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Genes Nov 2022TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by...
TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by developmental defects during embryogenesis. The phenotypic spectrum of TARP shows high clinical variability with patients either missing cardinal features or having additional clinical traits. Initially, TARP was considered a lethal syndrome, but patients with milder symptoms were recently described. The TARP-locus was mapped to the gene RNA-binding motif protein 10 () on the human X-chromosome. We clinically and genetically described a six-year-old boy with a TARP-phenotype. Clinical heterogeneity of symptoms prompted us to sequence the entire exome of this patient. We identified a novel splice variant (NM_005676: c.17+1G>C, p.?) in . A patient-derived cell line was used to verify the pathogenicity of the splice variant by RNA analyses, Western blotting, and immunofluorescence staining. Our molecular genetic findings together with the analyses of progressing clinical symptoms confirmed the diagnosis of TARP. It seems essential to analyze correlations between genotype, phenotype, and molecular/cellular data to better understand -associated pathomechanisms, assist genetic counseling, and support development of therapeutic approaches.
Topics: Male; Humans; Child; Pierre Robin Syndrome; Clubfoot; Vena Cava, Superior; Phenotype; Rare Diseases; RNA-Binding Proteins
PubMed: 36421828
DOI: 10.3390/genes13112154 -
Science Advances Nov 2022Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a noncoding region distal from the human gene causes the Pierre Robin sequence...
Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a noncoding region distal from the human gene causes the Pierre Robin sequence (PRS) characterized by the undersized lower jaw. Such a craniofacial-specific defect has been previously linked to enhancers transiently active in cranial neural crest cells (CNCCs). We demonstrate that the PRS region also strongly regulates in CNCC-derived Meckel's cartilage (MC), but not in limb cartilages, even after decommissioning of CNCC enhancers. Such an MC-specific regulatory effect correlates with the MC-specific chromatin contacts between the PRS region and , highlighting the importance of lineage-dependent chromatin topology in instructing enhancer usage. By integrating the enhancer signatures and chromatin topology, we uncovered >10,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings provide critical insights for understanding the choreography of gene regulation during development and interpreting the genetic basis of craniofacial pathologies.
Topics: Humans; Chromatin; Pierre Robin Syndrome; Enhancer Elements, Genetic; Cartilage
PubMed: 36417512
DOI: 10.1126/sciadv.abo3648 -
Frontiers in Surgery 2022Pierre Robin sequence (PRS) is a congenital craniofacial deformity characterized by micrognathia, glossoptosis and airway obstruction. Some affected neonates are born...
BACKGROUND
Pierre Robin sequence (PRS) is a congenital craniofacial deformity characterized by micrognathia, glossoptosis and airway obstruction. Some affected neonates are born with severe life-threatening upper airway obstruction that requires surgery. If without timely treatment, it is possible to cause not only organ damage and developmental abnormalities but also early newborn mortality.
CASE PRESENTATION
In this report, a 51-hours-old neonate was diagnosed with PRS, who had severe upper airway obstruction and required surgery. We performed the modified mandible traction with wires at four days old and achieved a satisfactory result in improving airway obstruction. No other complications were observed except for mild local infection. No overlap of other more complex syndromes was found, such as ocular abnormalities, hearing loss, other skeletal abnormalities, cardiac abnormalities or other atypical abnormalities. At the present follow-up until 2 years old, there were no significant differences in the maxillofacial appearance, teeth growth, breathing, feeding, growth and development between the patient and normal children.
CONCLUSION
The modified mandible traction with wires can safely and effectively resolve micrognathia, the key to treating PRS, which is minimally invasive, simple and provides immediate relief of airway obstruction with no long term complications compared with other surgical methods. This report aims to provide more evidence of the successful treatment of neonatal PRS micrognathia by modified mandible traction with wires.
PubMed: 36338644
DOI: 10.3389/fsurg.2022.899195 -
Perspectives of the ASHA Special... Aug 2022The aims of this study were, in a cohort of children with neonatal opioid withdrawal syndrome (NOWS), (a) to report 1-year neurodevelopmental outcomes and specifically...
