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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 -
World Journal of Pediatrics : WJP Oct 2017Progress in medical branches that has taken place since the first child with Goldenhare syndrome (GS) had been described in 1952 by Maurice Goldenhar, facilitated better... (Review)
Review
BACKGROUND
Progress in medical branches that has taken place since the first child with Goldenhare syndrome (GS) had been described in 1952 by Maurice Goldenhar, facilitated better understanding of this congenital defect. It also gave new perspectives and the opportunity to achieve satisfactory treatment results, mainly due to development of surgical techniques.
DATA SOURCES
Based on the literature and own experience, we discussed the phenotype of presentation of GS, ethiopathogenesis, genetic counselling and treatment with particular emphasis on surgery correction of hemifacial microsomia.
RESULTS
The spectrum of GS abnormalities ranges from mild to severe ones and include patients with barely noticeable facial asymmetry to very pronounced facial defect with more or less severe abnormalities of internal organs and/or skeleton. It is characterized most commonly by impaired development of eyes, ears, lips, tongue, palate, mandible, maxilla, zygomatic and orbital structures and deformations of the teeth structures. Ethiopathogenesis is multifactorial and dependent on genetic and environmental factors but there are still many unknowns about the syndrome which should be revealed.
CONCLUSIONS
Patients with GS due to a large variety of abnormalities and different severity of symptoms pose a challenge for clinicians. All of this necessitate an individual approach to each single patient and involvement a team of specialists in treatment planning. It is a complex, long-lasting, multidisciplinary process and should be divided into stages, according to patient's age, as well as the extent and severity of observed abnormalities. Neonatologists and pediatricians are involved in care of these patients from the onset.
Topics: Child; Goldenhar Syndrome; Humans
PubMed: 28623555
DOI: 10.1007/s12519-017-0048-z -
Journal of Medical Genetics May 2022Oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome is due to an abnormal development of first and second branchial arches derivatives during embryogenesis... (Review)
Review
Oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome is due to an abnormal development of first and second branchial arches derivatives during embryogenesis and is characterised by hemifacial microsomia associated with auricular, ocular and vertebral malformations. The clinical and genetic heterogeneity of this spectrum with incomplete penetrance and variable expressivity, render its molecular diagnosis difficult. Only a few recurrent CNVs and genes have been identified as causatives in this complex disorder so far. Prenatal environmental causal factors have also been hypothesised. However, most of the patients remain without aetiology. In this review, we aim at updating clinical diagnostic criteria and describing genetic and non-genetic aetiologies, animal models as well as novel diagnostic tools and surgical management, in order to help and improve clinical care and genetic counselling of these patients and their families.
Topics: Animals; Branchial Region; DNA Copy Number Variations; Goldenhar Syndrome; Humans
PubMed: 35110414
DOI: 10.1136/jmedgenet-2021-108219 -
Clinics in Plastic Surgery Apr 2019Clinicians use different diagnostic terms for patients with underdevelopment of facial features arising from the embryonic first and second pharyngeal arches, including... (Review)
Review
Clinicians use different diagnostic terms for patients with underdevelopment of facial features arising from the embryonic first and second pharyngeal arches, including first and second branchial arch syndrome, otomandibular dysostosis, oculoauriculovertebral syndrome, and hemifacial microsomia. Craniofacial microsomia has become the preferred term. Although no diagnostic criteria for craniofacial microsomia exist, most patients have a degree of underdevelopment of the mandible, maxilla, ear, orbit, facial soft tissue, and/or facial nerve. These anomalies can affect feeding, compromise the airway, alter facial movement, disrupt hearing, and alter facial appearance.
Topics: Biomedical Research; Diagnosis, Differential; Facial Asymmetry; Female; Goldenhar Syndrome; Humans; Male; Orthognathic Surgical Procedures; Osteogenesis, Distraction
PubMed: 30851752
DOI: 10.1016/j.cps.2018.12.001 -
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 -
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 -
Clinics in Plastic Surgery Apr 2019Treacher Collins syndrome is a rare genetic disorder of craniofacial development with a highly variable phenotype. The disorder displays an intricate underlying... (Review)
Review
Treacher Collins syndrome is a rare genetic disorder of craniofacial development with a highly variable phenotype. The disorder displays an intricate underlying dysmorphology. Affected patients may suffer life-threatening airway complications and functional difficulties involving sight, hearing, speech, and feeding. Deformation of facial structures produces a characteristic appearance that includes malar hypoplasia, periorbital soft tissue anomalies, maxillomandibular hypoplasia, and ear anomalies. Management requires a specialized craniofacial team, as comprehensive care starts at birth and may require life-long follow-up. Standard craniofacial procedures for bony and soft tissue reconstruction are used. This article outlines current treatment strategies and future concepts for surgical management.
Topics: Airway Obstruction; Ear; Face; Female; Humans; Male; Mandible; Mandibulofacial Dysostosis; Osteogenesis, Distraction
PubMed: 30851751
DOI: 10.1016/j.cps.2018.11.005 -
Facial Plastic Surgery Clinics of North... Nov 2016Craniofacial microsomia (CFM) encompasses a broad spectrum of phenotypes. It is thought to result from defective development of the first and second pharyngeal arch... (Review)
Review
Craniofacial microsomia (CFM) encompasses a broad spectrum of phenotypes. It is thought to result from defective development of the first and second pharyngeal arch structures, and generally presents with anomalies of the mandible and other facial bones, ears, and overlying soft tissues. The cause of CFM is thought to involve both extrinsic and genetic risk factors. Several classification systems have been developed to help stratify patients based on the severity of their defects. Treatment of patients includes repair of bony asymmetry as well as soft tissue defects and auricular anomalies. Surgical intervention is individualized based on each patient's deficits.
Topics: Goldenhar Syndrome; Humans; Mandible; Orthognathic Surgical Procedures; Osteogenesis, Distraction; Plastic Surgery Procedures; Temporomandibular Joint
PubMed: 27712817
DOI: 10.1016/j.fsc.2016.06.006 -
American Journal of Ophthalmology Dec 2021
Topics: Goldenhar Syndrome; Humans; Tomography, X-Ray Computed
PubMed: 34551320
DOI: 10.1016/j.ajo.2021.09.012 -
Human Mutation Feb 2016Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic... (Review)
Review
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
Topics: Abnormalities, Multiple; Amino Acid Motifs; Databases, Genetic; Gene Expression; Haploinsufficiency; Hearing Loss; Humans; Intellectual Disability; Mandibulofacial Dysostosis; Microcephaly; Models, Molecular; Molecular Sequence Data; Mutation; Penetrance; Peptide Elongation Factors; Phenotype; Protein Structure, Secondary; Protein Structure, Tertiary; RNA Splicing; Ribonucleoprotein, U5 Small Nuclear; Spliceosomes
PubMed: 26507355
DOI: 10.1002/humu.22924