Overexpression of Fgf18 in cranial neural crest cells recapitulates Pierre Robin sequence in mice.

The pivotal role of FGF18 in the regulation of craniofacial and skeletal development has been well established. Previous studies have demonstrated that mice with deficiency in Fgf18 exhibit severe craniofacial dysplasia. Recent clinical reports have revealed that the duplication of chromosome 5q32-35.3, which encompasses the Fgf18 gene, can lead to cranial bone dysplasia and congenital craniosynostosis, implicating the consequence of possible overdosed FGF18 signaling. This study aimed to test the effects of augmented FGF18 signaling by specifically overexpressing the Fgf18 gene in cranial neural crest cells using the Wnt1-Cre;pMes-Fgf18 mouse model. The results showed that overexpression of Fgf18 leads to craniofacial abnormalities in mice similar to the Pierre Robin sequence in humans, including abnormal tongue morphology, micrognathia, and cleft palate. Further examination revealed that elevated levels of Fgf18 activated the Akt and Erk signaling pathways, leading to an increase in the proliferation level of tongue tendon cells and alterations in the contraction pattern of the genioglossus muscle. Additionally, we observed that excessive FGF18 signaling contributed to the reduction in the length of Meckel's cartilage and disrupted the development of condylar cartilage, ultimately resulting in mandibular defects. These anomalies involve changes in several downstream signals, including Runx2, p21, Akt, Erk, p38, Wnt, and Ihh. This study highlights the crucial role of maintaining the balance of endogenous FGF18 signaling for proper craniofacial development and offers insights into potential formation mechanisms of the Pierre Robin sequence.

Pre-Operative Characteristics Helping to Avoid Gastrostomy Tube After Mandibular Distraction in Neonates With Pierre-Robin Sequence: A Institutional Case-Series and Review of the Literature.

OBJECTIVE: to investigate the ability of mandibular distraction osteogenesis (MDO) to avoid gastrostomy tube (G-tube). DATA SOURCES: PubMed, EBSCOhost, Cochrane, and Embase. REVIEW METHODS: We retrospectively reviewed the number of MDO cases performed at our institution for patients with Robin Sequence (RS) over the past 10 years. In our institutional review, patients were excluded if they had a G-tube already placed at the time of surgery. We also performed a systematic review of the literature. Articles were excluded if they did not detail feeding outcomes after MDO, or if MDO was performed on patients that did not have RS. RESULTS: In our systematic review, 12 articles were included that comprised a total of 209 neonates with RS that underwent MDO. A total of 174 (83.3%) patients avoided a G-tube once MDO was performed. A total of 14 patients met the inclusion criteria at our institution. Of the 14 RS patients, 9 (64%) avoided having a G-tube placed and all (14/14) avoided tracheostomy. The average birth weight of patients avoiding a G-tube was 3.11 kg compared to 2.25 kg (P = .045) in the group requiring a G-tube. In the group avoiding a G-tube, the average weight at time of operation was 3.46 kg compared to 2.83 kg (P = .037) in the group requiring a G-tube. CONCLUSION: MDO may be considered as a surgical option to prevent G-tube placement for neonates with non-syndromic RS who have difficulty with PO feeding but whose airway obstruction is not severe enough to require respiratory support. Based on our institutional experience, a minimum weight of 3.00 kg correlated with higher success rates of PO intake and avoiding a G-tube.

Pre-Epiglottic Baton Plate in Newborns With Pierre Robin Sequence: Revisiting the Practical Workflow.

We demonstrate pre-epiglottic baton plate as non-invasive treatment modality for initial airway management in newborns with Pierre Robin Sequence. A case example illustrates management of upper airway obstruction and feeding using digital technology to facilitate customization. Laryngoscope, 2024.

Impact of upper airway obstruction management in Robin Sequence on need for myringotomy tubes.

