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1.
Sci Prog ; 107(2): 368504241242278, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38629201

RESUMO

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder, typically inherited as an autosomal dominant condition. Here, we report on a family in which germline mosaicism for TCS was likely present. The proband was diagnosed with TCS based on the typical clinical features and a pathogenic variant TCOF1 (c.4369_4373delAAGAA, p.K1457Efs*12). The mutation was not detected in his parents' peripheral blood DNA samples, suggesting a de novo mutation had occurred in the proband. However, a year later, the proband's mother became pregnant, and the amniotic fluid puncture revealed that the fetus carried the same mutation as the proband. Prenatal ultrasound also indicated a maxillofacial dysplasia with unilateral microtia. The mother then disclosed a previous birth history in which a baby had died of respiratory distress shortly after birth, displaying a TCS-like phenotype. Around the same time, the proband's father was diagnosed with mild bilateral conductive hearing loss. Based on array data, we concluded that the father may have had germline mosaicism for TCOF1 mutation. Our findings highlight the importance of considering germline mosaicism in sporadic de novo TCOF1 mutations when providing genetic consulting, and prenatal diagnosis is important when the proband's parents become pregnant again.


Assuntos
Disostose Mandibulofacial , Mosaicismo , Humanos , Linhagem , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/genética , Mutação , Células Germinativas
2.
Mol Genet Genomic Med ; 12(4): e2426, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38562046

RESUMO

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. METHODS: A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing. RESULTS: The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. CONCLUSIONS: We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.


Assuntos
Deficiência Intelectual , Disostose Mandibulofacial , Microcefalia , Humanos , Microcefalia/patologia , Disostose Mandibulofacial/genética , Disostose Mandibulofacial/patologia , Fenótipo , Mutação , Deficiência Intelectual/genética , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo
3.
Mol Genet Genomic Med ; 12(3): e2405, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38444283

RESUMO

BACKGROUND: Treacher Collins Ι syndrome (TCS1, OMIM:154500) is an autosomal dominant disease with a series of clinical manifestations such as craniofacial dysplasia including eye and ear abnormalities, small jaw deformity, cleft lip, as well as repeated respiratory tract infection and conductive hearing loss. Two cases of Treacher Collins syndrome with TCOF1(OMIM:606847) gene variations were reported in the article, with clinical characteristics, gene variants and the etiology. METHODS: The clinical data of two patients with Treacher Collins syndrome caused by TCOF1 gene variation were retrospectively analyzed. The whole exome sequencing (WES) was performed to detect the pathogenic variants of TCOF1 gene in the patients, and the verification of variants were confirmed by Sanger sequencing. RESULTS: Proband 1 presented with bilateral craniofacial deformities, conductive hearing loss and recurrent respiratory tract infection. Proband 2 showed bilateral craniofacial malformations with cleft palate, which harbored similar manifestations in her family. She died soon after birth due to dyspnea and feeding difficulties. WES identified two novel pathogenic variants of TCOF1 gene in two probands, each with one variant. According to the American College of Medical Genetics and Genomics, the heterozygous variation NM_001371623.1: c.877del (p. Ala293Profs*34) of TCOF1 gene was detected in Proband 1, which was evaluated as a likely pathogenic (LP) and de novo variant. Another variant found in Proband 2 was NM_001135243.1: c.1660_1661del (p. D554Qfs*3) heterozygous variation, which was evaluated as a pathogenic variation and the variant inherited from the mother. To date, the two variants have not been reported before. CONCLUSION: Our study found two novel pathogenic variants of TCOF1 gene and clarified the etiology of Treacher Collins syndrome. We also enriched the phenotypic spectrum of Treacher Collins syndrome and TCOF1 gene variation spectrum in the Chinese population, and provided the basis for clinical diagnosis, treatment and genetic counseling.


Assuntos
Disostose Mandibulofacial , Infecções Respiratórias , Feminino , Humanos , China , Perda Auditiva Condutiva , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Estudos Retrospectivos
4.
Sci Rep ; 14(1): 7472, 2024 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-38553547

RESUMO

Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with Kd values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter (nolc1). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.


