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Oncogene Jan 2020Cells are repeatedly exposed to environmental or endogenous stresses that can alter normal cell behavior and increase cell vulnerability. In order to ensure tissue... (Review)
Review
Cells are repeatedly exposed to environmental or endogenous stresses that can alter normal cell behavior and increase cell vulnerability. In order to ensure tissue integrity and function, cells cope with cellular injuries by adapting their metabolism, protecting essential intracellular constituents, inhibiting cell death signaling pathways and activating those devoted to damage repair. The molecular chaperones of the heat-shock protein (HSP) family are critical effectors of this adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling cascades and preserve the intracellular signaling pathways that are essential for cell survival. Most HSPs are rapidly overexpressed in response to cellular injuries including genotoxic stress. DNA damage can dramatically alter cell behavior and contribute to a number of diseases including developmental defects, neurodegenerative disorders, and cancer. Thus, the ability of cells to repair DNA damage is essential for preserving cell integrity. DNA damage activates a coordinated response that includes detecting DNA lesions before their transmission to daughter cells, blocking cell cycle progression and DNA replication and repairing the damage. Although the role of HSPs in proteins homeostasis and cell death, especially apoptosis has been widely reported, much less is known about their function in DNA repair. This review aims to present the role of HSPs in DNA repair signaling pathways.
Topics: Animals; Apoptosis; Cell Survival; Congenital Abnormalities; DNA Damage; DNA Repair; Genomic Instability; Heat-Shock Proteins; Humans; Neoplasms; Neurodegenerative Diseases; Protein Folding; Signal Transduction
PubMed: 31541194
DOI: 10.1038/s41388-019-1016-y -
Clinical Oral Investigations Mar 2021Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This... (Review)
Review
OBJECTIVES
Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing.
MATERIALS AND METHODS
In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998-2019) in order (i) to study etiology (genetic causes, iatrogenic causes…) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies.
RESULTS
In our 10 patients' cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1.
CONCLUSIONS
From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown.
CLINICAL RELEVANCE
We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.
Topics: Animals; Craniofacial Abnormalities; Humans; Jaw Abnormalities; Mice; Mutation; Phenotype
PubMed: 32643087
DOI: 10.1007/s00784-020-03443-w -
Current Opinion in Pediatrics Aug 2020Over the past decade many previously poorly understood vascular malformation disorders have been linked to somatic activating mutations in PIK3CA, which regulates cell... (Review)
Review
PURPOSE OF REVIEW
Over the past decade many previously poorly understood vascular malformation disorders have been linked to somatic activating mutations in PIK3CA, which regulates cell survival and growth via activation of the mTOR1-AKT pathway. The goal of this article is to describe and provide an update on the clinical features, complications, and management strategies for the PIK3CA-related overgrowth spectrum (PROS).
RECENT FINDINGS
PROS encompasses a heterogenous group of disorders with complications related to the tissues harboring the mutation. Vascular malformation syndromes, such as Klippel-Trenaunay syndrome and Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities, have an increased risk of thromboembolic complications, which is accentuated postprocedurally. Asymmetric overgrowth, particularly of limbs, results in a high rate of orthopedic complications. Hypoglycemia screening in the neonatal period and ongoing monitoring for growth failure is recommended in megalencephaly capillary malformation due to its association with multiple endocrinopathies. Recently, sirolimus, an mTOR1 inhibitor, has shown promise in vascular anomalies and now PROS. PIK3CA direct inhibitor, Alpelisib (BYL719), was recently trialed with significant clinical benefit.
SUMMARY
As the pathogenesis of these conditions is better elucidated and targeted treatments are developed, recognizing the clinical features, comorbidities, and evolving therapeutic landscape across the PROS spectrum becomes more crucial for optimization of care.
Topics: Abnormalities, Multiple; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Genetic Testing; Growth Disorders; Humans; Mosaicism; Musculoskeletal Abnormalities; Mutation; Syndrome; Vascular Malformations
PubMed: 32692051
DOI: 10.1097/MOP.0000000000000923 -
The Journal of Pediatrics Aug 2023To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on...
OBJECTIVE
To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with cancer and congenital abnormalities.
STUDY DESIGN
Tumeur Et Développement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking.
RESULTS
From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm.
CONCLUSIONS
In the first Tumeur Et Développement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.