OBJECTIVE: Investigate an association between upper airway obstruction (UAO) management in Robin Sequence (RS) and need for bilateral myringotomy and tubes (BMT). METHODS: Retrospective chart review of RS patients treated at a tertiary free-standing pediatric hospital from 1995 to 2020 was performed. Patients were grouped based on airway management: conservative, tracheostomy, tongue-lip adhesion (TLA), and mandibular distraction osteogenesis (MDO). Demographic data, cleft palate (CP) association, numbers of BMT and ear infections, and audiogram data including tympanograms were collected. One-way ANOVA and Chi-square/Fisher's exact tests were used to compare continuous and categorical data, respectively. Multivariable regression analysis was used to compare BMT rates between treatment groups. RESULTS: One hundred forty-eight patients were included, 70.3 % of which had CP. Most patients (67.6 %) had at least one BMT; 29.1 % required two or more BMT. The rate of BMT was higher in patients with CP compared to those with intact palates (p = 0.003; 95 % CI 1.30-3.57) and those treated with tracheostomy (p = 0.043; 95 % CI 1.01, 2.27). Surgically managed patients were more likely to have hearing loss (67.5 % vs. 35.3 %, p = 0.017) and ear infections (42.1 % vs. 20.0 %, p = 0.014) pre-compared to post-procedure for airway management. CONCLUSION: Most RS patients require at least 1 set of BMT. Those with CP and/or treated with tracheostomy had a higher likelihood of needing BMT. Rate of hearing loss and ear infection was higher in surgically managed RS patients. Patients with RS and overt CP require a statistically higher number of BMTs compared to those with either submucous cleft palate or intact palate.

Interim management of Pierre Robin sequence using a custom-made face mask.

Pierre Robin sequence poses a great challenge for anesthesiologists during laryngoscopy and intubation, making oxygenation and ventilation difficult. The role of early surgical intervention is recommended for the improvement of the airway and overall survival of the neonate. The situation becomes even more challenging, when the neonate may not be fit for such surgical interventions. The present case posed such a challenge to the team. To the authors' knowledge, the decision to use a face mask as an interim life-saving measure was considered for the first time. This provided a greater window of opportunity for further course of action, only to be later managed by distraction osteogenesis of the mandible. The unconventional use of orthopedic appliances for the management of threatened airways may provide the clinician with time, where further management may be carried out. The present article will explain such a procedure that was carried out as a life-saving measure.

Genetic Analysis and Functional Assessment of a TGFBR2 Variant in Micrognathia and Cleft Palate.

Cleft lip and cleft palate are among the most common congenital anomalies and are the result of incomplete fusion of embryonic craniofacial processes or palatal shelves, respectively. We know that genetics play a large role in these anomalies but the list of known causal genes is far from complete. As part of a larger sequencing effort of patients with micrognathia and cleft palate we identified a candidate variant in transforming growth factor beta receptor 2 (TGFBR2) which is rare, changing a highly conserved amino acid, and predicted to be pathogenic by a number of metrics. The family history and population genetics would suggest this specific variant would be incompletely penetrant, but this gene has been convincingly implicated in craniofacial development. In order to test the hypothesis this might be a causal variant, we used genome editing to create the orthologous variant in a new mouse model. Surprisingly, Tgfbr2V387M mice did not exhibit craniofacial anomalies or have reduced survival suggesting this is, in fact, not a causal variant for cleft palate/ micrognathia. The discrepancy between in silico predictions and mouse phenotypes highlights the complexity of translating human genetic findings to mouse models. We expect these findings will aid in interpretation of future variants seen in TGFBR2 from ongoing sequencing of patients with congenital craniofacial anomalies.

Feeding Management and Palate Repair Timing in Infants with Cleft Palate with and without Pierre Robin Sequence: A Multisite Study.

OBJECTIVES: Compare the feeding management practices in infants with cleft palate with and without Pierre Robin sequence (PRS) and determine if specific feeding difficulties or interventions predict delayed palate repair. DESIGN: Retrospective cross-sectional study. SETTING: Seventeen cleft palate teams contributed data. PATIENTS: 414 infants were included in this study: 268 infants with cleft palate only and 146 infants with cleft palate and PRS. PROCEDURES: Data were collected via parent interview and electronic health records. MAIN OUTCOME MEASURES: Outcomes for the primary objective included categorical data for: history of poor growth, feeding therapy, milk fortification, use of enteral feeding, and feeding difficulties. The outcome for the secondary objective was age in months at primary palate repair. RESULTS: Infants with PRS had a significantly higher prevalence of feeding difficulties (81% versus 61%) and poor growth (29% versus 15%) compared to infants with cleft palate only. Infants with PRS received all feeding interventions-including feeding therapy, milk fortification, and enteral feeding-at a significantly higher frequency. Infants with PRS underwent primary palate repair at a mean age of 13.55 months (SD = 3.29) which was significantly (P < .00001) later than infants with cleft palate only who underwent palate repair at a mean age of 12.05 months (SD = 2.36). Predictors of delayed palate repair included diagnosis of PRS as well as Hispanic ethnicity and a history of poor growth. CONCLUSIONS: These findings can be used to establish clinical directives focused on providing early, multimodal feeding interventions to promote optimal growth and timely palate repair for infants with PRS.