Assuntos
Quadruplex G , Disostose Mandibulofacial , Animais , Humanos , DNA/metabolismo , Células HEK293 , Células HeLa , Disostose Mandibulofacial/genética , Disostose Mandibulofacial/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
5.
BMC Med Genomics ; 17(1): 75, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500116

RESUMO

BACKGROUND: Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder. METHODS: To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed. RESULTS: The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant. CONCLUSIONS: In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.


Assuntos
Disostose Mandibulofacial , Masculino , Humanos , Criança , Disostose Mandibulofacial/genética , Mutação , Éxons , Íntrons , China , Proteínas Nucleares/genética , Fosfoproteínas/genética
6.
Biochim Biophys Acta Mol Basis Dis ; 1870(4): 167128, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38508476

RESUMO

Nager syndrome (NS) is a rare acrofacial dysostosis caused by heterozygous loss-of-function variants in the splicing factor 3B subunit 4 (SF3B4). The main clinical features of patients with NS are characterized by facial-mandibular and preaxial limb malformations. The migration and specification of neural crest cells are crucial for craniofacial development, and mitochondrial fitness appears to play a role in such processes. Here, by analyzing our previously published transcriptome dataset, we aim to investigate the potential involvement of mitochondrial components in the pathogenesis of craniofacial malformations, especially in sf3b4 mutant zebrafish. We identified that oxidative phosphorylation (OXPHOS) defects and overproduction of reactive oxygen species (ROS) due to decreased antioxidants defense activity, which leads to oxidative damage and mitochondrial dysfunction. Furthermore, our results highlight that fish lacking sf3b4 gene, primarily display defects in mitochondrial complex I. Altogether, our findings suggest that mitochondrial dysfunction may contribute to the development of the craniofacial anomalies observed in sf3b4-depleted zebrafish.


Assuntos
Disostose Mandibulofacial , Doenças Mitocondriais , Peixe-Zebra , Animais , Perfilação da Expressão Gênica , Mutação , Fatores de Processamento de RNA/genética , Peixe-Zebra/genética , Modelos Animais de Doenças
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(3): 322-325, 2024 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-38448022

RESUMO

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Treacher-Collins syndrome (TCS) through whole exome sequencing (WES). METHODS: A TCS pedigree which was diagnosed at the Women and Children's Hospital Affiliated to Qingdao University on February 5, 2020 was selected as the study subject. Following collection of clinical data, WES was carried out. Candidate variant was validated through Sanger sequencing and bioinformatic analysis. RESULTS: The WES results showed that the proband has harbored a heterozygous c.3337C>T variant of the TCOF1 gene, and Sanger sequencing confirmed that his mother and brother also carried the same variant. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PM2_Supporting+PP4). CONCLUSION: The heterozygous c.3337C>T variant of the TCOF1 gene probably underlay the pathogenesis of TCS in this pedigree.


Assuntos
Povo Asiático , Disostose Mandibulofacial , Criança , Feminino , Humanos , Masculino , Povo Asiático/genética , China , Sequenciamento do Exoma , Disostose Mandibulofacial/genética , Mães , Proteínas Nucleares/genética , Linhagem , Fosfoproteínas/genética
8.
Int J Biol Macromol ; 266(Pt 2): 131216, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556235

RESUMO

Treacher Collins syndrome-3 (TCS-3) is a rare congenital craniofacial disorder attributed to variants in the RNA pol I subunit C (POLR1C). The pathogenesis of TCS-3 linked to polr1c involves the activation of apoptosis-dependent p53 pathways within neural crest cells (NCCs). This occurs due to disruptions in ribosome biogenesis, and the restoration of polr1c expression in early embryogenesis effectively rescues the observed craniofacial phenotype in polr1c-deficient zebrafish. Clinical variability in TCS patients suggests interactions between genes and factors like oxidative stress. Elevated production of reactive oxygen species (ROS) in epithelial cells may worsen phenotypic outcomes in TCS individuals. Our study confirmed excessive ROS production in facial regions, inducing apoptosis and altering p53 pathways. Deregulated cell-cycle and epithelial-to-mesenchymal transition (EMT) genes were also detected in the TCS-3 model. Utilizing p53 inhibitor (Pifithrin-α; PFT-α) or antioxidants (Glutathione; GSH and N-Acetyl-L-cysteine; NAC) effectively corrected migrated NCC distribution in the pharyngeal arch (PA), suppressed oxidative stress, prevented cell death, and modulated EMT inducers. Crucially, inhibiting p53 activation or applying antioxidants within a specific time window, notably within 30 h post-fertilization (hpf), successfully reversed phenotypic effects induced by polr1c MO.


