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Pierre Robin sequence
Pierre Robin sequence
Pierre Robin sequence
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Pierre Robin sequence
Other namesPierre Robin syndrome, Pierre Robin malformation, Pierre Robin anomaly, Pierre Robin anomalad[1]
Infant with Pierre Robin sequence
SpecialtyMedical genetics
SymptomsMicrognathia, glossoptosis, obstruction of the upper airway, sometimes cleft palate
Usual onsetDuring gestation, present at birth
Causesintrauterine compression of fetal mandible, de-novo mutations (on chromosomes 2, 4, 11, or 17) or Stickler syndrome
Diagnostic methodPhysical examination
TreatmentCraniofacial surgery, oral and maxillofacial surgery
Frequency1 in 8,500 to 14,000 people[2]

Pierre Robin sequence[a] (/pjɛər rɔːˈbæ̃/;[3] abbreviated PRS) is a congenital defect observed in humans which is characterized by facial abnormalities. The three main features are micrognathia (abnormally small mandible), which causes glossoptosis (downwardly displaced or retracted tongue), which in turn causes breathing problems due to obstruction of the upper airway. A wide, U-shaped cleft palate is commonly also present. PRS is not merely a syndrome, but rather it is a sequence—a series of specific developmental malformations which can be attributed to a single cause.[4]

Signs and symptoms

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Micrognathism in Pierre Robin sequence
Cleft palate in Pierre Robin sequence

PRS is characterized by an unusually small mandible, posterior displacement or retraction of the tongue, and upper airway obstruction. Cleft palate (incomplete closure of the roof of the mouth) is present in the majority of patients. Hearing loss and speech difficulty are often associated with PRS.[citation needed]

Causes

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Mechanical basis

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The physical craniofacial deformities of PRS may be the result of a mechanical problem in which intrauterine growth of certain facial structures is restricted, or mandibular positioning is altered.[4] One theory for the etiology of PRS is that, early in the first trimester of gestation, some mechanical factor causes the neck to be abnormally flexed such that the tip of the mandible becomes compressed against the sternoclavicular joint. This compression of the chin interferes with development of the body of the mandible, resulting in micrognathia. The concave space formed by the body of the hypoplastic mandible is too small to accommodate the tongue, which continues to grow unimpeded. With nowhere else to go, the base of the tongue is downwardly displaced, which causes the tip of the tongue to be interposed between the left and right palatal shelves. This in turn may result in failure of the left and right palatal shelves to fuse in the midline to form the hard palate.[1] This condition manifests as a cleft palate. Later in gestation (at around 12 to 14 weeks), extension of the neck of the fetus releases the pressure on the mandible, allowing it to grow normally from this point forward. At birth, however, the mandible is still much smaller (hypoplastic) than it would have been with normal development. After the child is born, the mandible continues to grow until the child reaches maturity.[citation needed]

Genetic basis

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Alternatively, PRS may also be caused by a genetic disorder. In the case of PRS which is due to a genetic disorder, a hereditary basis has been postulated, but it usually occurs due to a de-novo mutation. Specifically, mutations at chromosome 2 (possibly at the GAD1 gene), chromosome 4, chromosome 11 (possibly at the PVRL1 gene), or chromosome 17 (possibly at the SOX9 gene or the KCNJ2 gene) have all been implicated in PRS.[5] Some evidence suggests that genetic dysregulation of the SOX9 gene (which encodes the SOX-9 transcription factor) and/or the KCNJ2 gene (which encodes the Kir2.1 inward-rectifier potassium channel) impairs the development of certain facial structures, which can lead to PRS.[6][7]

PRS may occur in isolation, but it is often part of an underlying disorder or syndrome.[8] Disorders associated with PRS include Stickler syndrome, DiGeorge syndrome, fetal alcohol syndrome, Treacher Collins syndrome, and Patau syndrome.[9]

Diagnosis

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PRS is generally diagnosed clinically shortly after birth. The infant usually has respiratory difficulty, especially when supine. The palatal cleft is often U-shaped and wider than that observed in other people with cleft palate.[citation needed]

Management

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The goals of treatment in infants with PRS focus upon breathing and feeding, and optimizing growth and nutrition despite the predisposition for breathing difficulties. If there is evidence of airway obstruction (snorty breathing, apnea, difficulty taking a breath, or drops in oxygen), then the infant should be placed in the sidelying or prone position, which helps bring the tongue base forward in many children. One study of 60 infants with PRS found that 63% of infants responded to prone positioning.[10] Fifty-three percent of the infants in this study required some form of feeding assistance, either nasogastric tube or gastrostomy tube feedings (feeding directly into the stomach). In a separate study of 115 children with the clinical diagnosis of PRS managed at two different hospitals in Boston,[11] respiratory distress was managed successfully in 56% without an operation (either by prone positioning, short-term intubation, or placement of a nasopharyngeal airway). In this study, gastrostomy tube feeding were placed in 42% of these infants due to feeding difficulties.[citation needed]

Gastroesophageal reflux (GERD) seems to be more prevalent in children with PRS.[12] Because reflux of acidic contents in the posterior pharynx and upper airway can intensify the symptoms of PRS, specifically by worsening airway obstruction, it is important to maximize treatment for GER in children with PRS and reflux symptoms. Treatment may include upright positioning on a wedge (a tucker sling may be needed if the baby is in the prone position), small and frequent feedings (to minimize vomiting), and/or pharmacotherapy (such as proton pump inhibitors).[citation needed]