PURPOSE
The aims of this study were, in a cohort of children with neonatal opioid withdrawal syndrome (NOWS), (a) to report 1-year neurodevelopmental outcomes and specifically characterize speech, language, and hearing outcomes and (b) to report the prevalence of cleft lip and/or cleft palate.
METHOD
This prospective observational cohort study includes newborns with confirmed in utero opioid exposure who received pharmacological treatment for NOWS. During 1-year-old developmental visits, we administered standardized assessments (Bayley Scales of Infant and Toddler Development-Third Edition [Bayley-III] or Developmental Assessment of Young Children-Second Edition [DAYC-2]-due to COVID-19 restrictions). We compared Bayley-III scores to standardized population means using one-sample tests. We report estimates, 95% confidence intervals, and two-sided values.
RESULTS
We enrolled 202 infants (October 2018 to March 2020). Follow-up at 1-year was 80%. Infants with NOWS had lower Bayley-III scores at 1 year compared to published norms for cognitive, language, and motor domains. One infant with NOWS was diagnosed with isolated cleft palate and Pierre Robin sequence. All infants passed the newborn hearing screen, and 7.5% had a formal hearing evaluation after neonatal intensive care unit discharge, with 40% having abnormal or inconclusive results; middle ear effusion was the leading cause of abnormal hearing (66.7%). Ten percent of children received a speech-language pathology referral prior to 2 years of age. Infants born to mothers with mental health conditions were more likely to have Bayley-III or DAYC-2 scores below 95 in language or motor domains.
CONCLUSIONS
Infants with pharmacologically treated NOWS have significantly lower cognitive, language, and motor scores on standardized developmental testing compared to population means at 1 year of age. Early speech-language pathology referral is frequently necessary to promote optimal development in this population.
SUPPLEMENTAL MATERIAL
https://doi.org/10.23641/asha.20044403.
PubMed: 36211832
DOI: 10.1044/2022_PERSP-21-00270 -
Medicine Sep 2022Humidification is an important process in clinical oxygen therapy. We aimed to evaluate the effects and safety of humidified versus nonhumidified low-flow oxygen therapy... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Humidification is an important process in clinical oxygen therapy. We aimed to evaluate the effects and safety of humidified versus nonhumidified low-flow oxygen therapy in children with Pierre-Robin syndrome.
METHODS
This study was an open-label, single-centered randomized controlled trial (RCT) with a parallel group design. The study protocol has been registered in Chinese Clinical Trial Registry (ChiCTR1900021584). The children were randomized to the humidified versus nonhumidified groups. Average arterial oxygen partial pressure (PaO2) and carbon dioxide partial pressure (PaCO2), incidence of ventilator-associated pneumonia (VAP), nasal cavity dryness, nasal mucosal bleeding and bacterial contamination of the humidified bottle, the cost of nasal oxygen therapy and duration of intensive care unit (ICU) stay were analyzed.
RESULTS
A total of 213 children with Pierre-Robin syndrome were included. There were no significant differences in the gender, age, weight, prematurity, duration of anesthesia and surgery duration of mandibular traction between humidified group and nonhumidified group (all P > .05). No significant differences in the average arterial PaO2 and PaCO2 level on the postoperative day 1, 2, and ICU discharge between humidified group and nonhumidified group were found (all P > .05). There were no significant differences in the incidence of nasal cavity dryness, nasal mucosal bleeding, bacterial contamination and VAP, the duration of ICU stay between humidified group and nonhumidified group (all P > .05). The cost of nasal oxygen therapy in the humidified group was significantly less than that of nonhumidified group (P = .013).
CONCLUSIONS
Humidifying the oxygen with cold sterile water in the low-flow oxygen therapy in children may be not necessary. Future RCTs with lager sample size and rigorous design are warranted to further elucidate the effects and safety of humidified versus nonhumidified low-flow oxygen therapy.