Application of the MicroNAPS Classification for Robin Sequence.

OBJECTIVE: The only findings consistent among infants with Robin sequence (RS) are the presence of micrognathia, glossoptosis, and upper airway obstruction (UAO). Feeding and growth dysfunction are typical. The etiopathogenesis of these findings, however, is highly variable, ranging from sporadic to syndromic causes, with widely disparate levels of severity. This heterogeneity has created inconsistency within RS literature and debate about appropriate workup and treatment. Despite several attempts at stratification, no system has been broadly adopted. DESIGN: We recently presented a novel classification that is summarized by the acronym MicroNAPS. Each of 5 elements is scored: Micrognathia, Nutrition, Airway, Palate, Syndrome/comorbidities, and element scores are summarized into a "stage". RESULTS: Testing of this system in a sample of 100 infants from our center found it to be clinically relevant and to predict important management decisions and outcomes. CONCLUSIONS: We herein present an interactive website (www.prscalculator.com) and printable reference card for simple application of MicroNAPS, and we advocate for this classification system to be adopted for clinical care and research.

Weight Gain of Infants with Robin Sequence Treated Nonsurgically Using the Stanford Orthodontic Airway Plate (SOAP): 1-Year Follow-Up.

OBJECTIVE: To identify weight gain trends of infants with Robin sequence (RS) treated by the Stanford Orthodontic Airway Plate treatment (SOAP). DESIGN: Retrospective longitudinal cohort study. SETTING: Single tertiary referral hospital. PATIENTS: Eleven infants with RS treated with SOAP. INTERVENTIONS: Nonsurgical SOAP. MAIN OUTCOME MEASURES: Body weight, Weight-for-age (WFA) Z-scores, and WFA percentiles at birth (T0), SOAP delivery (T1), SOAP graduation (T2), and 12-months old (T3). RESULTS: Between T0 and T1, the weight increased but the WFA percentile decreased from 36.5% to 15.1%, and the Z-score worsened from -0.43 to -1.44. From T1 to T2, the percentile improved to 22.55% and the Z-score to -0.94. From T2 to T3, the percentile and the Z-scores further improved to 36.59% and -0.48, respectively. CONCLUSIONS: SOAP provided infants experiencing severe respiratory distress and oral feeding difficulty with an opportunity to gain weight commensurate with the WHO healthy norms without surgical intervention.

Occlusal Outcomes in Non-Robin Sequence Patients with Isolated Cleft Palate.

OBJECTIVES: 1. To assess the skeletal class occlusion and lateral cephalometry in children with isolated cleft palates (non-Robin sequence) and 2. to identify associations between these findings and pre-palatoplasty cleft palate measurements. STUDY DESIGN: Retrospective cohort study. SETTING: North American Institutional Tertiary Paediatric Center. PATIENTS: Our cleft database was reviewed, and patients were included if they had an isolated cleft palate without a Robin Sequence diagnosis, had a Furlow palatoplasty and had available per operative cleft palate measurements and available lateral cephalogram between 6 and 8 years old. Thirty-two patients matched to inclusion criteria. INTERVENTION: Furlow's Palatoplasty. MAIN OUTCOME AND MEASURES: Cleft size at palatoplasty, cephalometric measurements and skeletal occlusal classes were analysed. ANOVA was used to test the association between cephalometric measurements and occlusal classes. Results are presented as means with a 95% confidence interval. The association between cleft measurements and cephalometric parameters was tested with Spearman Correlation (rs). RESULTS: The skeletal occlusal outcome at 7 years old for this series of patients was: Class I: 19%; Class II: 59% and Class III: 22%. No single cleft measurement at palatoplasty was predictive of the skeletal occlusal outcome. A larger hard palate cleft was associated with a shorter antero-posterior maxilla. CONCLUSIONS: The skeletal occlusal class outcomes were similar to those found in a previous study in the literature. The occlusal prognosis appears to be better than in patients with Robin Sequence or with an associated cleft lip. No preoperative measurement was found to be associated with the occlusal outcome.

Use of At-Breast Supplementers to Facilitate Feeding Solely at the Breast for Infants with Retrognathia: Two Case Studies.

Objective: Infants with significant retrognathia often have difficulty forming a latch adequate to establish exclusive breastfeeding. This article describes the use of at-breast supplementers (ABSs) to facilitate extended breastfeeding relationships, even when supplementation is necessary for growth. Methods: Two cases are described where infants with severe retrognathia initially struggled with weight gain necessitating supplementation but were able to ultimately exclusively feed at-breast with the use of ABSs. Results: While the two cases differed in the form of supplemental milk used and duration of ABS use, both dyads breastfed for beyond 2 years. Conclusions: Feeding solely at the breast and subsequent extended breastfeeding may be possible even for infants who require supplementation, including those with anatomical or functional challenges such as retrognathia. The ABS is a relatively simple system that may be beneficial for difficulties such as poor latch and low milk supply. More awareness and education is needed so that clinicians consider supporting dyads with this approach.