Topics: Child; Humans; Cohort Studies; Intellectual Disability; Prospective Studies; Biological Specimen Banks; Central Nervous System Neoplasms; Congenital Abnormalities
PubMed: 37169337
DOI: 10.1016/j.jpeds.2023.113451 -
Advances in Experimental Medicine and... 2024Ebstein anomaly (EA) is a rare, congenital cardiac defect of the tricuspid valve with a birth prevalence between 0.5 and 1 in 20,000 [1]. It is characterized by... (Review)
Review
Ebstein anomaly (EA) is a rare, congenital cardiac defect of the tricuspid valve with a birth prevalence between 0.5 and 1 in 20,000 [1]. It is characterized by displacement of the tricuspid valve toward the apex of the right ventricle (RV) and "atrialization" of the RV (Fig. 57.1) [2]. EA accounts for about 0.5% of all congenital heart diseases (CHD) [2]. Depending on severity of the defect and due to heterogeneity of the disease, patient's presentation varies from severe heart failure symptoms and arrhythmia in neonatal life to asymptomatic adults.
Topics: Ebstein Anomaly; Humans; Tricuspid Valve; Genetic Predisposition to Disease; Mutation
PubMed: 38884759
DOI: 10.1007/978-3-031-44087-8_57 -
Current Opinion in Obstetrics &... Dec 2019The implementation of palliative care at birth has led to a significant rise in the number of couples who choose to continue with pregnancies complicated by... (Review)
Review
PURPOSE OF REVIEW
The implementation of palliative care at birth has led to a significant rise in the number of couples who choose to continue with pregnancies complicated by life-limiting malformations (LLMs). Prenatal counselling and appropriate antenatal/perinatal management in these cases are poorly studied and may pose significant challenges. The purpose of this review is to outline specific obstetric risks and to suggest management for mothers who choose to continue with pregnancies with the most common LLMs.
RECENT FINDINGS
In pregnancies complicated by LLMs where parents opt for expectant management, clinicians should respect parental wishes, whilst openly sharing potential serious maternal medical risks specific for the identified abnormalities. The focus of both antenatal and perinatal care should be maternal wellbeing rather than foetal survival. Follow-up ultrasound examinations and maternal surveillance should be aimed at achieving timely diagnosis and effective management of obstetric complications. A clear perinatal plan, agreed with the couples by a multi-disciplinary team including a foetal medicine specialist, a neonatologist and a geneticist, is crucial to reduce maternal morbidity.
SUMMARY
This review provides a useful framework for clinicians who face the challenges of counselling and managing cases complicated by LLMs where parents opt for pregnancy continuation.
Topics: Anencephaly; Congenital Abnormalities; Female; Genetic Counseling; Holoprosencephaly; Humans; Hydrops Fetalis; Neonatology; Obstetrics; Palliative Care; Patient Care Team; Pregnancy; Pregnancy Complications; Prenatal Care; Risk; Triploidy; Trisomy 13 Syndrome; Trisomy 18 Syndrome; Turner Syndrome; Ultrasonography
PubMed: 31693566
DOI: 10.1097/GCO.0000000000000583 -
The New England Journal of Medicine Sep 2021Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical...
BACKGROUND
Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach.
METHODS
We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring.
RESULTS
We identified homozygous mutations in , which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development.
CONCLUSIONS
Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).
Topics: Abnormalities, Multiple; Animals; Congenital Abnormalities; Disease Models, Animal; Fibroblasts; Gene Knock-In Techniques; Genes, Recessive; Genetic Pleiotropy; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Mutation; Pedigree; Phenotype; Receptors, G-Protein-Coupled; Syndrome; Wnt Proteins; Wnt Signaling Pathway
PubMed: 34587386
DOI: 10.1056/NEJMoa2033911 -
International Ophthalmology Jul 2022Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with...
BACKGROUND
Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with bilateral CEL and search for pathogenic genes and mutation sites.
MATERIALS AND METHODS
A total of 24 patients diagnosed with CEL from January 2019 to November 2019 were enrolled in this study, and their clinical data were collected and genome-wide deoxyribonucleic acid was extracted from peripheral venous blood. Targeted gene capture technology was used to obtain 188 exons of lens abnormality-related genes, which were sequenced using a high-throughput method. The mutation sites were determined through data analysis and verified by the Sanger method. According to the data from previous studies, the association between the genotype and clinical phenotype was analysed.
