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Molecular Syndromology Jul 2022Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis, is an inherited craniofacial defect. Here, we report a TCS family in which the members carry...
INTRODUCTION
Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis, is an inherited craniofacial defect. Here, we report a TCS family in which the members carry the same variant but present with phenotypic variability.
CASE PRESENTATION
A 19-year-old healthy primigravida was revealed by ultrasound at 12 weeks of gestation to have a fetus with micrognathia. Prenatal genetic testing detected a heterozygous single-nucleotide deletion (NM_015972:c.91del, p.Q31Rfs*10) in the gene, inherited from the healthy mother. Variants of have been reported to be associated with TCS. Family studies found that a paternal healthy cousin of the mother had a similar pregnancy outcome, with a fetus of TCS and the same variant.
DISCUSSION
Our study results pose a great challenge to prenatal diagnosis of TCS. The prenatal diagnosis cannot only rely on genetic testing. Instead, an early detailed sonographic survey will be helpful for the identification of TCS.
PubMed: 36158048
DOI: 10.1159/000521173 -
Italian Journal of Pediatrics Sep 2022Goldenhar syndrome (GS) is a rare congenital disease characterized by impaired development of different facial structures and deformations of the teeth structures....
BACKGROUND
Goldenhar syndrome (GS) is a rare congenital disease characterized by impaired development of different facial structures and deformations of the teeth structures. Sialorrhea, which can cause difficulties in breathing and language impairment, is very common in GS and often difficult to treat. This case report highlights the short- and long-term importance of the therapeutic choice - glycopyrronium in oral solution - for the treatment of sialorrhea in children with poly-malformative syndrome, complicated by outcomes of post-hemorrhagic hydrocephalus.
CASE PRESENTATION
We report the case of a 6-year-old child with GS, carrying a percutaneous endoscopic gastrostomy after tracheostomy. The child also presented developmental dysfunction of oral motor skills of feeding, complicated by severe sialorrhea, related to the maxillo-facial dysmorphism. Sialorrhea caused several respiratory tract infections and led to an increase in the care burden. Both the inoculations of botulinum toxin and the treatment with scopolamine transdermal patch have shown mild and transient efficacy. The therapeutic choice of glycopyrronium in oral solution was the most suitable for this patient, leading to long-term sialorrhea control.
CONCLUSIONS
This clinical experience represents the first long-term efficacy and tolerability evaluation in using glycopyrrolate oral solution in treating drooling in children with GS. The reduction of drooling over time and the lack of clinically relevant adverse events have contributed to the decrease of respiratory tract infections, the development of oral motor skills, and determining a positive psycho-social impact on the patient's quality of life and her family.
Topics: Child; Female; Glycopyrrolate; Goldenhar Syndrome; Humans; Quality of Life; Respiratory Tract Infections; Sialorrhea
PubMed: 36068575
DOI: 10.1186/s13052-022-01320-8 -
Journal of Clinical Sleep Medicine :... Jan 2023We report the first case of bilateral hypoglossal nerve stimulator implantation in a patient with Treacher Collins syndrome and very severe obstructive sleep apnea, who...
UNLABELLED
We report the first case of bilateral hypoglossal nerve stimulator implantation in a patient with Treacher Collins syndrome and very severe obstructive sleep apnea, who was initially intolerant of continuous positive airway pressure (CPAP) treatment. Novel bilateral hypoglossal nerve stimulation in combination with CPAP allowed near obliteration of snoring, improved sleep quality, and ability to maintain the CPAP mask in position in the setting of craniofacial changes associated with this condition.
CITATION
Wong ACL, Jones A, Stone A, MacKay SG. Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report. . 2023;19(1):197-199.
Topics: Humans; Continuous Positive Airway Pressure; Hypoglossal Nerve; Mandibulofacial Dysostosis; Electric Stimulation Therapy; Sleep Apnea, Obstructive
PubMed: 36038987
DOI: 10.5664/jcsm.10274 -
Journal of Developmental Biology Jul 2022Mandibulofacial dysostosis (MFD) is a human congenital disorder characterized by hypoplastic neural-crest-derived craniofacial bones often associated with outer and...