Screening for congenital hearing impairment with brainstem evoked response audiometry in isolated orofacial cleft.

Brainstem evoked response audiometry (BERA) is the most established and recommended objective audiometric method for the clinical diagnosis of hearing impairment in high-risk infants. It is unclear whether infants with orofacial clefts meet the criteria for the high-risk group. This retrospective cohort study evaluated the need for diagnostic BERA in infants with cleft palate with or without cleft lip by assessing the predisposition to and diagnosis of congenital hearing impairment. Data from 122 patients treated at a single cleft centre were evaluated. BERA was conducted at the time of palate repair at 4-6 months of age. Clinical follow-up was analysed up to 4 years. The presence of a syndrome was examined as a risk factor for congenital hearing impairment. Among the 122 patients, four had congenital sensorineural or mixed hearing loss requiring hearing aids. All affected patients had syndromes in addition to the cleft. Most patients with elevated hearing thresholds had transient conductive hearing loss. Most suspected sensorineural hearing loss initially diagnosed was refuted. However, a higher incidence of sensorineural hearing loss was found in patients with syndromic clefts, supporting the diagnostic use of BERA with initial surgery only in patients with syndromic clefts.

Mid-term effect of mandibular distraction osteogenesis on clinical and polysomnography findings of patients with Robin sequence.

The study aimed to evaluate the mid-term effect of MDO in children with Robin sequence (RS). In this case series, 13 patients with RS who underwent MDO were followed up for more than 5 years. Data were collected using clinical history and physical examination. Polysomnography was performed and endoscopic evaluations of the airway was performed if patients still presented obstructive signs of upper airways and/or dysphagia. The patients' clinical signs improved in the mid-term after versus before MDO (inspiratory noise, 92,3% vs 30,8%; apnea, 84,6% vs 7,7%; cyanosis, 76,9% vs 0%; desaturations, 69,2% vs 0%; and suprasternal/intercostal retractions, 61,5% vs 0%; p < 0.05). Statistically significant improvement was noted in the following polysomnographic parameters evaluated in the pre and postoperative mid-term: apnea-hypopnea index, total sleep time and desaturation index (p < 0.05). Within the limitations of the study it seems that MDO is an effective surgical option for children with RS, not only in the short term as previously demonstrated, but also in the mid-term.

Intellectual Functioning of Children With Isolated PRS, PRS-Plus, and Syndromic PRS.

OBJECTIVE: Describe the intelligence quotient (IQ) of children with Pierre Robin sequence (PRS). DESIGN: Prospective cohort study. SETTING: Neurodevelopmental follow-up clinic within a hospital. PATIENTS: Children with PRS (n = 45) who had been in the Neonatal Intensive Care Unit (NICU) were classified by a geneticist into 3 subgroups of isolated PRS (n = 20), PRS-plus additional medical features (n = 8), and syndromic PRS (n = 17) based on medical record review and genetic testing. MAIN OUTCOME MEASURE: Children with PRS completed IQ testing at 5 or 8 years of age with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) or Fourth Edition (WPPSI-IV) or the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) or Fifth Edition (WISC-V). RESULTS: IQ scores were more than 1 to 2 standard deviations below the mean for 36% of the overall sample, which was significantly greater compared to test norms (binomial test P = .001). There was a significant association between PRS subtype and IQ (Fisher's exact P = .026). While only 20% of children with isolated PRS were within 1 standard deviation below average and 35% of children with syndromic PRS were below 1 to 2 standard deviations, 75% of PRS-plus children scored lower than 1 to 2 standard deviations below the mean. CONCLUSION: PRS subgroups can help identify children at risk for cognitive delay. The majority of children with PRS-plus had low intellectual functioning, in contrast to the third of children with syndromic PRS who had low IQ and the majority of children with isolated PRS who had average or higher IQ.

Failure of Mandibular Distraction Osteogenesis in Klippel- Feil Syndrome- 4: A Case Report of a Rare Syndromic Robin Sequence.