Topics: Carbon Dioxide; Child; Humans; Oxygen; Oxygen Inhalation Therapy; Pierre Robin Syndrome; Water
PubMed: 36197167
DOI: 10.1097/MD.0000000000030329 -
Polymers Sep 2022This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer...
This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer resin Dental LT Clear (V2). The explained workflow includes intraoral and CT scanning, patient virtualization, digital appliance design, additive manufacturing, and clinical application with evaluation of the appliance intended for patients with cranio-facial syndromes. The presented concept defines virtual 3D fusion of intraoral optical scan and segmented CT as sufficient and accurate data defining the 3D surface of the face, intraoral and airway morphology necessary for the 3D design of complex personalized intraoral and extraoral parts of the orthopedic appliance. A central aspect of the concept is a feasible utilization of composite resin for biomedical prototyping of the sequence of marginally different appliances necessary to keep the pace with the patient rapid growth. Affordability, noninvasiveness, and practicality of the appliance update process shall be highlighted. The methodology is demonstrated on a particular case of two-year-old infant with Pierre Robin sequence. Materialization by additive manufacturing of this photopolymer provides a highly durable and resistant-to-fracture two-part appliance similar to a Tübingen palatal plate, for example. The paper concludes with the viability of the described method and material upon interdisciplinary clinical evaluation of experts from departments of orthodontics and cleft anomalies, pediatric pneumology and phthisiology, and pediatric otorhinolaryngology.
PubMed: 36146014
DOI: 10.3390/polym14183858 -
Genes Aug 2022Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD),...
Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in ZC4H2 (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) ZC4H2, or GFP report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT ZC4H2. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of ZC4H2 were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against ZC4H2. The results also demonstrated that decreasing the expression of ZC4H2 significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that ZC4H2 c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR.
Topics: Animals; Apraxias; Carrier Proteins; Codon, Nonsense; Contracture; Female; Genetic Diseases, X-Linked; Intracellular Signaling Peptides and Proteins; Muscular Atrophy; Nuclear Proteins; Ophthalmoplegia; Phenotype
PubMed: 36140726
DOI: 10.3390/genes13091558 -
The Cleft Palate-craniofacial Journal :... Feb 2024To describe perioperative feeding performance in infants with Robin sequence (RS) who underwent mandibular distraction osteogenesis (MDO). A retrospective study of...
To describe perioperative feeding performance in infants with Robin sequence (RS) who underwent mandibular distraction osteogenesis (MDO). A retrospective study of infants that underwent MDO from May 2010 to December 2019. Tertiary pediatric hospital. A total of 40 patients underwent MDO and 20 met inclusion criteria. Of the included infants, 6 had an associated syndrome and 80% were male. Time to full oral feeds, rate of G-tube placement, and change in weight percentile following MDO. Average oral intake prior to MDO was 22.1% of individual goal feeds. Among the 15 (75%) children that did not require G-tube placement, mean time to full oral feeds after MDO was 11 days ± 5.7 days, with 80% of infants reaching full oral feeds within 2 weeks after extubation. The proportion of G-tube placement in patients with a syndrome was higher than in isolated RS (-0.6; 95% CI: -1.0, -0.2). Mean percentages of weight-for-age percentile decreased during the first 3 months after the procedure. This was followed by a mean upturn in weight starting after the third month after MDO with a recovery to preoperative mean weight-for-age percentiles by 6 months after surgery. This study suggests that infants with RS may achieve full oral feeds despite poor feeding performance before MDO. Infants with syndromic RS are more likely to require G-tube. These findings may be used to inform G-tube discussion and offer a timeline to work toward goal oral feeds for infants with RS after MDO.
Topics: Infant; Humans; Male; Child; Female; Retrospective Studies; Pierre Robin Syndrome; Osteogenesis, Distraction; Treatment Outcome; Mandible; Airway Obstruction
PubMed: 36128745
DOI: 10.1177/10556656221127542 -
World Journal of Clinical Cases Jul 2022It has been shown that children with Pierre Robin sequence (PRS) have a higher risk of difficult intubation before surgery. When mask ventilation or tracheobronchial...