RESULT
Of the 24 patients, 23 had mutations in the fibrillin-1 (FBN1) gene, and 20 were diagnosed with Marfan syndrome. The 23 cases of FBN1 mutations were all heterozygous mutations, including 17 missense mutations, 3 splicing variants, 2 exon deletion mutations, 1 codon mutation, and 9 new mutations. A total of 17 mutations were located in the calcium-binding epidermal growth factor domain, including 16 mutations that contained missense mutations of cysteine. In addition, a heterozygous mutation of the gap junction protein alpha 8 (GJA8) gene was detected in one patient.
CONCLUSION
In this study, we identified 23 FBN1 gene mutations and 1 GJA8 gene mutation in 24 patients with CEL. Of these, 9 new FBN1 mutations and 14 known mutations were found. The results expanded the mutation spectrum of the FBN1 gene, suggesting that FBN1 mutation may be the main cause of CEL in Chinese patients.
Topics: China; DNA Mutational Analysis; Ectopia Lentis; Fibrillin-1; Fibrillins; High-Throughput Nucleotide Sequencing; Humans; Marfan Syndrome; Microfilament Proteins; Mutation; Pedigree; Phenotype
PubMed: 35612688
DOI: 10.1007/s10792-022-02224-6 -
American Journal of Medical Genetics.... May 2021Trisomy 13 is one of the three most common aneuploidy syndromes in live-born infants. It is associated with mortality rates as high as 90% within the first year of life,... (Review)
Review
Trisomy 13 is one of the three most common aneuploidy syndromes in live-born infants. It is associated with mortality rates as high as 90% within the first year of life, in large part, due to the high prevalence of severe congenital abnormalities that increase mortality and morbidity. However, life-saving and life-prolonging medical interventions are being performed at a higher rate for these infants, resulting in increased rates of survival. Although cardiac complications have been well described in infants with trisomy 13, these patients also experience other complications such as respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic complications that can impact their quality of life. The goal of this review is to present a comprehensive description of complications in children with trisomy 13 to aid in the development of monitoring and treatment guidelines for the increasing number of providers who will be caring for these patients throughout their lives. Where the evidence is available, this review presents screening recommendations to allow for more rapid detection and documentation of these complications.
Topics: Aneuploidy; Congenital Abnormalities; Early Medical Intervention; Female; Guidelines as Topic; Humans; Infant, Newborn; Male; Trisomy 13 Syndrome
PubMed: 33709620
DOI: 10.1002/ajmg.a.62133 -
American Journal of Medical Genetics.... Jun 2022Oral clefts (OCs) are frequently co-occurring with other non-OC congenital anomalies. The types and the prevalence of anomalies co-occurring with OCs vary in the...
Oral clefts (OCs) are frequently co-occurring with other non-OC congenital anomalies. The types and the prevalence of anomalies co-occurring with OCs vary in the reported studies. The aims of this report were to study the types and the prevalence of the anomalies co-occurring with OCs in a well-defined population. The types and the prevalence of anomalies co-occurring in cases with OCs were ascertained in all terminations of pregnancy, stillbirths, and live births in 387,067 births occurring consecutively during the period 1979-2007 in the area covered by our registry of congenital anomalies which is population based, 789 cases of OCs were registered during the study period with a prevalence of 20.4 per 10,000 births, 39.5% of the cases had associated non-OC anomalies. Associated anomalies were more common in cases with cleft palate (52.4%) than in cases with cleft lip and palate (37.3%) and in cases with cleft lip only (16.8%). Chromosomal abnormalities were present in 94 (11.9%) cases including 27 trisomies 13, 15 trisomies 18, 12 22 q11.2 deletion, and 40 other chromosomal abnormalities. Nonchromosomal recognizable conditions were diagnosed in 38 cases (4.8%) including syndromes, associations, spectrums and sequences. Multiple congenital anomalies (MCAs) were present in 180 cases (22.8%). The most frequent MCA were in the musculoskeletal system (16.7%), the central nervous system (15.0%), the urogenital system (13.7%), the cardiovascular system (8.6%), and the digestive system (6.6%). The high prevalence of associated anomalies justifies a thorough screening for other congenital anomalies in cases with OCs.
Topics: Abnormalities, Multiple; Chromosome Aberrations; Cleft Lip; Cleft Palate; Female; Heart Defects, Congenital; Humans; Musculoskeletal Diseases; Pregnancy; Prevalence; Trisomy
PubMed: 35179301
DOI: 10.1002/ajmg.a.62689