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Pierre Robin sequence is a congenital disorder classically characterized by retrognathia, glossoptosis and upper airway obstruction with or without cleft palate. This condition affects neonates and can cause serious respiratory and feeding difficulties requiring prompt intervention. Currently there are no standardized management algorithms for neonates with Pierre Robin sequence and management of the condition remains a challenge. Assuring adequate breathing and feeding should always be the first point of concern. Early diagnosis, sequential planning of treatment, adequate monitoring and multidisciplinary approach are essential for infants referred with Pierre Robin sequence. We discuss here the full scope of the disease and the various management options.

IntroductionThe Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS.MethodsWe explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion.ResultsOur systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS.ConclusionSpinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.

Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.

IntroductionThe Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS.MethodsWe explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion.ResultsOur systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS.ConclusionSpinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.

Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.

Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays to enable directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene. We demonstrate that the gene trap insertion creates a null mutation replicating the Pierre Robin sequence-type cleft palate phenotype of other Prdm16 mutant mice. Consecutive breeding to Flpe and Emx1(IREScre) deleter mice spatially restricted Prdm16 loss to regions of the forebrain expressing the homeobox gene Emx1, demonstrating the utility of the technology for the analysis of tissue-specific gene functions.

Background Pierre Robin Sequence (PRS) is a common craniofacial anomaly comprising of micrognathia, cleft palate, glossoptosis and upper airway obstruction. It is a condition which affects 1 in 6000 neonates, often resulting in airway and feeding difficulties. Although it is a well-known condition, many aspects about the diagnosis, aetiology and management of Pierre Robin Sequence are contentious or unknown. Specifically, the exact phenotypic spectrum of this condition has been poorly studied. The major aim of this Master of Surgery is to provide an accurate phenotypic characterisation of a large cohort of non-syndromic Pierre Robin Sequence patients. A retrospective review of diagnosis and management of this cohort was also performed, along with a preliminary investigation into the possible genetic aetiology of a subset of patients. Methods A cohort of 141 non-syndromic PRS patients managed at the Royal Children’s Hospital in Melbourne from 1985 to 2012 was identified by cross-referencing two clinical databases. A detailed review of each patient’s medical file was performed and patients were categorised into either “Isolated PRS” or “PRS-Plus” groups. A subset of patients with a family history of cleft and/or a musculoskeletal anomaly were selected for targeted DNA sequencing of the non-coding elements of SOX9 (chromosome 17), a potential candidate gene for non-syndromic PRS. Results Our cohort comprised 83 Isolated PRS patients and 58 PRS-Plus patients. In the PRS-Plus group, the most common malformations beyond the craniofacial region involved were the musculoskeletal and ocular systems, with choanal stenosis/atresia being the single most common coexisting condition. PRS-Plus patients were found to have worse outcomes at birth as well as during the neonatal period, with a higher proportion being born small-for-gestational-age, have failure to thrive and require surgical intervention for airway and feeding. No significant genetic mutations were identified in the n

Congenital cervico-thoracic kyphosis has been encountered in a girl with Pierre Robin sequence. The constellation of the spine malformation complex such as incomplete development of the vertebral bodies associated with defective ossification of the cervico-thoracic pedicles causing effectively the development of complete spinal cord injury at the kyphotic level of C7/T1 were present. Congenital kyphosis secondary to vertebral body hypoplasia has not been reported in connection with Pierre Robin sequence., Die Auswirkungen einer congenitalen cervico-thorakalen Kyphose bei einem Mädchen mit Pierre-Robin-Syndrom werden beschrieben. Die Ausprägung der spinösen Malformationen wie inkomplette Entwicklung der Wirbelkörper verbunden mit Ossifikationsdefizit der Pedikel führten zu einer Kompression des Myelons im Bereich des kyphotischen Scheitels C7/Th1. Eine congenitale Kyphose bedingt durch Hypoplasie eines Wirbelkörpers wurde bisher in Verbindung mit Pierre-Robin-Syndrom noch nicht berichtet.

The Pierre Robin sequence manifests itself in the neonatal period with symptoms of respiratory distress and feeding difficulties. We report our experience in the clinical management of this entity over 14 years and present an appraisal of risk factors for the surgical treatment of the cleft lip/palate and late outcome. Between 1986 and 1999, out of a series of 159 consecutive patients operated in our department for cleft palate closure, 30 had Pierre Robin sequence. Conservative pediatric management included positioning and cardiorespiratory monitoring. In the case of failure of the conservative treatment, endotracheal intubation and/or different surgical procedures were used. The cleft palate was closed according to Malek's technique. Associated malformations were found in 10 cases (33%) with cardiorespiratory immaturity in five of those patients. Acute respiratory distress was present in 12 newborns (40%). Among them, endotracheal intubation was necessary in seven cases and maintained for 1 to 4 days in three patients. Glossopexy or subperiosteal release of the floor of mouth musculature was done in four of these patients followed by tracheotomy in two. Nasogastric feeding was needed in 14 infants (47%) for a variable period with a mean of 57 days (range 1-210 days). Polysomnography studies, done in 24 patients, showed significant obstructive apnea episodes in 10 infants. Gastroesophageal reflux was found in 11 patients (37%). Hearing loss was found in 29 infants (96%) with a mean threshold of 40 dB. Sensorineural hearing abnormalities were revealed in 10 patients (33%). Palate repair was done at the average age of 5 months (range 3-12 months). Difficulties of intubation were encountered in all the cases with severe malformations (five infants). Myringotomy and/or ventilation tubes were used in 21 infants at the same time of palate closure. An early palatal plate was used before surgery in 18 cases (60%). Immediate postoperative complications included two local he, SCOPUS: ar.j, info:eu-repo/semantics/published