Klippel-Feil syndrome-4 (KFS4), a rare autosomal recessive form of Klippel- Feil syndrome, is characterized by facial dysmorphism, nemaline myopathy, and short stature. Only 10 cases of KFS4 have been previously published in the literature. We report a novel case of a 1- month-old girl with known KFS4 and Robin Sequence (RS). At 2 months old, she underwent bilateral mandibular distraction osteogenesis to correct significant airway obstruction. Despite adequate mandibular advancement, the patient failed extubation twice and eventually required a tracheostomy. Due to the multiple anomalies present in KFS4, mandibular distraction osteogenesis may have a decreased likelihood of surgical success.

The Impact of Mandibular Distraction Osteogenesis on Cephalometric Measurements in Infants with Pierre Robin Sequence.

BACKGROUND: The obstruction of the upper airway (UAO) in infants diagnosed with Robin Sequence (RS) is caused by micrognathia, and in severe cases, it can result in obstructive sleep apnea (OSA). Mandibular distraction osteogenesis (MDO) is a secure and efficient remedy for significant UAO. However, there is insufficient data on the related cephalometric changes. Therefore, this study meticulously analyzes the mandibular cephalometric changes in infants with RS who have undergone MDO using internal devices. The aim is to gain a more comprehensive understanding of the short- and long-term impacts of distraction on the mandible. METHODS: The study examined 73 consecutive cases of mandibular distraction osteogenesis (MDO) performed by a single surgeon. Preoperative and postoperative lateral cephalograms, as well as CT scans of the mandible, were utilized to assess population averages for both time points. A two-sample T-Test with equal variance was used for this analysis. RESULTS: After the MDO procedure, 19 out of 21 cephalometric parameters exhibited significant morphological changes. On average, there were notable improvements of 20.3 mm (60.7%) in length, 9.8 mm (49.7%) in height, 12.6 mm (36.1%) in width, and 211% in airway parameters. However, most parameters showed only mild regression at the time of device removal and 6 to 12 months post-MDO. Nonetheless, the cephalometric parameters remained significantly improved compared to the preoperative measurements. CONCLUSIONS: The use of cephalometric measurement is a potent approach that provides a clear and measurable understanding of how MDO influences both immediate and long-term growth of the mandible. This quantitative assessment of the effects of mandibular distraction allows for the refinement of surgical techniques and the optimization of outcomes. Therefore, incorporating cephalometric measurements in the evaluation of patients undergoing MDO can lead to better surgical planning and more favorable results.

The Outcome of Mandibular Distraction Osteogenesis in Infants with Severe Pierre Robin Sequence in Vietnam.

The purpose of this study was to provide the experience of a single center with mandibular distraction osteogenesis (MDO) in Pierre Robin Sequence (PRS) patients. A longitudinal research analysis was conducted to identify PRS patients who underwent MDO at Vietnam National Children's Hospital between 2019 and 2021. The following criteria were used to determine inclusion: 1) those pediatric patients with PRS who were not well handled with conservative therapy, 2) those who received MDO with internal mandibular distractors, and 3) no previous treatment elsewhere. Demographic data, postoperative complications, and surgical results were all evaluated. The inclusion criteria were met by 73 patients. There were no difficulties associated with our distraction strategy. The majority of individuals with tracheostomies were successfully decannulated, and the remainder were able to avoid tracheostomies. Using MDO in PRS is an effective technique to avoid future airway issues. The success rate was lower and the complication rate higher for patients who had a tracheotomy before distraction and for those who underwent distraction at an age older than 2 months. The presence of laryngomalacia, gastric reflux disease, cardiac abnormalities, and GI anomalies did not increase the likelihood of MDO failure in PRS patients.

The Evolution of Robin Sequence Treatment Based on the Biomimetic Interdisciplinary Approach: A Historical Review.

The Robin sequence is a congenital anomaly characterized by a triad of features: micrognathia, glossoptosis, and airway obstruction. This comprehensive historical review maps the evolution of approaches and appliances for its treatment from the past to the current modern possibilities of an interdisciplinary combination of modern engineering, medicine, materials, and computer science combined approach with emphasis on designing appliances inspired by nature and individual human anatomy. Current biomimetic designs are clinically applied, resulting in appliances that are more efficient, comfortable, sustainable, and safer than legacy traditional designs. This review maps the treatment modalities that have been used for patients with a Robin sequence over the years. Early management of the Robin sequence focused primarily on airway maintenance and feeding support, while current management strategies involve both nonsurgical and surgical interventions and biomimetic biocompatible personalized appliances. The goal of this paper was to provide a review of the evolution of management strategies for patients with the Robin sequence that led to the current interdisciplinary biomimetic approaches impacting the future of Robin Sequence treatment with biomimetics at the forefront.