KEY POINTS
- 1.
Pierre Robin sequence (PRS) is an association of congenital micrognathia, glossoptosis, and cleft palate that presents with tongue-based airway obstruction.
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Infants with PRS can present with a host of findings ranging from severe respiratory distress to mild feeding difficulties.
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Evaluation of an infant found to have PRS should include direct visualization of the airway with flexible laryngoscopy, assessment of adjunctive measures to relieve airway obstruction (e.g., prone positioning, nasal trumpet), and evaluation of feeding and weight gain.
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Nonsurgical treatment options include prone positioning, oropharyngeal or nasopharyngeal airway, continuous positive airway pressure, and endotracheal intubation.
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Surgical options considered if nonsurgical management fails include tongue-lip adhesion, subperiosteal release of floor of mouth, mandibular distraction osteogenesis, and tracheostomy.
- 6.
The majority of infants with PRS can be managed nonsurgically, although many will initially require nasogastric tube feeding and possibly gastrostomy tube placement; however, most will be successfully consuming an oral diet by 3 years of age.
Introduction
Pierre Robin sequence (PRS) was named after Dr. Pierre Robin, a French stomatologist who first described its features in 1923. PRS is an association of congenital micrognathia, glossoptosis, and airway obstruction. The association of a wide, U-shaped cleft palate was added to the sequence in 1934. PRS is not considered a syndrome in itself but rather a sequence, where multiple anomalies result from a sequential chain of malformations. Patients typically present with respiratory distress, feeding difficulties, and failure to thrive. Mortality rates of 2% to 26% have been described historically, but recent studies report a mortality rate of 10% significantly associated with syndromic PRS and the presence of neurologic anomalies.
Overall, the estimated incidence of PRS is approximately 1 in 8000 to 14,000 individuals. The highest rate of incidence is found in the United States, where it is estimated to occur in 1 in 3120 individuals. PRS affects males and females equally. There appears to be a genetic basis for this sequence due to the high incidence of twins with PRS, and studies have shown that family members of infants with PRS have a higher incidence of cleft lip and palate. Additionally, 50% to 62% of PRS cases are syndromic. The three most common syndromes include velocardiofacial, Treacher Collins, and Stickler syndromes, which account for 65% of cases.
Pathophysiology
Genetic Contributions to PRS
PRS is a heterogenic entity and can be found as isolated disease (nonsyndromic PRS) or in association with other syndromes (syndromic PRS). Nonsyndromic PRS is linked to the SOX9 gene. The SOX9 gene is located on the long (q) arm of chromosome 17 at position 23 (17q23). SOX9 is an HMG-box transcription factor that regulates chondrogenesis and testis development. In humans, haploinsufficiency in the coding sequence of SOX9 causes campomelic dysplasia, a semilethal, rare, autosomal-dominant disorder involving shortening and bowing of long bones, skeletal malformations, and male-to-female sex-reversal. Disruptions upstream or downstream of an intact SOX9 coding region result in milder phenotypes including the nonsyndromic form of PRS.
To date, the Online Mendelian Inheritance in Man (OMIM) database identifies 34 conditions related to syndromic PRS. Stickler syndrome is a frequent cause of syndromic PRS and is due to an autosomal-dominant connective-tissue disorder caused by mutations in COL genes ( COL2A1 , COL9A1 , COL11A1 , or COL11A2 ), which affect type 2 and type 11 collagen. It is characterized by ocular, orofacial, auditory, and skeletal manifestations. The characteristic facial appearance includes midface hypoplasia, micrognathia, elongated philtrum, and palatal abnormalities such as cleft palate, bifid uvula, or high arched palate.
Velocardiofacial syndrome is an autosomal-dominant disorder caused by a microdeletion from chromosome 22 at the q11.2 band. It has an extremely expansive phenotypic spectrum, and no single clinical feature occurs in 100% of cases. Common features include congenital heart defects, facial anomalies, palatal anomalies, neonatal hypocalcemia, speech and learning disabilities, and hypoplastic thymus.
Treacher Collins syndrome derives from mutations in the TCOF1 , POLR1C , and POLR1D genes. These genes play a critical role in the early development of structures that become bones and tissues of the face. Treacher Collins syndrome can be inherited in an autosomal dominant or autosomal recessive manner. Typical features include bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, retrognathia, and external ear abnormalities.
There are three major embryologic hypotheses to explain the sequence of events resulting in PRS:
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Mandibular hypoplasia: During normal palatal development, the tongue lies between the two palatal shelves. The mandible starts growing ventrally and inferiorly during week 7 of development, pulling the tongue in the same direction. Due to a defect in Meckel’s cartilage, which is involved in the formation and growth of the mandible, the hypoplastic mandible results in the developing tongue being forced upward and backward (glossoptosis). , Glossoptosis subsequently prevents fusion of the vertical palatal shelves, leading to the development of a wide, U-shaped cleft palate. This was demonstrated in animal (zebrafish and murine) models. There is thought to be mandibular catch-up growth by 1 year of age, suggesting that ex utero, the mandible growth can normalize.