In nasopharyngeal cannulation (or placement of the nasopharyngeal airway or tube), the infant is fitted with a blunt-tipped length of surgical tubing (or an endotracheal tube fitted to the child), which is placed under direct visualization with a laryngoscope, being inserted into the nose and down the pharynx (or throat), ending just above the vocal cords. Surgical threads fitted through holes in the outside end of the tube are attached to the cheek with a special skin-like adhesive material called 'stomahesive', which is also wrapped around the outside end of the tube (but not over the opening at the end) to keep the tube in place. This tube or cannula, which itself acts as an airway, primarily acts as a sort of "splint" which maintains patency of the airway by keeping the tongue from falling back on the posterior pharyngeal wall and occluding the airway, therefore preventing airway obstruction, hypoxia and asphyxia. Nasopharyngeal airways are not available at every center; however, when available, nasopharyngeal cannulation should be favored over the other treatments mentioned in this article, as it is far less invasive; it allows the infant to feed without the further placement of a nasogastric tube. This treatment may be utilized for multiple months, until the jaw has grown enough so that the tongue assumes a more normal position in the mouth and airway (at birth, the jaws of some infants are so underdeveloped that only the tip of the tongue can be seen when viewed in the throat). Some institutions discharge the infant home with a nasopharyngeal tube in place.[13]

Distraction osteogenesis (DO), also known as "Mandibular Distraction," is employed to address the abnormal smallness of one or both jaws in patients with PRS. By enlarging the lower jaw, this procedure advances the tongue, preventing it from obstructing the upper airway. The DO process starts with a preoperative assessment, during which doctors use three-dimensional imaging to identify the parts of the patient's facial skeleton that need realignment and determine the required magnitude and direction of distraction. They then select the most suitable distraction device or, if necessary, have custom devices made. Whenever possible, intraoral devices are used.

DO surgery starts with an osteotomy (surgical division or sectioning of bone) followed by the distraction device being placed under the skin and across the osteotomy. A few days later, the two ends of the bone are very gradually pulled apart through continual adjustments that are made to the device by the parents at home. The adjustments are made by turning a small screw that protrudes through the skin, usually at a rate of 1 mm per day. This gradual distraction leads to formation of new bone between the two ends. After the process is complete, the osteotomy is allowed to heal over a period of six to eight weeks. A small second surgery is then performed to remove the device.

The cleft palate is generally repaired between the ages of 6½ months and 2 years by a plastic surgeon, an oromaxillofacial surgeon, or an otorhinolaryngologist (ENT surgeon). In many centres there is now a cleft lip and palate team comprising these specialties, as well as a coordinator, a speech and language therapist, an orthodontist, sometimes a psychologist or other mental health specialist, an audiologist, and nursing staff. The glossoptosis and micrognathism generally do not require surgery, as they improve to some extent unaided, though the mandibular arch remains significantly smaller than average. In some cases jaw distraction is needed to aid in breathing and feeding. Lip-tongue attachment is performed in some centres, though its efficacy has been recently questioned.

A cleft palate (PRS or not) makes it difficult for individuals to articulate speech sounds, which may be due to the physical nature of cleft palate or the hearing loss that is associated with the condition.[14] This is typically why a speech language pathologist and/or audiologist is involved with the patient. Hearing should be checked by an audiologist regularly and can be treated with hearing amplification such as hearing aids. Because middle ear effusion is found in many patients with PRS, tympanostomy (ventilation) tubes are often a treatment option.[15]

One study with children showed that patients with PRS displayed a moderate and severe hearing loss most frequently.[15] Planigraphs of temporal bones in these patients displayed an underdeveloped pneumatization of the mastoid bone in all PRS patients and in most patients with cleft palate (without PRS).[15] There were no abnormalities of the inner or middle ear anatomy in patients with PRS.[15]

Prognosis

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Children affected with PRS usually reach full development and size. However, it has been found internationally that children with PRS are often slightly below average size, raising concerns of incomplete development due to chronic hypoxia related to upper airway obstruction as well as lack of nutrition due to early feeding difficulties or the development of an oral aversion. However, the general prognosis is quite good once the initial breathing and feeding difficulties are overcome in infancy. Most PRS babies grow to lead a healthy and normal adult life.

The most important medical problems are difficulties in breathing and feeding. Affected infants very often need assistance with feeding, for example needing to stay in a lateral (on the side) or prone (on the tummy) position which helps bring the tongue forward and opens up the airway. Babies with a cleft palate will need a special cleft feeding device (such as the Haberman Feeder). Infants who are unable to take in enough calories by mouth to ensure growth may need supplementation with a nasogastric tube. This is related to the difficulty in forming a vacuum in the oral cavity related to the cleft palate, as well as to breathing difficulty related to the posterior position of the tongue. Given the breathing difficulties that some babies with PRS face, they may require more calories to grow (as working of breathing is somewhat like exercising for an infant). Infants, when moderately to severely affected, may occasionally need nasopharyngeal cannulation, or placement of a nasopharyngeal tube to bypass the airway obstruction at the base of the tongue. in some places, children are discharged home with a nasopharyngeal tube for a period of time, and parents are taught how to maintain the tube. Sometimes endotracheal intubation or tracheostomy may be indicated to overcome upper respiratory obstruction. In some centers, a tongue lip adhesion is performed to bring the tongue forward, effectively opening up the airway. Mandibular distraction can be effective by moving the jaw forward to overcome the upper airway obstruction caused by the posterior positioning of the tongue. Given that some children with PRS will have Stickler syndrome, it is important that children with PRS be evaluated by an optometrist or ophthalmologist. Because the retinal detachment that sometimes accompanies Stickler syndrome is a leading cause of blindness in children, it is very important to recognize this diagnosis.[citation needed]