Assuntos
Antioxidantes , Benzotiazóis , Modelos Animais de Doenças , Disostose Mandibulofacial , Estresse Oxidativo , Espécies Reativas de Oxigênio , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53 , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Disostose Mandibulofacial/genética , Disostose Mandibulofacial/tratamento farmacológico , Antioxidantes/farmacologia , Benzotiazóis/farmacologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Tolueno/farmacologia , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Apoptose/efeitos dos fármacos , RNA Polimerase I/antagonistas & inibidores , RNA Polimerase I/metabolismo , RNA Polimerase I/genética
9.
J Coll Physicians Surg Pak ; 34(2): 187-192, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38342870

RESUMO

OBJECTIVE: To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and electrophysiological variants of Guillain-Barre syndrome. STUDY DESIGN: Cross-sectional study. Place and Duration of the Study: Department of Neurology, Mayo Hospital and King Edward Medical University, Lahore, Pakistan, from November 2022 to April 2023. METHODOLOGY: Fourty-six Guillain-Barre syndrome patients, aged 12-70 years, were included in the study diagnosed by using the Brighton's criteria. Functional disability and respiratory insufficiency were assessed by using the modified Hughes disability score and the Erasmus Guillain-Barre syndrome respiratory insufficiency score, respectively. Serum neutrophil-to-lymphocyte ratio and cerebrospinal fluid total protein were calculated for each patient at the time of admission. RESULTS: Axonal variants had a higher mean neutrophil-to-lymphocyte ratio (5.29 ± 4.38) than demyelinating variants (4.71 ± 3.4) and Miller-Fischer syndrome (3 ± 2.828). This ratio was positively correlated with the modified Hughes's disability score (r = 0.790, p = 0.001) and the Erasmus Guillain-Barre syndrome respiratory insufficiency score (r = 0.936, p = 0.002). Mean cerebrospinal fluid total protein was higher for demyelinating (218 ± 136 mg/dl) than axonal variants (86 ± 56 mg/dl) and Miller-Fischer syndrome (34 ± 21 mg/dl). However, higher modified Hughes disability score (4-6) (r = 0.020, p = 0.117) and a high Erasmus Guillain-Barre syndrome respiratory insufficiency score (5-7) (r = 0.115, p = 0.302) did not significantly affect mean cerebrospinal fluid total proteins. CONCLUSION: Serum neutrophil-to-lymphocyte ratio can be regarded as a reliable biomarker to assess disease severity and clinical outcome in Guillain-Barre syndrome. Cerebrospinal fluid total protein is a poor predictor of the prognosis and severity of Guillain-Barre syndrome. KEY WORDS: Guillain-Barre syndrome (GBS), Clinical outcome, Cerebrospinal fluid total protein (CSF-TP), Neutrophil-to-lymphocytic ratio (NLR), Prognostic biomarker.


Assuntos
Anormalidades Múltiplas , Deleção Cromossômica , Síndrome de Guillain-Barré , Deformidades Congênitas dos Membros , Disostose Mandibulofacial , Micrognatismo , Insuficiência Respiratória , Síndrome WAGR , Humanos , Síndrome de Guillain-Barré/diagnóstico , Neutrófilos , Estudos Transversais , Biomarcadores , Linfócitos , Cromossomos Humanos Par 11
10.
J Craniofac Surg ; 35(1): 18-22, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37646339