Mandibulofacial dysostosis (MFD) is a human congenital disorder characterized by hypoplastic neural-crest-derived craniofacial bones often associated with outer and middle ear defects. There is growing evidence that mutations in components of the spliceosome are a major cause for MFD. Genetic variants affecting the function of several core splicing factors, namely , , , and , are responsible for MFD in five related but distinct syndromes known as Nager and Rodriguez syndromes (NRS), craniofacial microsomia (CFM), mandibulofacial dysostosis with microcephaly (MFDM), cerebro-costo-mandibular syndrome (CCMS) and Burn-McKeown syndrome (BMKS), respectively. Animal models of NRS and MFDM indicate that MFD results from an early depletion of neural crest progenitors through a mechanism that involves apoptosis. Here we characterize the knockdown phenotype of Eftud2, Snrpb and Txnl4a in embryos at different stages of neural crest and craniofacial development. Our results point to defects in cranial neural crest cell formation as the likely culprit for MFD associated with , and haploinsufficiency, and suggest a commonality in the etiology of these craniofacial spliceosomopathies.
PubMed: 35893124
DOI: 10.3390/jdb10030029 -
Proceedings of the National Academy of... Aug 2022Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its...
Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe a cellular and molecular mechanism underlying the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCCs), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCCs particularly sensitive to rRNA synthesis defects. Consistent with this model, NCC-specific deletion of Pol I subunits , , and associated factor in mice cell-autonomously diminishes rRNA synthesis, which leads to p53 protein accumulation, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbate the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins syndrome and Acrofacial Dysostosis-Cincinnati type. Mechanistically, we demonstrate that diminished rRNA synthesis causes an imbalance between rRNA and ribosomal proteins. This leads to increased binding of ribosomal proteins Rpl5 and Rpl11 to Mdm2 and concomitantly diminished binding between Mdm2 and p53. Altogether, our results demonstrate a dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of congenital craniofacial disorders.
Topics: Animals; Craniofacial Abnormalities; Mandibulofacial Dysostosis; Mice; Neural Crest; Proto-Oncogene Proteins c-mdm2; RNA Polymerase I; RNA, Ribosomal; Ribosomal Proteins; Skull; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 35881792
DOI: 10.1073/pnas.2116974119 -
European Journal of Human Genetics :... Oct 2022Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated...
Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated with OAVS and common molecular pathways, such as retinoic acid and the PAX-SIX-EYA-DACH (PSED) network, are being implicated in the disease pathophysiology. Biallelic homozygous nonsense or hypomorphic missense mutations in PAX1 cause otofaciocervical syndrome type 2 (OTFCS2), a similar but more severe multi-system disorder that can be accompanied by severe combined immunodeficiency due to thymic aplasia. Here we have identified a multi-generational family with mild features of OAVS segregating a heterozygous frameshift in PAX1. The four base duplication is expected to result in nonsense-mediated decay, and therefore cause a null allele. While there was full penetrance of the variant, expressivity of facial and ear features were variable. Our findings indicate there can be monoallelic and biallelic disorders associated with PAX1, and further implicate the PSED network in OAVS.
Topics: Goldenhar Syndrome; Homozygote; Humans; Mutation, Missense; Paired Box Transcription Factors; Severe Combined Immunodeficiency; Tretinoin
PubMed: 35879406
DOI: 10.1038/s41431-022-01154-2 -
Journal of Cranio-maxillo-facial... Aug 2022This study aimed to investigate the potential progressiveness of mandibular asymmetry and to study factors that influence chin point deviation in patients with...
This study aimed to investigate the potential progressiveness of mandibular asymmetry and to study factors that influence chin point deviation in patients with unilateral craniofacial microsomia (CFM). Paediatric patients with unilateral CFM with available radiologic imaging and medical photographs were included. Chin point deviation was measured on clinical photographs. A Jonckheere-Terpstra test and linear mixed model for repeated measurements assessed the relation of chin point deviation on natural growth, Pruzansky-Kaban score, and soft tissue score. A total of 110 patients were included. The linear mixed model showed no statistically significant changes of chin point deviation during growth (effect estimate -0.006°, 95% CI -0.04° to -0.03°, p = 0.74). A statistical significant relation between both the Pruzansky-Kaban and soft tissue score on chin point deviation was found (effect estimate -5.10°, 95% CI -6.45° to -3.75°, p ≤ 0.001 and effect estimate -3.42°, CI -5.86° to -0.98°, p ≤ 0.001, respectively). Within the limitations of the study it seems that craniofacial microsomia may be a non-progressive disorder, because chin point deviation did not change over time.
Topics: Child; Chin; Goldenhar Syndrome; Humans; Mandible; Retrospective Studies
PubMed: 35872040
DOI: 10.1016/j.jcms.2022.07.006 -
Cold Spring Harbor Molecular Case... Jun 2022Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental...