Epidemiology

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The prevalence of PRS is estimated to be 1 in 5,400 to 14,000 people.[2][16]

Hearing loss has a higher incidence in those with cleft palate versus non-cleft palate. One study showed hearing loss in PRS at an average of 83%, versus an average of 60% of individuals with cleft without PRS.[17] Another study with children showed that hearing loss was found more frequently with PRS (73.3%) compared to those with cleft and no PRS (58.1%).[15] Hearing loss with PRS typically is a bilateral, conductive loss (affecting the outer/middle portion of the ear).[17]

History

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The condition is named for the French dental surgeon Pierre Robin.[18][19]

It is thought that Noel Rosa, one of the most famous and influential artists in the history of Brazilian music, had PRS,[20] although others claim that his sunken chin was the result of a forceps accident during childbirth.[21]

See also

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Notes

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References

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Sources

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pierre Robin sequence

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from Grokipedia
Pierre Robin sequence (PRS), also known as Pierre Robin syndrome, is a congenital craniofacial anomaly characterized by a triad of micrognathia (underdeveloped lower jaw), glossoptosis (posterior displacement of the tongue), and resultant upper airway obstruction, frequently associated with a cleft palate. This condition arises during fetal development when impaired mandibular growth displaces the tongue posteriorly, obstructing the airway and potentially interfering with palatal fusion, leading to a U-shaped cleft palate in up to 90% of cases. It occurs in approximately 1 in 8,500 to 14,000 newborns and can present as an isolated anomaly or as part of a broader genetic syndrome, with approximately 40–60% of cases being syndromic, such as Stickler syndrome (in about 47% of syndromic cases) or Treacher Collins syndrome. Infants with PRS often exhibit severe breathing difficulties shortly after birth, including episodes of apnea or , as well as feeding challenges due to the tongue's position blocking the oropharynx, which can lead to , , or chronic ear infections from . Diagnosis is primarily clinical, based on revealing the characteristic features, with prenatal detection possible via showing micrognathia; genetic testing may be recommended to identify underlying mutations, such as those near the gene on chromosome 17, which disrupt jaw development. Management is multidisciplinary and tailored to severity, beginning with conservative measures like prone positioning to alleviate airway obstruction, stenting, or (CPAP) for mild cases. In moderate to severe instances, surgical interventions such as tongue-lip adhesion, to lengthen the jaw, or cleft repair are employed, with tracheostomy reserved for life-threatening obstructions in about 10% of isolated cases. Early intervention is critical to prevent complications like or developmental delays, and while the jaw often catches up in growth by , long-term outcomes depend on whether PRS is isolated (with excellent prognosis and low mortality risk) or syndromic (with up to 16.6% overall mortality risk).

Clinical features

Characteristic triad

Pierre Robin sequence is characterized by a classic triad of abnormalities: micrognathia, or an underdeveloped with a small lower and recessed ; glossoptosis, the posterior displacement of the into the ; and resultant upper airway obstruction. A U-shaped cleft is frequently associated, often involving both the hard and . This triad forms the core diagnostic criteria, with micrognathia present in nearly all cases, glossoptosis in 70-85%, upper airway obstruction in most cases, and the associated cleft in 80-90%. The pathophysiological sequence begins with micrognathia, which develops due to impaired mandibular growth starting around the 7th week of , resulting in a smaller oral cavity. This causes the to be displaced posteriorly (glossoptosis) by approximately the 11th week, positioning it high in the oral cavity and mechanically obstructing the elevation and fusion of the shelves during embryonic formation between weeks 8 and 10. Consequently, the acts as a physical barrier, preventing normal midline fusion and leading to the characteristic U-shaped cleft , while also predisposing to upper airway obstruction. In newborns, the triad manifests with immediate clinical challenges, primarily severe airway compromise due to glossoptosis narrowing the oropharynx, resulting in symptoms such as , , intercostal retractions, apnea, and oxygen desaturations. Feeding difficulties are also prominent, as the and airway instability disrupt the suck-swallow-breathe coordination, increasing risks of aspiration and poor weight gain. The severity of the triad's impact varies widely, from mild cases where airway obstruction resolves spontaneously with mandibular growth and requires no intervention, to severe presentations involving life-threatening ventilatory failure, persistent desaturations, or necessitating urgent supportive measures. Approximately 70% of affected infants experience manageable obstruction with conservative positioning, while the remainder exhibit moderate to severe compromise, often assessed via metrics like the apnea-hypopnea index (AHI >5 events/hour indicating moderate severity).