RESUMO

BACKGROUND: Patients with Treacher Collins syndrome (TCS) and attendant airway dysmorphology may be predisposed to airway complications in the perioperative period. However, limited data correlates severity of mandibular hypoplasia and airway status. This study aims to improve risk stratification for perioperative airway insufficiency in TCS by using a previously proposed mandibular severity index. METHODS: Patient demographics, perioperative airway status, difficulty of intubation, and Cormack Lehane grade were collected and compared using a TCS mandibular hypoplasia severity grading scale in patients with TCS treated between 2000 and 2022. RESULTS: Twenty-six patients underwent 222 procedures with institutional mandibular severity gradings as follows: 23% Grade I, 31% Grade II, 39% Grade III, 8% Grade IV. Our severity index was associated with intubation difficulty ( P <0.001) and difficult airway status ( P <0.001), with 72% of difficult airways found in grade III and grade IV patients. Mandibular retrusion and ramal hypoplasia subscores were positively correlated with measures of airway severity ( P <0.001), whereas the gonial angle was negatively correlated ( P <0.001). Age was negatively correlated with difficult visualization for endotracheal intubation ( P =0.02) but had no association with difficult airway status ( P =0.2). CONCLUSIONS: This study found a positive correlation between severity of maxillomandibular dysmorphology and perioperative airway difficulty in TCS patients. Our findings suggest that severely affected patients require heightened vigilance throughout life, as difficult airways may not completely resolve with aging. Given the risk of morbidity and mortality associated with airway complications, proper identification and preparation for challenging airways is critical for TCS patients.


Assuntos
Disostose Mandibulofacial , Retrognatismo , Humanos , Disostose Mandibulofacial/cirurgia , Disostose Mandibulofacial/complicações , Intubação Intratraqueal/métodos , Mandíbula/cirurgia , Mandíbula/anormalidades , Retrognatismo/complicações , Envelhecimento
11.
Rev. Odontol. Araçatuba (Impr.) ; 44(3): 41-45, set.-dez. 2023. ilus
Artigo em Português | LILACS, BBO - Odontologia | ID: biblio-1553132

RESUMO

Treacher Collins também chamada de disostose mandibulofacial, é uma alteração genética dominante rara caracterizada pela má-formação dos ossos e tecidos da face. É uma síndrome crânio-facial que apresenta alterações bilaterais e simétricas de estruturas originadas do primeiro e segundo arcos branquiais. A maioria dos casos possui transmissão autossômica dominante e expressividade variável. O objetivo do presente estudo é realizar um relato de caso sobre o impacto do tratamento odontológico na qualidade de vida do paciente portador de Treacher Collins. Paciente, 39 anos, sexo feminino compareceu a uma clínica odontológica em Belo Horizonte, com a queixa principal de falhas dentárias e sensibilidade. Durante a anamnese a paciente relatou ter a STC, durante o exame clínico extraoral verificou a presença de hipoplasia malar e mandibular, malformação dos pavilhões auriculares com perda auditiva, obliquidade e coloboma palpebral inferior. Ao exame intraoral observou ser classe II de Angle, ausência dos dentes 11, 12, 13, 21 e 22 e extrusão do dente 41 e recessão gengival e periodontite estágio I grau A. Após exames de periodontograma e complementares foi realizado uma raspagem nas áreas com profundidade de sondagem maior que 3mm, frenectomia labial inferior, aplicação de laser para sensibilidade, enxerto gengival e colocação de prótese parcial removível. A paciente ao final do tratamento relatou ter se sentido realizada e contente com a sua conclusão, ela foi encaminhada ao Sistema único de Saúde para realizar as cirurgias para corrigir as alterações crânio-faciais. O tratamento odontológico deve ser adaptado a cada indivíduo de acordo com sua necessidade, tendo uma abordagem multidisciplinar, possibilitando uma melhora na qualidade de vida e estética do paciente(AU)


Treacher Collins syndrome is a rare dominant genetic disorder characterized by malformation of the bones and tissues of the face. It is a craniofacial syndrome that presents bilateral and symmetrical alterations of structures originating from the first and second branchial arches. The aim of the present study is to perform a case report on the impact of dental treatment on the quality of life of a patient with CTS. Patient, 39 years old, female, attended a dental clinic in Belo Horizonte, with the main complaint of dental flaws and sensitivity. During the anamnesis the patient reported having CTS, during the extraoral clinical examination she verified the presence of malar and mandibular hypoplasia, malformation of the pinnae with hearing loss, obliquity and lower eyelid coloboma. Intraoral examination revealed Angle class II, missing teeth 11, 12, 13, 21 and 22, extrusion of tooth 41, gingival recession and stage I periodontitis grade A. After periodontogram and complementary exams it was performed a scaling in areas with a probing depth greater than 3mm, lower lip frenectomy, laser application for sensitivity, gingival graft and placement of partial removable prosthesis. The patient at the end of treatment reported feeling fulfilled and happy with its completion, she was referred to the Unique Health System to undergo surgery to correct the craniofacial changes. The current treatment aims at functional and aesthetic correction and the need for psychosocial support, having the joint participation of a multidisciplinary team to achieve this goal(AU)


