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Disease Models & Mechanisms Apr 2022Craniosynostosis is a major congenital craniofacial disorder characterized by the premature fusion of cranial suture(s). Patients with severe craniosynostosis often have... (Review)
Review
Craniosynostosis is a major congenital craniofacial disorder characterized by the premature fusion of cranial suture(s). Patients with severe craniosynostosis often have impairments in hearing, vision, intracranial pressure and/or neurocognitive functions. Craniosynostosis can result from mutations, chromosomal abnormalities or adverse environmental effects, and can occur in isolation or in association with numerous syndromes. To date, surgical correction remains the primary treatment for craniosynostosis, but it is associated with complications and with the potential for re-synostosis. There is, therefore, a strong unmet need for new therapies. Here, we provide a comprehensive review of our current understanding of craniosynostosis, including typical craniosynostosis types, their clinical manifestations, cranial suture development, and genetic and environmental causes. Based on studies from animal models, we present a framework for understanding the pathogenesis of craniosynostosis, with an emphasis on the loss of postnatal suture mesenchymal stem cells as an emerging disease-driving mechanism. We evaluate emerging treatment options and highlight the potential of mesenchymal stem cell-based suture regeneration as a therapeutic approach for craniosynostosis.
Topics: Animals; Cranial Sutures; Craniosynostoses; Humans; Mesenchymal Stem Cells; Mutation; Syndrome
PubMed: 35451466
DOI: 10.1242/dmm.049390 -
Genes Sep 2021Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development. Features of... (Review)
Review
Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development. Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis. TCS occurs in the general population at a frequency of 1 in 50,000 live births. Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the , , and genes. Genetically, the gene contains 27 exons which encodes the Treacle protein. In , over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon. In the presented article, we review the genetics and phenotype of TCS as well as the management and surgical procedures utilized for treatment.
Topics: Choanal Atresia; DNA-Directed RNA Polymerases; Humans; Mandibulofacial Dysostosis; Nuclear Proteins; Phosphoproteins; Syndrome
PubMed: 34573374
DOI: 10.3390/genes12091392 -
The Veterinary Quarterly Dec 2022Brachycephalic obstructive airway syndrome (BOAS) is a chronic, lifelong, debilitating, primarily obstructive airway disease which adversely affects the quality of life... (Review)
Review
Brachycephalic obstructive airway syndrome (BOAS) is a chronic, lifelong, debilitating, primarily obstructive airway disease which adversely affects the quality of life of many popular dog breeds. Respiratory restriction in bulldog breeds, pugs and Boston terriers frequently co-exist with pathologies of the gastrointestinal tract. In addition, many brachycephalic dogs that appear clinically normal are, in fact suffering from chronic hypoxia and its systemic consequences. Concurrent gastroesophageal reflux-associated conditions, sleep disorders and systemic hypertension further impact the welfare of affected dogs. Acceptance of BOAS and associated clinical signs as being 'normal for the breed' is common amongst owners. While surgical correction of the upper airway is the mainstay of treatment, the provision of subsequent, frequently lifelong medical management is equally important for the maintenance of an acceptable quality of life, at least for some affected patients. Here we review the current knowledge concerning brachycephaly, combine it with shared clinical experience in the management of this debilitating condition, and discuss ethical considerations and the responsibility of veterinarians to contribute public education and to support appropriate breed standards for animals under our care.
Topics: Dogs; Animals; Quality of Life; Dog Diseases; Craniosynostoses; Airway Obstruction
PubMed: 36342210
DOI: 10.1080/01652176.2022.2145621 -
Nature Communications Apr 2023Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set...
Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.
Topics: Animals; Mice; Goldenhar Syndrome; Facial Asymmetry; Pedigree; Forkhead Transcription Factors
PubMed: 37041148
DOI: 10.1038/s41467-023-37703-6 -
Neurosurgery Clinics of North America Jan 2022Hydrocephalus, the abnormal accumulation and impaired circulation/clearance of cerebrospinal fluid, occurs as a common phenotypic feature of a diverse group of genetic... (Review)
Review
Hydrocephalus, the abnormal accumulation and impaired circulation/clearance of cerebrospinal fluid, occurs as a common phenotypic feature of a diverse group of genetic syndromes. In this review, we outline the genetic mutations, pathogenesis, and accompanying symptoms underlying syndromic hydrocephalus in the context of: L1 syndrome, syndromic craniosynostoses, achondroplasia, NF 1/2, Down's syndrome, tuberous sclerosis, Walker-Warburg syndrome, primary ciliary dyskinesia, and osteogenesis imperfecta. Further, we discuss emerging genetic variants associated with syndromic hydrocephalus.
Topics: Craniosynostoses; Humans; Hydrocephalus; Syndrome
PubMed: 34801143
DOI: 10.1016/j.nec.2021.09.006 -
The Indian Journal of Medical Research Nov 2020
Topics: Humans; Rubinstein-Taybi Syndrome
PubMed: 35345227
DOI: 10.4103/ijmr.IJMR_2399_19 -
Italian Journal of Dermatology and... Aug 2023Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in... (Review)
Review
Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in approximately 60% and 10% respectively. These genes encode two highly evolutionarily conserved, ubiquitously expressed, and homologous lysine-acetyltransferases, that are involved in number of basic cellular activities, such as DNA repair, cell proliferation, growth, differentiation, apoptosis of cells, and tumor suppression. It is mainly characterized by global developmental delay, moderate to severe intellectual disability, postnatal retardation, microcephaly, skeletal anomalies including broad/short, angled thumbs and/or large first toes, short stature, and dysmorphic facial features. There is an increased risk to develop tumors mainly meningiomas and pilomatrixomas, without a clear genotype-phenotype correlation. Although not considered as characteristic manifestations, numerous cutaneous anomalies have also been reported in patients with this entity. Both susceptibility to the formation of keloids and pilomatricomas are the most often associated cutaneous features. In this review, we discuss the genetics, diagnosis, and clinical features in Rubinstein-Taybi Syndrome with a review of the major dermatological manifestations.