- 2.
Neurologic maturation theory: The inability of the developing fetus to engage in mandibular exercise prevents the tongue from descending, leading to mandibular hypoplasia. In PRS patients, delays in neurologic maturation have been noted on electromyography of the tongue, the pharyngeal pillars, the palate, and hypoglossal nerve conduction. Fetal oral muscular activity (including swallowing) is thought to be required for normal mandibular growth. The spontaneous correction with age supports this theory. Additionally, PRS is associated with several other conditions that are characterized by hypotonia.
- 3.
Compression of mandible in utero: This may be the etiology for a small percentage of infants born with PRS. The fetal head is flexed with the growing mandible against the chest during the first 6 weeks of development. The gradual extension of the head results in a normal outgrowth of the mandible. Factors that could result in intrauterine restriction, such as oligohydramnios, twin pregnancies, or an abnormal embryonic implantation site, may lead to micrognathia. In addition, studies show a higher incidence of PRS in twins than in the general population.
Clinical Features
Pierre Robin sequence is a triad of congenital micrognathia, glossoptosis, and airway obstruction. Micrognathia is often accompanied by overjet measurement >4 mm. Overjet is defined as the extent of anterior-posterior overlap of the maxillary central incisors over the mandibular central incisors. Glossoptosis causes airway obstruction at the level of the tongue base, and the severity of obstruction varies greatly between patients. Obstruction can happen spontaneously, with feeding, and while awake or asleep. Airway obstruction may also be progressive, so serial airway evaluations (flexible versus rigid endoscopy) are important. Polysomnography may demonstrate the presence of obstructive sleep apnea, and serial capillary gases can be used to evaluate for CO 2 retention. Patients can present with stridor, retractions, and cyanosis. Severe obstruction can lead to feeding difficulties and failure to thrive, so it is important to follow daily weight gain. Feeding difficulties are prevalent in 25% to 45% of patients with PRS, and these difficulties are secondary to airway obstruction and cleft palate. Infants cannot form the negative intraoral pressure required for adequate suck. Infants with PRS may need nasogastric tube feeding for several months, and some may even require gastrostomy tube placement. The prevalence and severity of feeding difficulties are higher in syndromic compared with nonsyndromic cases. It is important to note that infants may have feeding difficulties without airway obstruction, or these difficulties may persist even after airway obstruction has been corrected.
The overall goals of PRS treatment are airway maintenance, adequate feeding, and weight gain. If untreated or inadequately treated, infants with PRS can suffer from chronic hypoxia with CO 2 retention, increased pulmonary vascular resistance, cor pulmonale, and malnutrition/failure to thrive.
Evaluation
The approach to evaluation of an infant suspected to have Pierre Robin sequence should include not only direct assessment of the airway with flexible endoscopy but also the degree of airway obstruction, feeding difficulties, and presence of reflux disease, along with potential investigation for comorbid abnormalities with genetics consult, ophthalmology consultation, and audiogram, given the high likelihood of hearing loss and otitis media with effusion.
Direct airway evaluation should initially take place with flexible nasolaryngoscopy, which can allow for examination of the upper airway structures, identification of abnormalities, and localization of the site of obstruction. Evaluation of the infant should include assessment of the nasal cavities, the choana, the pharynx including the tongue base, and the larynx. Obstruction at the level of the tongue base is a characteristic feature of PRS, but other associated abnormalities include laryngomalacia, vocal cord paralysis, and less frequently, tracheomalacia, choanal atresia/stenosis, and hypoplastic epiglottis.
Because approximately 8% of infants with PRS have been shown to have lower airway abnormalities, rigid or flexible bronchoscopy should be considered to evaluate the subglottis, trachea, and bronchi. , Bronchoscopy should occur prior to other (nonairway) surgical procedures or surgical correction of tongue base obstruction and in cases with persistent obstruction after surgical correction.
Drug-induced sleep endoscopy (DISE) can also be performed in the operating room to determine the site of dynamic airway obstruction during inspiration while asleep. Obstruction of the level of the tongue base is seen in PRS, but other sites of obstruction that can lead to pediatric sleep-disordered breathing or obstructive sleep apnea include inferior turbinate hypertrophy and laryngomalacia. Findings elicited during DISE not only can be utilized for initial surgical planning but can also help elucidate the etiology of persistent obstruction after surgical correction of a tongue base obstruction.
Objective data should be measured to quantify hypoxemia and hypercapnia. Initially, pulse oximetry can help determine oxygen saturation in arterial blood. Repeated airway obstruction has also been shown to lead to elevated partial pressure of carbon dioxide (P co 2 ), and capillary P co 2 testing can be followed longitudinally. , Polysomnography has long been considered the gold standard for the diagnosis of obstructive sleep apnea/hypopnea syndrome and can help quantify the severity of airway obstruction.