Associated findings

In addition to the characteristic triad of micrognathia, glossoptosis, and upper airway obstruction, Pierre Robin sequence frequently presents with secondary oral and facial anomalies that contribute to functional challenges. A small oral cavity often results from the hypoplastic , limiting space for the and complicating oral intake. is a common of the underdeveloped , leading to long-term dental alignment issues. Ear anomalies, such as low-set or posteriorly rotated ears, are observed in syndromic cases, including those associated with or velocardiofacial syndrome. Eye abnormalities, including , have been documented in select presentations, particularly within syndromic contexts. Respiratory complications extend beyond initial airway obstruction and are prevalent in affected infants. commonly persists, with studies showing incomplete resolution in many cases following certain interventions, necessitating ongoing monitoring. Recurrent respiratory infections arise frequently due to aspiration from glossoptosis and dysfunction, increasing the risk of chronic issues. Other systemic findings often accompany Pierre Robin sequence, especially in non-isolated forms. is noted in syndromic variants, such as velocardiofacial syndrome, contributing to feeding difficulties and motor delays. Developmental delays occur more often in these cases, with neurodevelopmental impairment reported in up to 19% overall and 10% in isolated presentations, potentially linked to recurrent hypoxia. Cardiac anomalies, including ventricular septal defects, are associated with syndromes like velocardiofacial syndrome, elevating morbidity in complex cases. The presence of these associated findings typically signals syndromic involvement, which comprises 35-60% of Pierre Robin sequence cases depending on cohort studies, differentiating them from isolated occurrences through multisystem involvement.

Etiology

Developmental mechanisms

Pierre Robin sequence (PRS) primarily arises through mechanical processes during early fetal development, where primary disrupts normal orofacial . According to the mechanical theory, reduced mandibular growth in the first trimester positions the posteriorly (glossoptosis), obstructing the elevation and fusion of the palatal shelves and resulting in a U-shaped , as well as upper airway obstruction. This cascade begins with intrinsic delays in mandibular elongation, compounded by extrinsic forces, leading to the characteristic triad of micrognathia, glossoptosis, and . Mandibular development originates from neural crest cells that migrate to the first pharyngeal arch between weeks 4 and 6 of gestation, forming the cartilaginous framework for the lower jaw. By week 7, the mandible normally grows ventrally and inferiorly to accommodate tongue descent; in PRS, hypoplasia at this stage prevents this, causing the tongue to fill the oral cavity and block the nasopharynx. Palatal shelf elevation and midline fusion then fail between weeks 6 and 12, as the displaced tongue mechanically impedes apposition of the lateral palatine processes. Intrauterine constraints, such as oligohydramnios or multifetal gestation, further exacerbate micrognathia by limiting mandibular excursion and promoting molding forces on the fetal face. Isolated PRS, accounting for approximately 40 to 60 percent of cases, occurs sporadically without syndromic features and lacks clear etiologic triggers in most instances. Environmental influences, including maternal and exposure to teratogens, have been implicated as potential contributors to mandibular in these nonsyndromic forms. Animal models provide robust evidence for the mechanical , with studies in mice exhibiting mandibular defects (e.g., Prdm16 mutants) replicating of micrognathia-induced glossoptosis and secondary cleft palate. Experimental mandibular lengthening in these models, simulating , has been shown to avert palatal clefting and airway issues by restoring normal positioning during critical embryogenic windows. In contrast to isolated PRS, syndromic cases often involve genetic perturbations that amplify these mechanical disruptions.

Genetic and syndromic associations

Pierre Robin sequence (PRS) is associated with various genetic syndromes in approximately 40-60% of cases, with the remainder classified as isolated or nonsyndromic. The most common syndromic association is , accounting for up to 47% of syndromic PRS cases, caused by mutations in the COL2A1 gene on chromosome 12q13.11-q13.2, which encodes essential for cartilage formation. Other notable syndromes include , resulting from mutations in TCOF1 (5q13.1), POLR1C (6p21.1), or POLR1D (13q12.2) genes, and velocardiofacial syndrome due to a 22q11.2 microdeletion encompassing the TBX1 gene. These syndromes often disrupt cell migration and differentiation during early craniofacial development, leading to mandibular as a shared feature with PRS. In syndromic PRS, the genetic defects typically impair the proliferation or survival of neural crest-derived mesenchymal cells in the first , contributing to the micrognathia that secondarily causes glossoptosis and cleft . For instance, TCOF1 mutations in reduce ribosome biogenesis in neural crest cells, resulting in widespread craniofacial anomalies including those of PRS. Similarly, the 22q11.2 deletion affects TBX1, a critical for development, often leading to conotruncal heart defects alongside PRS features. Less common associations include (SOX9 mutations on 17q24.3-q25.1) and Marshall syndrome (also COL2A1-related), both involving skeletal and ocular manifestations. These genetic disruptions converge on a mechanical pathway where mandibular deficiency displaces the posteriorly, obstructing the airway. Isolated PRS, comprising 40-60% of cases, is usually sporadic but includes rare familial occurrences linked to specific mutations. Reported genes include , where regulatory element disruptions (e.g., deletions or point mutations) lead to altered expression affecting chondrogenesis and mandibular growth. Other implicated genes are KCNJ2 (17q24.2), associated with Andersen-Tawil syndrome features in some cases, BMPR1B (4q22.3), and (17p13.1), which encodes myosin heavy chain 3 and has been linked to distal arthrogryposis variants with PRS. Recent systematic reviews have identified additional genes associated with isolated PRS, including SLC39A11 and ZNF804B. Polygenic influences may contribute to susceptibility in nonsyndromic forms, though no single high-penetrance locus predominates. Inheritance patterns vary: most syndromic PRS follows autosomal dominant transmission, as seen in Stickler and Treacher Collins syndromes, with variable expressivity and penetrance. Velocardiofacial syndrome often arises from de novo 22q11.2 deletions, though parental mosaicism occurs rarely. Isolated PRS is predominantly sporadic, but autosomal recessive patterns have been reported in some familial clusters, potentially involving or MYH3. Early identification of syndromic associations has critical diagnostic implications, guiding multidisciplinary management and family counseling. , including chromosomal microarray analysis for copy number variants like 22q11.2 deletions and targeted sequencing panels for genes such as COL2A1, TCOF1, and , is recommended in all PRS cases to detect underlying etiologies. Whole may uncover novel variants in unresolved cases, enabling prognosis assessment for associated complications like or cardiac defects.

