the drug before their last menstrual period or within 56 days thereafter. A plea is made for the development of better methods of collecting information on the occurrence of congenital malformations, with the aid of practising physicians.
Topics: Abnormalities, Drug-Induced; Canada; Ectromelia; Extremities; Female; Fetal Death; Humans; Infant; Infant Mortality; Infant, Newborn; Maternal-Fetal Exchange; Mothers; Parturition; Pregnancy; Statistics as Topic; Stillbirth; Thalidomide; Toxicology
PubMed: 14076167
DOI: No ID Found -
JNMA; Journal of the Nepal Medical... May 2022The complete absence of limbs is a rare occurrence. Though the causes are various, it is hard to elicit most of the time. They are usually diagnosed via anomaly scan but...
UNLABELLED
The complete absence of limbs is a rare occurrence. Though the causes are various, it is hard to elicit most of the time. They are usually diagnosed via anomaly scan but the lack of access to the same can often lead to a term presentation. It is still not uncommon to receive pregnant patients at term to the hospital or in labour as the first antenatal visit. Increasing the feasibility of the scan can help in the early diagnosis and management. Here, we report a rare combination of limb defects that we managed in a district-level hospital and highlight the difficulties in the management and referral of the patients while working in rural areas.
KEYWORDS
amelia; antenatal care; congenital limb deformities; fetal ultrasonography.
Topics: Abnormalities, Multiple; Ectromelia; Female; Humans; Limb Deformities, Congenital; Pregnancy; Prenatal Care; Ultrasonography, Prenatal
PubMed: 35633231
DOI: 10.31729/jnma.7486 -
Cell Cycle (Georgetown, Tex.) Mar 2022Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including , CdLS) and (RBS). Though...
Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including , CdLS) and (RBS). Though ESCO2 activates cohesin, CdLS and RBS etiologies are currently considered non-synonymous and for which pharmacological treatments are unavailable. Here, we identify a unifying mechanism that integrates these genetic maladies to pharmacologically-induced teratogenicity via thalidomide. Our results reveal that Esco2 and cohesin co-regulate the transcription of a component of CRL4 ubiquitin ligase through which thalidomide exerts teratogenic effects. These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments.
Topics: Acetyltransferases; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; DNA-Binding Proteins; De Lange Syndrome; Ectromelia; Humans; Hypertelorism; Ligases; Mutation; Receptors, Interleukin-17; Thalidomide; Ubiquitin; Ubiquitin-Protein Ligases; Cohesins
PubMed: 34989322
DOI: 10.1080/15384101.2021.2023304 -
American Journal of Human Genetics Jul 1994
Topics: Bone Morphogenetic Proteins; Ectoderm; Ectromelia; Embryonic Induction; Extremities; Gene Expression; Genes, Homeobox; Humans; Mesoderm; Morphogenesis; Polydactyly; Proteins; Signal Transduction
PubMed: 7912883
DOI: No ID Found -
Microorganisms Dec 2022Amidst the ongoing monkeypox outbreak, global awareness has been directed towards the prevention of viral transmission and case management, with the World Health... (Review)
Review
Amidst the ongoing monkeypox outbreak, global awareness has been directed towards the prevention of viral transmission and case management, with the World Health Organization declaring the outbreak a public health emergency of international concern. Monkeypox virus is one of several species in the Orthopoxvirus genus, with other species of the genus including the variola, cowpox, mousepox, camelpox, raccoonpox, skunkpox, and volepox viruses. Although the nomenclature of these species is based on the animal host from which they were originally isolated, transmission from animals to humans has been reported with several species. The progression of disease, following an incubation period, typically consists of a prodromal phase with systemic flu-like symptoms. Various organ systems may be affected in addition to the formation of pathognomonic skin lesions. As monkeypox poses a continued public health concern, the ophthalmic sequelae of monkeypox virus, especially those leading to vision loss, warrant consideration as well. This review provides a comprehensive summary of the ophthalmic implications of poxviruses in clinical and laboratory settings reported in the literature, as well as areas of unmet need and future research.
PubMed: 36557740
DOI: 10.3390/microorganisms10122487 -
Simultaneous femoral and tibial lengthening for severe limb length discrepancy in fibular hemimelia.Journal of Orthopaedic Surgery and... Nov 2023Fibular Hemimelia (FH) is the most common longitudinal limb deficiency. Significant limb length discrepancy (LLD) will necessitate long treatment times and multiple... (Review)
Review
BACKGROUND
Fibular Hemimelia (FH) is the most common longitudinal limb deficiency. Significant limb length discrepancy (LLD) will necessitate long treatment times and multiple settings to compensate for LLD when associated with femoral shortening. This study evaluates the outcome of simultaneous femoral and tibial lengthening using the Ilizarov frame.
METHODS
This retrospective study included the cases of 12 children with severe limb length discrepancy caused by combined FH and ipsilateral femoral shortening from May 2015 to August 2022. The total LLD ranged from 7 to 14.5 cm. All patients underwent single-session femoral and tibial lengthening using the Ilizarov ring external fixator technique. Additional procedures were performed in the same setting, including Achilles tendon lengthening, fibular anlage excision, peroneal tendons lengthening, and iliotibial band release. Follow-up ranged from 2 to 4 years.