Assuntos
Humanos , Feminino , Adulto , Assistência Odontológica , Disostose Mandibulofacial , Boca , Periodontite , Disostose Craniofacial , Retração Gengival , Freio Labial , Freio Labial/cirurgia , Má Oclusão Classe II de Angle , Mandíbula/anormalidades
12.
Eur J Paediatr Dent ; 24(4): 334-336, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38015115

RESUMO

BACKGROUND: Mandibulofacial dysostosis Guion-Almeida Type (MFDGA; OMIM#610536) is a rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the EFTUD2 gene. Mandibulofacial dysostoses are characterised by the core triad malar hypoplasia, maxillary hypoplasia and dysplastic ears, all derived by the impaired development of the first and second branchial arches. Differential diagnosis is often challenging. The early genetic diagnosis is extremely useful, not only for the correct management of cranial malformations, but also for the early diagnosis and treatment of the comorbidities associated to the disease, which greatly benefit from early treatment.


Assuntos
Região Branquial , Disostose Mandibulofacial , Humanos , Disostose Mandibulofacial/genética , Diagnóstico Diferencial , Zigoma , Fatores de Alongamento de Peptídeos , Ribonucleoproteína Nuclear Pequena U5
13.
Clin Dysmorphol ; 32(4): 156-161, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37646764

RESUMO

Treacher Collins syndrome (TCS) is a rare disorder of craniofacial development following different patterns of inheritance. To date, mutations in four genes ( TCOF1, POLR1D, POLR1C , and POLR1B ) have been found to cause the condition. The molecular defect remains unidentified in a significant proportion of patients. In the current study, whole exome sequencing including analysis of copy number variants was applied for genetic testing of eight Egyptian patients with typical TCS phenotype, representing the first molecular analysis of TCS patients in Egypt as well as in Arab countries. Five heterozygous frameshift mutations were reported, including four variants in the TCOF1 gene (c.3676_3694delinsCTCTGG, c.3984_3985delGA, c.4366_4369delGAAA, and c.3388delC) and one variant in the POLR1D gene (c.60dupA). Four variants were novel extending the disease mutation spectrum. In three affected individuals, no variants of interest were identified in genes associated with TCS or clinically overlapping conditions. Additionally, no relevant variant was detected in genes encoding other subunits of RNA polymerase (pol) I. Molecular analysis is important to provide accurate genetic counseling. It would also contribute to reduced disease incidence. Further studies should be designed to investigate other possible etiologies when no pathogenic variants were revealed in either of the known genes.


Assuntos
Disostose Mandibulofacial , Humanos , Egito , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/genética , Mutação da Fase de Leitura , Aconselhamento Genético , Testes Genéticos , RNA Polimerases Dirigidas por DNA/genética
14.
Artigo em Chinês | MEDLINE | ID: mdl-37640998