Diagnosis

Prenatal assessment

Prenatal assessment of Pierre Robin sequence (PRS) begins with routine fetal anomaly scans performed between 18 and 22 weeks of , which allow for the identification of key structural anomalies associated with the condition. These scans are standard in and may prompt referral to a fetal medicine specialist if risk factors such as a family history of craniofacial syndromes or other congenital anomalies are present. Early detection enables multidisciplinary planning, though postnatal confirmation is often required to assess the full clinical triad. Ultrasound is the primary modality for detecting PRS features, with micrognathia appearing as a small on sagittal profile views, quantified by an inferior facial angle less than 50° (below mean -2 SD). , resulting from impaired fetal swallowing due to glossoptosis, is a common associated finding observed in up to 60% of cases and serves as an indirect clue prompting further facial evaluation; associated findings may include chromosomal anomalies (e.g., 21 or 18 in ~10% of cases), warranting karyotyping. Visualization of a , particularly a posterior U-shaped cleft, becomes feasible in the second trimester using transvaginal or transperineal approaches, enhancing diagnostic specificity when combined with micrognathia. For more detailed evaluation, fetal (MRI) is recommended from 18 to 20 weeks in suspected cases, providing superior contrast to assess tongue position (glossoptosis) and potential airway obstruction without the acoustic shadowing limitations of . This advanced imaging helps differentiate isolated PRS from syndromic forms and informs severity grading. Despite these tools, prenatal diagnosis has limitations, including false negatives in mild or isolated micrognathia cases where mandibular size falls within borderline percentiles or cleft palate is not yet evident. Upon suspicion of PRS, comprehensive counseling should address variable prognosis—ranging from spontaneous resolution in mild cases to potential need for immediate neonatal interventions—and delivery planning, such as transfer to a tertiary center equipped for ex utero intrapartum treatment (EXIT) procedures in severe airway compromise scenarios.

Postnatal evaluation

Upon delivery, infants suspected of having Pierre Robin sequence undergo immediate postnatal to confirm the characteristic triad of micrognathia, glossoptosis, and upper airway obstruction, often building on any prenatal findings that suggested mandibular . The prioritizes assessing the degree of airway compromise and overall severity to guide initial care. Clinical examination begins with a thorough of the newborn's craniofacial features, including of mandibular size relative to normative values for to quantify micrognathia. inspection reveals the typical U-shaped cleft in approximately 90% of cases, while assessment of airway patency involves observing for signs of obstruction such as , retractions, or desaturation during crying or feeding; adaptations of the or direct visualization via nasopharyngoscopy may be used to evaluate tongue position and posterior displacement (glossoptosis). Imaging studies provide objective data to support the clinical findings and delineate airway anatomy. Lateral cephalometry measures mandibular length and retrognathia, often showing a shortened below the -2 standard deviation threshold. quantifies the apnea-hypopnea index to assess obstructive events, with severe cases exhibiting indices greater than 10 events per hour. Computed tomography (CT) or (MRI) offers three-dimensional visualization of the upper airway, identifying the level of obstruction and tongue-base contact with the posterior pharyngeal wall. A multidisciplinary team, including otolaryngologists (), geneticists, and neonatologists, collaborates to perform the evaluation and classify severity. Severity is graded using systems like the Robin Severity Score, which incorporates factors such as supplemental oxygen requirements, feeding tolerance (e.g., ability to maintain oral intake without aspiration), and respiratory distress levels, categorizing cases as mild (no intervention needed), moderate (positioning or monitoring), or severe (requiring advanced support). Differential diagnosis excludes isolated conditions mimicking the triad, such as (which presents with unilateral mandibular and ear anomalies) or neuromuscular disorders like congenital (characterized by and generalized weakness without primary craniofacial defects). and syndromic screening help distinguish isolated Pierre Robin sequence from associated syndromes.