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental delay, craniofacial malformations such as malar and mandibular hypoplasia, and ear anomalies. Here, we report a 4.5-yr-old female patient with symptoms fitting MFDM. Using whole-genome sequencing, we identified a de novo start-codon loss (c.3G > T) in the We examined expression in the patient by RNA sequencing and observed a notable functional consequence of the variant on gene expression in the patient. We identified a novel variant for the development of MFDM in humans. To the best of our knowledge, this is the first report of a start-codon loss in associated with MFDM.
Topics: Codon; Female; Humans; Mandibulofacial Dysostosis; Microcephaly; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear
PubMed: 35732499
DOI: 10.1101/mcs.a006206 -
Orthodontics & Craniofacial Research Feb 2023To analyse the prevalence and distribution of craniofacial microsomia (CFM) cases in Finland and their most frequent comorbidities. The second aim was to analyse the...
OBJECTIVES
To analyse the prevalence and distribution of craniofacial microsomia (CFM) cases in Finland and their most frequent comorbidities. The second aim was to analyse the patients' need for specialized healthcare services.
MATERIALS AND METHODS
Data were gathered from two complementary registers: The Register of Congenital Malformations and the Care Register for Social Welfare and Health Care (Hilmo) of the Finnish Institute for Health and Welfare (THL).
RESULTS
The prevalence of CFM patients in Finland was 1:10 057. They were evenly distributed across the five university hospital districts. Their most frequently used ICD-10 diagnosis codes were F40-48 (Neurotic, stress-related and somatoform disorders), 60% of patients in adolescent and adult psychiatry; Q67.0 (Facial asymmetry), 43% in plastic surgery; Z00.4 (General psychiatric examination, not elsewhere classified), 31% in child psychiatry; Z31.5 (Genetic counselling), 28% in clinical genetics and Q67.40 (Other congenital deformities of the skull, face and jaw, Hemifacial atrophy), 18% in dental, oral and maxillofacial diseases. Of the patients, 70% had had visits in clinical genetics, 60% in plastic surgery, 41% in dental, oral and maxillofacial diseases, 28% in adolescent/adult psychiatry and 21% in child psychiatry. The majority of the patients' plastic surgery visits were concentrated in one university hospital. Other services were mainly provided by patients' own hospital districts.
CONCLUSIONS
Even though the majority of CFM patients' visits in specialized healthcare services are related to correction of facial asymmetry and ear malformations, the obvious need for psychiatric care was apparent in all age groups.
Topics: Child; Adult; Adolescent; Humans; Goldenhar Syndrome; Facial Asymmetry; Skull; Delivery of Health Care; Prevalence
PubMed: 35689427
DOI: 10.1111/ocr.12592 -
Developmental Dynamics : An Official... Nov 2022POLR1D is a subunit of RNA Polymerases I and III, which synthesize ribosomal RNAs. Dysregulation of these polymerases cause several types of diseases, including...
BACKGROUND
POLR1D is a subunit of RNA Polymerases I and III, which synthesize ribosomal RNAs. Dysregulation of these polymerases cause several types of diseases, including ribosomopathies. The craniofacial disorder Treacher Collins Syndrome (TCS) is a ribosomopathy caused by mutations in several subunits of RNA Polymerase I, including POLR1D. Here, we characterized the effect of a missense mutation in POLR1D and RNAi knockdown of POLR1D on Drosophila development.
RESULTS
We found that a missense mutation in Drosophila POLR1D (G30R) reduced larval rRNA levels, slowed larval growth, and arrested larval development. Remarkably, the G30R substitution is at an orthologous glycine in POLR1D that is mutated in a TCS patient (G52E). We showed that the G52E mutation in human POLR1D, and the comparable substitution (G30E) in Drosophila POLR1D, reduced their ability to heterodimerize with POLR1C in vitro. We also found that POLR1D is required early in the development of Drosophila neural cells. Furthermore, an RNAi screen revealed that POLR1D is also required for development of non-neural Drosophila cells, suggesting the possibility of defects in other cell types.
CONCLUSIONS
These results establish a role for POLR1D in Drosophila development, and present Drosophila as an attractive model to evaluate the molecular defects of TCS mutations in POLR1D.
Topics: Animals; Humans; DNA-Directed RNA Polymerases; Drosophila; Mandibulofacial Dysostosis; Mutation; Phosphoproteins; Drosophila Proteins
PubMed: 35656583
DOI: 10.1002/dvdy.505