RESUMO

Objective:By analyzing the clinical phenotypic characteristics and gene sequences of two patients with Treacher Collins syndrome(TCS), the biological causes of the disease were determined. Then discuss the therapeutic effect of hearing intervention after bone bridge implantation. Methods:All clinical data of the two family members were collected, and the patients signed the informed consent. The peripheral blood of the proband and family members was extracted, DNA was extracted for whole exome sequencing, and Sanger sequencing was performed on the family members for the mutation site.TCOF1genetic mutations analysis was performed on the paitents. Then, the hearing threshold and speech recognition rate of family 2 proband were evaluated and compared under the sound field between bare ear and wearing bone bridge. Results:In the two pedigrees, the probands of both families presented with auricle deformity, zygomatic and mandibular hypoplasia, micrognathia, hypotropia of the eye fissure, and hypoplasia of the medial eyelashes. The proband of Family 1 also presents with specific features including right-sided narrow anterior nasal aperture and dental hypoplasia, which were consistent with the clinical diagnosis of Treacher Collins syndrome. Genetic testing was conducted on both families, and two heterozygous mutations were identified in the TCOF1 gene: c. 1350_1351dupGG(p. A451Gfs*43) and c. 4362_4366del(p. K1457Efs*12), resulting in frameshift mutations in the amino acid sequence. Sanger sequencing validation of the TCOF1 gene in the parents of the proband in Family 1 did not detect any mutations. Proband 1 TCOF1 c. 1350_1351dupGG heterozygous variants have not been reported previously. The postoperative monosyllabic speech recognition rate of family 2 proband was 76%, the Categories of Auditory Performance(CAP) score was 6, and the Speech Intelligibility Rating(SIR) score was 4. Assessment using the Meaningful Auditory Integration Scale(MAIS) showed notable improvement in the patient's auditory perception, comprehension, and usage of hearing aids. Evaluation using the Glasgow Children's Benefit Inventory and quality of life assessment revealed significant improvements in the child's self care abilities, daily living and learning, social interactions, and psychological well being, as perceived by the parents. Conclusion:This study has elucidated the biological cause of Treacher Collins syndrome, enriched the spectrum of TCOF1 gene mutations in the Chinese population, and demonstrated that bone bridge implantation can improve the auditory and speech recognition rates in TCS patients.


Assuntos
Disostose Mandibulofacial , Criança , Humanos , Disostose Mandibulofacial/genética , Qualidade de Vida , Fala , Pais , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética
15.
Eur Rev Med Pharmacol Sci ; 27(3 Suppl): 1-10, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37129330

RESUMO

OBJECTIVE: Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development. TCS occurs with an incidence of 1:50,000, and more than 60% of TCS cases have no previous family history and arise as the result of de novo mutations. The high rate of de novo mutations, together with the extreme variability in the degree to which individuals can be affected, makes the provision of genetic counseling extremely complicated. Consequently, every case of TCS is unique and needs to be assessed individually. Patients with TCS frequently undergo multiple reconstructive surgeries from birth through adulthood, which rarely are fully corrective in the long-term. The nascent field of regenerative medicine offers the promise to improve some of these treatments. In particular, structural fat grafting (SFG) seems to be a good strategy not only to restore the normal volume and contour of the face, but also to provide a source of adipose-derived stem cells (ADSCs) with a multilineage differentiation potential. In this work, we present genetical analyses of ADSC affected by TCS. MATERIALS AND METHODS: ADSCs from were analyzed for their stemness properties and shared many characteristics with those of a healthy subject. Screening of the genome of the TCS patient using array-Comparative Genomic Hybridization allowed us to identify some chromosomal imbalances that are probably associated with TCS. RESULTS: We found that some alterations, involving the TIMELESS gene, were usually associated with embryonic stem cells. CONCLUSIONS: With the aim to improve the final results, we need to consider combining knowledge of genetic alterations and expression profiles as a fundamental step before starting with surgical procedures.


Assuntos
Disostose Mandibulofacial , Procedimentos de Cirurgia Plástica , Feminino , Humanos , Disostose Mandibulofacial/etiologia , Disostose Mandibulofacial/genética , Hibridização Genômica Comparativa , Mutação , Células-Tronco
16.
Int J Gynaecol Obstet ; 163(3): 778-781, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37231986

RESUMO

Treacher Collins syndrome (TCS) should be suspected if the triad of micrognathia, glossoptosis, and posterior cleft palate, and deformed external ears are observed during prenatal ultrasonography, excepting Pierre Robin sequence. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures are conducive to differentiation. Molecular genetics testing can establish a definite diagnosis. A 28-year-old pregnant Chinese woman was referred for systematic ultrasound examination at 24 weeks. Two-dimensional and three-dimensional ultrasound showed polyhydramnios, micrognathia, absence of nasal bone, microtia, secondary cleft palate, mandibular hypoplasia, glossoptosis, and normal limbs and vertebrae. Pierre Robin sequence was misdiagnosed with the triad of micrognathia, glossoptosis, and posterior cleft palate. Final diagnosis of TCS was confirmed by whole-exome sequencing. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures can facilitate a differential diagnosis between Pierre Robin sequence and TCS, with the triad of micrognathia, glossoptosis, and posterior cleft palate.