Management

Airway and respiratory support

The initial of airway obstruction in infants with Pierre Robin sequence prioritizes non-surgical interventions to ensure adequate oxygenation and ventilation while minimizing risks associated with invasive procedures. These strategies aim to reposition the anteriorly and the airway, addressing the glossoptosis and micrognathia that cause obstruction. Close monitoring is essential to assess efficacy and guide escalation if needed. Positioning techniques form the cornerstone of conservative airway support, with prone or side-lying positions recommended to advance the forward and reduce posterior displacement into the . This approach can alleviate mild to moderate obstruction in many cases, often serving as the first-line intervention in neonatal intensive care settings. Nasopharyngeal prongs, such as nasopharyngeal airways, provide a temporary non-invasive stenting option by maintaining pharyngeal patency without requiring surgical intervention. For infants with moderate to severe obstruction, modalities like (CPAP) delivered via nasal masks or prongs effectively reduce upper airway collapse by providing positive pressure to keep the airway open. High-flow (HFNC) offers an alternative for milder cases or as a bridge to CPAP, delivering humidified oxygen flows that help stabilize the airway and improve respiratory effort. These methods have been shown to decrease the need for tracheostomy in select patients by improving and sleep quality. Ongoing monitoring of respiratory status is critical, utilizing to track levels and to assess end-tidal for detection. provides objective metrics, such as the obstructive apnea-hypopnea index (OAHI), with values exceeding 5 events per hour indicating significant obstruction warranting intensified support. These tools help determine response to interventions and criteria for escalation to more advanced care. Recent advances in non-surgical include custom orthodontic appliances, such as the Tubingen palatal plate or Stanford orthodontic airway plate, which mold the and reposition the to enhance airway patency over weeks to months. These represent a targeted, device-based approach that can facilitate weaning from ventilatory support in stable infants, promoting long-term respiratory independence.

Surgical interventions

Surgical interventions for Pierre Robin sequence (PRS) primarily target the structural anomalies causing airway obstruction and associated complications, with mandibular distraction osteogenesis (MDO) emerging as the preferred approach for severe cases. These procedures aim to elongate the , reposition the , and facilitate subsequent repairs like cleft palate closure, often performed in neonates or infants to avert long-term interventions such as tracheostomy. Mandibular distraction osteogenesis involves bilateral of the , typically via an extraoral Risdon incision with subperiosteal exposure and a near-complete vertical ramus , followed by placement of semiburied distraction devices. After a latency period of about 5 days, the devices are activated to achieve gradual lengthening at a rate of 1 mm per day until adequate mandibular advancement is reached, with removal occurring around 8 weeks post-distraction. Indications include severe airway obstruction, defined by showing an apnea-hypopnea index (AHI) of ≥20 or significant retention, particularly in neonates failing conservative management. Success rates for airway improvement range from 92% to 100%, with MDO avoiding tracheostomy in approximately 95% of cases and enabling decannulation in 80% of those previously intubated. Cleft palate repair in PRS patients is typically performed between 9 and 18 months of age, often delayed to allow mandibular growth and resolution of acute airway issues, with an optimal window around 11 to 12 months to minimize growth disturbances. Common techniques include the von Langenbeck palatoplasty, which uses bipedicled mucoperiosteal flaps for closure, and the Furlow double-opposing , which incorporates levator veli palatini muscle retropositioning for improved function and speech outcomes. These repairs face challenges in PRS due to the small oral cavity and retrognathia, potentially increasing operative complexity and risk of formation, though the Furlow technique has demonstrated superior speech results compared to von Langenbeck in cleft palate cases generally. Other procedures include tracheostomy for temporary in 5-10% of severe, non-responsive cases, and tongue-lip (TLA), which sutures the tongue to the lower lip to prevent posterior displacement but is now rarely used due to higher reoperation rates (22-45%) and preference for MDO. Tracheostomy carries significant morbidity, with serious complications in 43% of cases and a 0.7% mortality rate, while TLA achieves full oral feeding in about 70% but risks and abscesses. Outcomes from early MDO include reduced tracheostomy needs and improved feeding, with 87% achieving full oral intake, though complications occur in up to 34% of cases, including infections (most common, treated with antibiotics), injury, dental damage, scarring, and rare major issues like (9%). Relapse of mandibular position can occur, necessitating monitoring, but overall, MDO demonstrates lower long-term intervention rates compared to alternatives like TLA or tracheostomy.

Feeding and multidisciplinary care

Infants with Pierre Robin sequence (PRS) often face significant feeding challenges due to the posterior displacement of the tongue (glossoptosis) and micrognathia, which impair the ability to suck and coordinate swallowing with breathing. These difficulties can lead to inadequate nutrition, dehydration, and failure to thrive if not addressed promptly. Initial management typically involves positioning the infant prone or on their side to facilitate feeding, along with the use of specialized bottles or nipples that require less sucking effort, such as those with compressible reservoirs. In cases where oral feeding remains insufficient, temporary nasogastric tube supplementation is employed to ensure caloric intake, while severe or prolonged issues may necessitate gastrostomy tube placement to support growth. Speech and language development in children with PRS can be compromised by the associated cleft and anatomical abnormalities, often resulting in velopharyngeal insufficiency that affects articulation and . Early repair, typically performed around 9-12 months, plays a critical role in mitigating these delays by improving palatal function and facilitating better speech outcomes. Additionally, recurrent with effusion is prevalent, occurring in over 90% of cases with at least one episode, due to from the craniofacial anomalies, which can lead to in approximately 45% of affected children and further impact auditory processing and . Routine screenings, including and hearing tests starting in infancy, are essential to detect and manage these issues through interventions like tympanostomy tubes if necessary. A multidisciplinary team approach is fundamental to the holistic management of PRS, involving specialists such as neonatologists, speech-language pathologists, orthodontists, otolaryngologists, and psychologists to address the diverse needs of the child. Speech therapists focus on early intervention to support oral-motor skills and communication development, while orthodontists monitor jaw growth and dental alignment to prevent long-term . Psychologists contribute by evaluating cognitive and emotional development, and the team collectively oversees growth monitoring through regular anthropometric assessments and developmental screenings to identify delays promptly. Recent developments as of 2025 include the adoption of adaptable standardized stepwise approaches, such as the Adaptable Standardized Stepwise Approach (ASSA), which integrates early and multidisciplinary decision-making to standardize care and reduce variability in treatment outcomes. Long-term follow-up for children with PRS extends into pediatric and adolescent care, emphasizing neurodevelopmental surveillance given the elevated risk of impairments in and motor skills. This includes annual evaluations by the multidisciplinary team to track speech progress, hearing status, and nutritional status, with transitions to specialized clinics for ongoing orthodontic and psychological support. Addressing impacts, such as potential issues related to facial differences or speech challenges, involves family counseling and school-based interventions to promote and emotional .