BACKGROUND
It has been shown that children with Pierre Robin sequence (PRS) have a higher risk of difficult intubation before surgery. When mask ventilation or tracheobronchial intubation is expected to be challenging, flexible bronchoscopy (FB) is advantageous in airway safety when it is used to guide tracheobronchial intubation (TI).
AIM
To evaluate the complications of TI using FB in children with PRS and explore the effect of nursing services on postoperative complications.
METHODS
One hundred and five children with PRS underwent TI using FB before early mandibular distraction osteogenesis. One hundred and eight children with common pneumonia who did not have a difficult airway were set as the control group. Demographic data, success rates of TI, time required for TI, number of TI attempts, and the incidence of postoperative complications were assessed. Besides, the strategies used to attenuate complications were investigated.
RESULTS
The success rate of TI was 100% in children with PRS, while the success rate at the first attempt in the PRS group was significantly lower than that in the control group (88.6% 98.2%, = 0.005). The time required for TI in the PRS group was markedly longer than that in the control group ( < 0.001). Children in the PRS group required repetitive operations to enter the glottis successfully ( = 0.017). The incidence of complications was noticeably higher in the PRS group (50/105, 47.6%) than in the control group (36/108, 33.3%) ( = 0.034). Seven of 105 PRS children experienced laryngeal edema (LE) (6.7%), compared with one (0.9%) in the control group ( = 0.034). Out of the seven patients who had LE, all were reintubated and managed with steroids: six recovered with inhaled steroids alone before extubated, and one was given systemic corticosteroids before recovery.
CONCLUSION
FB contributes to a high success rate of TI in children with PRS. To prevent LE, operators should pay more attention to catheter material, catheter lubrication and intubation time.
PubMed: 35979283
DOI: 10.12998/wjcc.v10.i19.6464 -
Pediatric Research Apr 2023Obstructive sleep apnea in infants with Pierre Robin sequence is sleep-position dependent. The influence of sleep position on obstructive events is not established in...
BACKGROUND
Obstructive sleep apnea in infants with Pierre Robin sequence is sleep-position dependent. The influence of sleep position on obstructive events is not established in other infants.
METHODS
We re-evaluated ten-year pediatric sleep center data in infants aged less than six months, with polysomnography performed in different sleep positions. We excluded infants with syndromes, genetic defects, or structural anomalies.
RESULTS
Comparison of breathing between supine and side sleeping positions was performed for 72 infants at the median corrected age of 4 weeks (interquartile range (IQR) 2-8 weeks). Of the infants, 74% were male, 35% were born prematurely, and 35% underwent study because of a life-threatening event or for being a SIDS sibling. Upper airway obstruction was more frequent (obstructive apnea-hypopnea index (OAHI), p < 0.001), 95th-percentile end-tidal carbon dioxide levels were higher (p = 0.004), and the work of breathing was heavier (p = 0.002) in the supine than in the side position. Median OAHI in the supine position was 8 h (IQR 4-20 h), and in the side position was 4 h (IQR 0-10 h).
CONCLUSIONS
Obstructive upper airway events in young infants are more frequent when supine than when sleeping on the side.
IMPACT
The effect of sleep position on obstructive sleep apnea is not well established in infants other than in those with Pierre Robin sequence. A tendency for upper airway obstruction is position dependent in most infants aged less than 6 months. Upper airway obstruction is more common, end-tidal carbon dioxide 95th-percentile values higher, and breathing more laborious in the supine than in the side-sleeping position. Upper airway obstruction and obstructive events have high REM sleep predominance. As part of obstructive sleep apnea treatment in young infants, side-sleeping positioning may prove useful.
Topics: Child; Humans; Male; Infant; Infant, Newborn; Female; Pierre Robin Syndrome; Carbon Dioxide; Sleep Apnea, Obstructive; Sleep; Airway Obstruction; Supine Position
PubMed: 35974159
DOI: 10.1038/s41390-022-02202-9