Assuntos
Fissura Palatina , Glossoptose , Disostose Mandibulofacial , Micrognatismo , Síndrome de Pierre Robin , Gravidez , Feminino , Humanos , Adulto , Disostose Mandibulofacial/diagnóstico por imagem , Disostose Mandibulofacial/genética , Síndrome de Pierre Robin/diagnóstico por imagem , Síndrome de Pierre Robin/genética , Micrognatismo/diagnóstico por imagem , Micrognatismo/genética , Glossoptose/complicações , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/genética , Diagnóstico Pré-Natal
17.
Am J Hum Genet ; 110(5): 809-825, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37075751

RESUMO

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.


Assuntos
Anormalidades Craniofaciais , Disostose Mandibulofacial , Humanos , Camundongos , Animais , Disostose Mandibulofacial/genética , Apoptose , Mutagênese , Ribossomos/genética , Fenótipo , Crista Neural/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia
18.
AANA J ; 91(1): 55-60, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36722784

RESUMO

Patients with Treacher Collins syndrome have a known difficult airway particularly if intubation is required. In most institutions that perform full mouth dental restoration (FMDR) procedures the patient is nasally intubated to protect the airway from debris and irrigation fluid. For patients with Treacher Collins syndrome the actual intubation and securing the airway can be more difficult and traumatic than the actual dental restoration itself. However, there is an airway technique using nasopharyngeal airways combined with a dental technique called "dry prepping" that can provide those patients a safe way of receiving an FMDR without intubation. A recent case report of a 29-month-old child with Treacher Collins syndrome received an FMDR without intubation.


Assuntos
Disostose Mandibulofacial , Criança , Humanos , Pré-Escolar , Boca , Intubação Intratraqueal
19.
Am J Med Genet A ; 191(5): 1210-1221, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36714960

RESUMO

Two to three thousand syndromes modify facial features: their screening requires the eye of an expert in dysmorphology. A widely used tool in shape characterization is geometric morphometrics based on landmarks, which are precise and reproducible anatomical points. Landmark positioning is user dependent and time consuming. Many automatic landmarking tools are currently available but do not work for children, because they have mainly been trained using photographic databases of healthy adults. Here, we developed a method for building an automatic landmarking pipeline for frontal and lateral facial photographs as well as photographs of external ears. We evaluated the algorithm on patients diagnosed with Treacher Collins (TC) syndrome as it is the most frequent mandibulofacial dysostosis in humans and is clinically recognizable although highly variable in severity. We extracted photographs from the photographic database of the maxillofacial surgery and plastic surgery department of Hôpital Necker-Enfants Malades in Paris, France with the diagnosis of TC syndrome. The control group was built from children admitted for craniofacial trauma or skin lesions. After testing two methods of object detection by bounding boxes, a Haar Cascade-based tool and a Faster Region-based Convolutional Neural Network (Faster R-CNN)-based tool, we evaluated three different automatic annotation algorithms: the patch-based active appearance model (AAM), the holistic AAM, and the constrained local model (CLM). The final error corresponding to the distance between the points placed by automatic annotation and those placed by manual annotation was reported. We included, respectively, 1664, 2044, and 1375 manually annotated frontal, profile, and ear photographs. Object recognition was optimized with the Faster R-CNN-based detector. The best annotation model was the patch-based AAM (p < 0.001 for frontal faces, p = 0.082 for profile faces and p < 0.001 for ears). This automatic annotation model resulted in the same classification performance as manually annotated data. Pretraining on public photographs did not improve the performance of the model. We defined a pipeline to create automatic annotation models adapted to faces with congenital anomalies, an essential prerequisite for research in dysmorphology.


Assuntos
Disostose Mandibulofacial , Doenças Raras , Adulto , Humanos , Criança , Algoritmos , Imageamento Tridimensional/métodos , Pontos de Referência Anatômicos/anatomia & histologia
20.
J Clin Invest ; 133(4)2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36637912

RESUMO

Mutations of G protein-coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here, we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduced the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, which may provide the basis for drug design targeting GPCRs.


Assuntos
Disostose Mandibulofacial , Animais , Camundongos , Humanos , Disostose Mandibulofacial/genética , Mutação com Ganho de Função , Ligantes , Sítios de Ligação , Mutação , Receptores Acoplados a Proteínas G/genética , Ligação Proteica , Alopecia/genética , Sítio Alostérico
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