Prognosis

Short-term outcomes

In infants with Pierre Robin sequence (PRS), short-term airway outcomes have improved significantly with modern multidisciplinary management, including mandibular distraction osteogenesis (MDO) and supportive measures. Approximately 95% of affected infants avoid tracheostomy altogether through conservative or surgical interventions, while decannulation rates following tracheostomy reach 97.6% with MDO, often within the first year of life. Airway-related mortality is very low (less than 1%) in isolated cases with contemporary care. Feeding success in the neonatal and early infantile period is closely tied to airway stabilization, with most infants transitioning to full oral feeds post-intervention. Nasogastric tube dependence decreases markedly after treatments like MDO or palatal appliances, with 75% of infants avoiding long-term gastrostomy tube placement, enabling adequate caloric intake and reducing aspiration risks. Early multidisciplinary support, including speech therapy and nutritional monitoring, facilitates this progression in the majority of cases. Growth outcomes during the first year show catch-up mandibular development particularly in isolated PRS, where and length Z-scores improve from initial deficits (e.g., from -1.17 to -0.44 by 12 months) following prompt interventions that prevent failure-to-thrive. Isolated cases generally exhibit better short-term resolution of airway and feeding issues compared to syndromic PRS, with no reported airway-related deaths in isolated cohorts versus higher risks in syndromic presentations due to associated anomalies. These differences underscore the influence of underlying on early functional recovery.

Long-term complications

Individuals with Pierre Robin sequence (PRS) often face ongoing craniofacial challenges beyond infancy, including persistent micrognathia that fails to fully resolve with conservative management alone. Studies indicate that approximately 39% of such patients require in or early adulthood, primarily for mandibular advancement to correct class II . Dental issues, such as crowding and , are also prevalent due to the underdeveloped , necessitating orthodontic interventions in many cases. Speech and language outcomes remain a significant concern, with velopharyngeal insufficiency commonly occurring after repair, resulting in hypernasality in 14-88% of patients depending on surgical technique and other factors. This condition affects articulation and resonance, often requiring secondary surgeries like pharyngoplasty in up to 20-30% of cases to improve velopharyngeal competence. Early multidisciplinary interventions, including , can mitigate some delays but do not eliminate the need for ongoing monitoring. In syndromic PRS, such as that associated with , patients exhibit elevated risks of (up to 47%) and vision impairments, including retinal detachments and cataracts. is more frequent in PRS-plus (non-syndromic with additional anomalies) and syndromic forms, where the majority (approximately 63%) and about one-third (35%), respectively, demonstrate mild to severe cognitive impairments, compared to near-normal functioning in isolated PRS. Psychosocially, adolescents with PRS may experience peer mockery and related to facial appearance, contributing to slightly reduced in domains like physical and social relationships, with depression symptoms noted in 19%. However, comprehensive multidisciplinary follow-up supports overall satisfactory , with most patients achieving good self-confidence and autonomy. Recent meta-analyses as of 2025 confirm high success rates (>90%) for MDO in tracheostomy avoidance or decannulation, further improving long-term prognosis.

Epidemiology

Incidence and prevalence

Pierre Robin sequence (PRS) is a rare congenital anomaly with a global incidence estimated at 1 in 8,500 to 14,000 live births. A comprehensive 2023 meta-analysis of 34 studies involving 2,722 cases reported a pooled birth of 9.5 per 100,000 live births (95% CI: 7.1–12.1), with individual study estimates ranging from 1.2 to 40.4 per 100,000 live births. This variability likely stems from differences in diagnostic criteria, study methodologies, and population demographics. Approximately 50% to 70% of PRS cases are isolated, meaning they occur without association with other syndromes or major anomalies, while the remainder are syndromic. For instance, European population-based data from the EUROCAT registry (1998–2017) indicated that 68.2% of 1,294 PRS cases were isolated, with a regional of 7.8 per 100,000 births for isolated cases (95% CI: 6.7–9.2). Regional variations exist, such as a higher rate of 12.5 per 100,000 births reported in based on national registry data from 2000–2019. The incidence of PRS has remained stable over recent decades, with no significant temporal trends observed in longitudinal studies spanning 10–20 years. Data from the early 2020s, including analyses of birth cohorts during and post-COVID-19, show no substantial changes in prevalence, consistent with findings from national and international birth defect registries like EUROCAT. However, advancements in prenatal imaging and screening may enhance early detection, potentially influencing future reported rates without altering underlying occurrence.