Topics: Humans; Rubinstein-Taybi Syndrome; Mutation; Intellectual Disability; Genetic Association Studies; Pilomatrixoma; Skin Neoplasms
PubMed: 37282850
DOI: 10.23736/S2784-8671.23.07547-3 -
Developmental Dynamics : An Official... Sep 2020The spliceosome is a complex of RNA and proteins that function together to identify intron-exon junctions in precursor messenger-RNAs, splice out the introns, and join... (Review)
Review
The spliceosome is a complex of RNA and proteins that function together to identify intron-exon junctions in precursor messenger-RNAs, splice out the introns, and join the flanking exons. Mutations in any one of the genes encoding the proteins that make up the spliceosome may result in diseases known as spliceosomopathies. While the spliceosome is active in all cell types, with the majority of the proteins presumably expressed ubiquitously, spliceosomopathies tend to be tissue-specific as a result of germ line or somatic mutations, with phenotypes affecting primarily the retina in retinitis pigmentosa, hematopoietic lineages in myelodysplastic syndromes, or the craniofacial skeleton in mandibulofacial dysostosis. Here we describe the major spliceosomopathies, review the proposed mechanisms underlying retinitis pigmentosa and myelodysplastic syndromes, and discuss how this knowledge may inform our understanding of craniofacial spliceosomopathies.
Topics: Animals; Humans; Mandibulofacial Dysostosis; Mutation; Myelodysplastic Syndromes; Retinitis Pigmentosa; Spliceosomes
PubMed: 32506634
DOI: 10.1002/dvdy.214 -
Neuro-Chirurgie Nov 2019The aim of this review was to report on recent advances in trigonocephaly since the last report on craniosynostosis published in 2006. (Review)
Review
INTRODUCTION
The aim of this review was to report on recent advances in trigonocephaly since the last report on craniosynostosis published in 2006.
MATERIAL AND METHODS
The review was conducted in accordance with the PRISMA guidelines. Research focused on four main topics: epidemiology, neurodevelopmental disorders, genetics and surgical techniques.
RESULTS
Forty reports were included. The prevalence of trigonocephaly increased during the last two decades both in Europe and in the United States, but no clear contributing factors have yet been identified. Neurodevelopmental disorders are frequent in syndromic trigonocephaly and not particularly rare in non-syndromic cases (up to 34%). Developmental retardation (speech, motor or global) was almost always present in children exposed to valproic acid. Chromosomal abnormalities described in metopic synostosis comprised deletion of chromosome 11q24, deletion or trisomy of 9p and deletion of 7p, deletions of 3q, 13q, 12pter, 22q11, and duplication of 15q25. SMAD6 mutations should be systematically screened for in familial cases. Recent advances in surgical techniques have mainly concerned endoscopic-assisted procedures, as they significantly reduce perioperative morbidity.
CONCLUSIONS
Neurosurgeons, maxillofacial and plastic surgeons will be increasingly concerned with trigonocephaly because of the increase in prevalence observed over the last two decades. Cytogenetic alterations are probably underestimated in this craniosynostosis, considering the high rate of neurodevelopmental retardation compared to other single-suture synostoses. Genetic counselling is therefore more and more effective in this pathology. An objective method to evaluate the cosmetic results of both endoscopic and open surgeries is necessary, as some under-corrections have been reported with minimally invasive surgery.
Topics: Anticonvulsants; Child; Child, Preschool; Craniosynostoses; Humans; Infant; Infant, Newborn; Intellectual Disability; Mass Screening; Plastic Surgery Procedures; Valproic Acid
PubMed: 31568780
DOI: 10.1016/j.neuchi.2019.09.014 -
Indian Journal of Ophthalmology Jul 2022The current literature review aims to evaluate the ocular findings and associated ophthalmic features in Crouzon syndrome. Craniosynostoses are syndromes characterized... (Review)
Review
The current literature review aims to evaluate the ocular findings and associated ophthalmic features in Crouzon syndrome. Craniosynostoses are syndromes characterized by premature fusion of sutures of the skull and Crouzon syndrome is the most common of the craniosynostosis syndromes. Early fusion of sutures results in craniofacial anomalies, including abnormalities of the orbits. To prepare this review of the ophthalmic findings in this disorder, an organized search on online databases such as PubMed, Scopus, Cochrane Library, and Ovid was carried out. The key terms searched were "Crouzon", "craniosynostosis", "eye" and "ophthalmic", and 51 research items were found. A total of 17 articles were included after scrutiny of the databases and a further 25 articles were added after augmented search. A detailed review was performed from the final 42 articles. A comprehensive description of associated anomalies is given along with the author's own technique of surgical management in cases with Crouzon syndrome having bilateral luxation bulbi with exposure keratopathy. However, for optimum management of cranial and oculo-facial dysmorphisms, a multidisciplinary team of specialists is required.
Topics: Craniofacial Dysostosis; Craniosynostoses; Eye; Face; Humans; Syndrome
PubMed: 35791116
DOI: 10.4103/ijo.IJO_3207_21