RESULTS
The planned limb lengthening was achieved in ten cases (83%). No cases of joint subluxation or dislocation were encountered. No neurovascular injury has occurred during the treatment course. In all cases, the bone healing index was better on the femoral side than on the tibia. Poor regeneration and deformity of the tibia occurred in two cases (16.6%).
CONCLUSION
Simultaneous femoral and tibial lengthening using the Ilizarov fixator is a relatively safe procedure with the result of correction of total LLD in one session in a shorter time and less morbidity.
Topics: Child; Humans; Tibia; Ectromelia; Retrospective Studies; Fibula; Bone Lengthening; Ilizarov Technique; Leg Length Inequality; Leg; Treatment Outcome
PubMed: 37936235
DOI: 10.1186/s13018-023-04229-y -
Turk Patoloji Dergisi 2020Sirenomelia, which is also known as mermaid syndrome and characterized by the fusion of the lower extremities, is the most severe form of caudal regression syndrome and...
Sirenomelia, which is also known as mermaid syndrome and characterized by the fusion of the lower extremities, is the most severe form of caudal regression syndrome and one of the rare and lethal congenital malformations. The anomalies that might be seen in this syndrome include pelvic-sacral dysplasia, genital anomalies, bilateral pelvic renal fusion accompanied by renal dysplasia, colon atresia, unilateral umbilical artery, and imperforated anus. The incidence of sirenomelia is 0.8-1 cases in 60,000-100,000 deliveries and the male/female ratio is 2.7-3:1. The case reported in the present study was a 13-week-old male fetus 30 g in weight with a macerated appearance. The upper extremities had a relatively normal appearance but the lower extremities were conjoined and there was a single lower extremity consisting of conjoined feet and toes. In the face, the nasal bridge was sunken, the ears had a low position, and there were cleft palate and cleft lip. Examination of the external genital organs revealed that the penile part was in the anal region. There was no anus opening. The crown-rump length was 8.5cm, the heel-toe length was approx. 1cm, and the rump-heel length was approx. 3.7cm. There were none of the two kidneys, ureter, bladder, urethra, or rectum. In the umbilical cord, there were 2 venous structures, one of which was the artery. Perivillous congestion and hyperemia, perivillous calcification, deciduitis, and focal infarct regions were observed in placental tissues. This report aims to discuss this very rare case together with the literature.
Topics: Abnormalities, Multiple; Ectromelia; Female; Fetus; Humans; Male; Pregnancy
PubMed: 32525213
DOI: 10.5146/tjpath.2020.01491 -
PLoS Genetics Dec 2020Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities,... (Review)
Review
Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.
Topics: Acetyltransferases; Animals; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; DNA Damage; Ectromelia; Genomic Instability; Humans; Hypertelorism
PubMed: 33382686
DOI: 10.1371/journal.pgen.1009219 -
Journal of Virology Sep 2021Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control...
Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood. We demonstrate here that not only ECTV but also vaccinia virus and lymphocytic choriomeningitis virus induce CD4-CTL, though the response to ECTV is stronger. Using ECTV, we also demonstrate that in contrast to CD8-CTL, CD4-CTL differentiation requires constant virus replication and ceases once the virus is controlled. We also show that major histocompatibility complex class II molecules on CD11c cells are required for CD4-CTL differentiation and for mousepox resistance. Transcriptional analysis indicated that antiviral CD4-CTL and noncytolytic T helper 1 (Th1) CD4 T cells have similar transcriptional profiles, suggesting that CD4-CTL are terminally differentiated classical Th1 cells. Interestingly, CD4-CTL and classical Th1 cells expressed similar mRNA levels of the transcription factors ThPOK and GATA-3, necessary for CD4 T cell linage commitment, and Runx3, required for CD8 T cell development and effector function. However, at the protein level, CD4-CTL had higher levels of the three transcription factors, suggesting that further posttranscriptional regulation is required for CD4-CTL differentiation. Finally, CRISPR/Cas9-mediated deletion of in CD4 T cells inhibited CD4-CTL but not classical Th1 cell differentiation in response to ECTV infection. These results further our understanding of the mechanisms of CD4-CTL differentiation during viral infection and the role of posttranscriptionally regulated Runx3 in this process. While it is well established that cytotoxic CD4 T cells (CD4-CTLs) directly contribute to viral clearance, it remains unclear how CD4-CTL are induced. We now show that CD4-CTLs require sustained antigen presentation and are induced by CD11c-expressing antigen-presenting cells. Moreover, we show that CD4-CTLs are derived from the terminal differentiation of classical T helper 1 (Th1) subset of CD4 cells. Compared to Th1 cells, CD4-CTLs upregulate protein levels of the transcription factors ThPOK, Runx3, and GATA-3 posttranscriptionally. Deletion of Runx3 in differentiated CD4 T cells prevents induction of CD4-CTLs but not classical Th1 cells. These results advance our knowledge of how CD4-CTLs are induced during viral infection.
Topics: Animals; Antigen-Presenting Cells; CD11 Antigens; CD4-Positive T-Lymphocytes; Cell Differentiation; Core Binding Factor Alpha 3 Subunit; Cytotoxicity, Immunologic; Ectromelia virus; Ectromelia, Infectious; Histocompatibility Antigens Class II; Liver; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Spleen; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th1 Cells; Transcriptome; Virus Diseases; Virus Replication
PubMed: 34260270
DOI: 10.1128/JVI.00566-21