Risk factors and demographics

Pierre Robin sequence (PRS) is influenced by several maternal and environmental factors that may contribute to its development, though the exact mechanisms remain under investigation. greater than 35 years has been associated with an increased of PRS, with a of 1.26 (95% CI 1.05-1.51) for total cases and 1.33 (95% CI 1.00-1.64) for isolated cases, based on a large European population study. during the periconceptional period is linked to a modestly elevated , with an of 1.3 (95% CI 1.0-1.6) for PRS-related , and heavy (25+ cigarettes per day) showing a stronger association (OR 2.5, 95% CI 0.9-7.0). In contrast, low to moderate maternal alcohol consumption does not appear to significantly increase the . has been proposed as a potential contributor, though evidence is limited and primarily drawn from broader studies on orofacial clefts. Additionally, twinning and associated intrauterine crowding are noted factors, potentially restricting mandibular growth, with a higher incidence observed in twin pregnancies. may also play a role by limiting and development. Demographically, PRS shows no strong racial or ethnic , though some variation exists; for instance, it is more frequently diagnosed in non-Hispanic white populations compared to non-Hispanic Black or Asian groups, potentially reflecting diagnostic or reporting differences rather than true incidence disparities. Overall, males and females are affected equally. Syndromic forms of PRS occur at higher rates in populations with increased of associated genetic syndromes. Environmental exposures during pregnancy, such as valproic acid use for epilepsy management, are implicated in elevating the risk of craniofacial anomalies including PRS. Maternal infections during pregnancy have also been suggested as possible contributors, though specific associations with PRS require further confirmation. Familial recurrence in isolated PRS is relatively low, estimated at 2-3% for siblings or offspring, compared to higher rates in syndromic cases where underlying genetic conditions may increase inheritance risks up to 50% depending on the syndrome. The overall incidence of PRS, serving as context, is approximately 1 in 8,500 to 14,000 live births.

History

Initial description

Pierre Robin first described the condition that bears his name in a 1923 report published in the Bulletin de l'Académie de Médecine, titled "La chute de la base de la langue considérée comme une nouvelle cause de gêne dans la respiration nasopharyngée." In this seminal paper, Robin detailed clinical observations from cases of infants experiencing severe respiratory distress due to the posterior displacement of the tongue base, a phenomenon he termed glossoptosis. He emphasized the role of mandibular —later refined as micrognathia—as a primary structural abnormality that positioned the tongue abnormally, obstructing the nasopharyngeal airway and leading to life-threatening episodes of apnea and . These initial descriptions focused on isolated occurrences in otherwise healthy newborns, without immediate recognition of associated syndromic features. Robin's observations highlighted the acute challenges in the pre-antibiotic era, where infants with compromised airways were highly susceptible to secondary complications such as and upper respiratory infections, contributing to mortality rates exceeding 50% in early reported cases. Without modern supportive care, management relied on positional interventions like prone positioning to alleviate glossoptosis, but outcomes remained poor due to the lack of effective treatments and advanced respiratory support. This historical context underscored the urgency of early recognition, as untreated cases often progressed rapidly to fatal . The early terminology surrounding the condition sparked debate between labeling it a ""—implying a multifactorial —and a "," reflecting a predictable cascade of developmental anomalies. This distinction was clarified in the 1970s, with the term "anomalad" proposed by in 1976 to describe the patterned malformation as a initiated by mandibular deficiency, leading sequentially to glossoptosis and potential cleft formation. This conceptual shift emphasized the condition's mechanistic progression rather than a disparate set of symptoms, laying the groundwork for later understandings, including modern genetic insights into its .

Evolution of understanding

In the mid-20th century, the understanding of Pierre Robin sequence (PRS) began to expand beyond its initial description, with growing recognition of its frequent syndromic associations during the 1950s and 1960s. Researchers identified links to conditions such as , first delineated in 1965, which is the most common syndrome associated with PRS. By the 1970s, the terminology shifted from "syndrome" to "sequence" to reflect its developmental cascade rather than a single genetic etiology, a change proposed by in 1976 to emphasize the patterned malformation. During the 1980s and , embryological studies solidified the mechanical theory of PRS , positing that early mandibular leads to tongue displacement (glossoptosis) and secondary clefting due to physical obstruction , as evidenced by models and human fetal analyses from Poswillo's foundational work in the and subsequent refinements. This period also saw the introduction of mandibular (MDO) in the mid-1990s as a transformative treatment for severe airway obstruction, pioneered by McCarthy et al. in 1995, enabling gradual jaw lengthening to alleviate respiratory distress without immediate tracheostomy. The 2010s marked significant genetic advancements, with discoveries revealing the role of regulatory elements in PRS ; non-coding mutations distant from were linked to isolated PRS in a 2009 study, highlighting disruptions in cell migration during craniofacial development. Concurrently, prenatal improved through techniques, which enhanced detection of micrognathia and associated features like , achieving sensitivities up to 70% by the mid-2010s compared to traditional 2D imaging. Multidisciplinary protocols, integrating , otolaryngology, and , dramatically reduced mortality rates from historical figures of 20-30% in untreated severe cases to under 5% by the early 2020s, primarily through early and nutritional support. In the 2020s, focus has shifted toward long-term neurodevelopmental outcomes, with longitudinal studies showing that up to 30% of PRS children experience delays in and motor skills, often linked to syndromic forms or hypoxic episodes, underscoring the need for extended follow-up beyond infancy. Recent efforts as of 2025 include developing consensus protocols for and to standardize care across multidisciplinary teams, alongside advancements in prenatal such as four-section 2D sonography and enhanced 3D/4D techniques for earlier and more accurate detection.

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