Given the prevalence of feeding difficulties seen in infants with PRS, a feeding assessment and objective swallowing evaluation should be performed. Often these are performed by or in conjunction with a speech-language pathologist. An infant who demonstrates low oral intake with inadequate weight gain, prolonged feeding time, fatigue, and coughing or gagging with feeds may benefit from nasogastric tube placement. Infants may appear to have clinically satisfactory feeding outcomes but be silently aspirating, so a feeding assessment should be performed in all infants with PRS. Objective evaluation can be performed with videofluoroscopic swallowing studies or fiberoptic endoscopic evaluation of swallowing.
Additionally, there is a high prevalence of gastroesophageal reflux disease (GERD) in the PRS population and objective evaluation should be strongly considered, especially in the case of persistent airway obstruction after intervention. , Standard tests for evaluation of GERD in infants include barium swallow, esophagoscopy, and pH monitoring.
Genetics consultation should be considered early once an infant with PRS has been identified, given its association with multiple syndromes. Depending on the presence of any syndromes and associated abnormalities, routine ophthalmology and audiology assessments may be crucial and lead to early interventions.
Management
There are a variety of nonsurgical and surgical options that can be used to treat airway obstruction, with management decisions individualized and based on the severity of respiratory feeding difficulties and comorbidities. Nonsurgical options include prone positioning, oropharyngeal or nasopharyngeal airway, orthodontic appliance, continuous positive airway pressure (CPAP), and endotracheal intubation. Surgical options include tongue-lip adhesion (TLA), subperiosteal release of the floor of the mouth, mandibular distraction osteogenesis (MDO), and tracheostomy. Several studies have been performed to risk-stratify patients with PRS, and certain patient factors are predictive of need for surgical intervention, including prematurity, need for intubation or tracheotomy in the first 24 hours of life, CPAP/bilevel positive airway pressure (BiPAP) use, and the presence of comorbid neurologic disease. ,
The first-line intervention, which is simple to perform and can lead to rapid benefit, is prone positioning. This maneuver allows for forward movement of the mandible and tongue, which can relieve tongue-base obstruction. Prone positioning has been shown to be successful in 40% to 70% of children with PRS. , Drawbacks to prone positioning include the difficulty of monitoring an infant for signs or symptoms of airway obstruction and its association with sudden infant death syndrome.
Placement of a nasopharyngeal airway, either a nasal trumpet or a modified endotracheal tube placed intranasally and positioned in the oropharynx, has also been shown to relieve high upper airway obstruction. This technique can be taught to the infant’s parents or caregivers, and if successful, it can act as an effective temporizing measure for months as the mandible grows ( Fig. 68.1 ). One drawback to this method, however, is that it often precludes oral feeding, necessitating nasogastric or gastric tube placement for enteral feeding. Polysomnography can be performed to assist in determining the timing of removal, with the average duration of nasopharyngeal airway use being approximately 8 months.
CPAP is not often used in the long-term management of PRS due to the difficulty in utilizing this technique in infants, the infeasibility of using this method long-term, and the paucity of data regarding the success of the method in relieving airway obstruction. Furthermore, prolonged CPAP use has been shown to lead to acquired maxillary hypoplasia.
For infants who have moderate to severe obstruction that does not resolve with noninvasive interventions, surgical procedures must be considered. The majority of these target airway obstruction at the level of the tongue base. Flexible nasolaryngoscopy must be performed in all infants who are being considered for surgical intervention to help determine the level of obstruction and thus the surgical procedure most likely to have benefit.
TLA can be utilized for obstruction isolated to the tongue base. This procedure anchors the anterior tongue to the lip and the posterior tongue to the mandible. The genioglossus can also be released from the floor of mouth. There does exist controversy regarding the success of TLA in relieving airway obstruction, and there is a lack of long-term objective data in the literature. A small study demonstrated a drop in the mean apnea-hypopnea index from 37.6 to 21.6, indicating that despite an improvement, infants who underwent TLA still had persistent severe airway obstruction. Furthermore, this study also demonstrated that 4 out of 15 patients who underwent TLA ultimately required tracheostomy. Those who underwent mandibular distraction osteogenesis did not require postprocedure tracheostomy. The GILLS score has been proposed to predict the likelihood of TLA success by assigning 1 point to each of the following: gastroesophageal reflux, intubation preoperatively, late operation (older than 2 weeks), low birth weight (<2500 g), and syndromic diagnosis. TLA demonstrates a success rate of 100% in infants with a GILLS score of 2 or less and a failure rate of 43% in infants with a GILLS score of 3 or more.
MDO is the only surgical procedure addressing mandibular hypoplasia. It involves creating a bilateral mandibular osteotomy and then gradually advancing the mandible forward to relieve tongue-base obstruction. It is being performed more frequently in place of tracheostomy, although it does have contraindications and should not be performed in a child with absent mandibular condyles, absent coronoid processes, and a poorly defined glenoid fossa. , Preoperatively, lateral and anteroposterior cephalograms, an orthopantomogram, and, when necessary, three-dimensional computed tomography imaging should be performed to determine the vector of distraction. Using the three-dimensional models, virtual surgical planning is used to plan the mandibular correction procedure ( Figs. 68.2 and 68.3 ).
