OVERVIEW: What every practitioner needs to know

Are you sure your patient has Pierre Robin Sequence? What are the typical findings for this disease?

Pierre Robin sequence (PRS; also known as Robin sequence, Robin complex, Pierre Robin syndrome, Pierre Robin triad, or Robin anomalad) is a constellation of congenital abnormalities that includes glossoptosis, micrognathia, and cleft palate. PRS is sometimes associated with other congenital anomalies and syndromes, or can occur in isolation.

The cause of PRS is uncertain and is probably multifactorial; it is thought to result primarily from micrognathia during the 9th week of development. Children with PRS also frequently have airway obstruction, obstructive sleep apnea, and feeding problems, and often interventions including special positioning, alternate feeding strategies and even surgery are required. Initial treatment should be geared toward managing the airway and ensuring that the infant can feed.

PRS is characterized by:

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  • Micrognathia

  • Glossoptosis

  • Cleft palate – occurs in up to 90% of children with PRS

Some authors have included airway obstruction as the 4th component of PRS, but children with mild micrognathia may not have overt airway difficulty.

What other symptoms can be associated with Pierre Robin Sequence?

PRS is frequently associated with the following diseases/conditions:

  • Feeding difficulty

  • Gastroesophageal reflux

  • Airway obstruction

  • Obstructive sleep apnea/sleep disordered breathing

  • Hearing loss

What other disease/condition shares some of these symptoms?

  • Most Common

    Stickler syndrome

    Velocardiofacial syndrome (also known as DiGeorge syndrome or chromosome 22q11.2 deletion syndrome)

  • Less Common

    Treacher-Collins syndrome

    Marshall syndrome

    Auriculocondylar syndrome

    Fetal alcohol syndrome

    Craniofacial microsomia

    Goldenhar syndrome

    Weissenbacher-Zweymüller syndrome

    Other chromosomal abnormalities

What caused this disease to develop at this time?

Micrognathia is considered to be the inciting event that causes glossoptosis, and the posterior and superior positioning of the tongue then results in cleft palate. The mandible forms from the neural crest cells and mesoderm of the first branchial arch before the 10th week of gestation. When there is hypoplasia of the mandible, the tongue is posteriorly displaced and can cause a failure of the palatine shelves to fuse, resulting in cleft palate.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies are not required to confirm isolated PRS. However, since so many of these children have associated syndromes (up to 80%) genetic testing is usually recommended if a genetic syndrome is suspected, including the following:

Chromosome analysis

FISH for deletion of 22q11

DNA testing for mutations in collagen genes indicated in Stickler syndrome

Because airway compromise is a primary concern in PRS, a blood gas can be used to monitor for CO2 retention. Some authors have also suggested that serum electrolytes can be used to monitor CO2 over time.

Polysomnography is also useful, as is continuous daytime pulse oximetry to monitor for daytime obstruction.

Would imaging studies be helpful? If so, which ones?

  • Prenatal diagnosis via ultrasound is difficult and has low sensitivity.

  • As PRS is typically a diagnosis by physical exam, radiographic studies are not needed for diagnosis but may be helpful in evaluation of the airway and extent of micrognathia/glossoptosis. Studies are often required before surgical correction of the mandible or palate.

  • Plain films can show glossoptosis, bilateral symmetric hypoplasia of the mandible, and, if present, cleft palate

    However, this modality is rarely required as physical examination can confirm cleft palate and micrognathia. In addition, glossoptosis can be verified and characterized by an otolaryngologist with a flexible nasopharyngoscope without the need for ionizing radiation.

  • Computed tomography (CT) is considered the gold standard for defining the anatomy for congenital branchial arch syndromes such as PRS, and 3D CT scans are now commonly used to fully characterize the anatomy and airway prior to surgery.

    IV contrast may or may not be used.

    Again, these scans may not be required if the child is doing well and the diagnosis was confirmed by physical examination.

  • Upper GI or video fluoroscopic swallow studies with oral contrast may be recommended in children wtih feeding difficulty after a bedside swallow evaluation, which can include flexible endoscopic evaluation of swallowing (FEES). FEES is usually carried out with the assistance of both an otolaryngologist and a speech language pathologist.

If you are able to confirm that the patient has Pierre Robin Sequence, what treatment should be initiated?

Evaluation of airway obstruction and feeding should be carried out immediately. Flexible fiberoptic nasopharygoscopy should be performed by an otolaryngologist prior to intervention to evaluate the degree of glossoptosis and verify that no additional airway anomalies exist.

If further information is needed, laryngoscopy and bronchoscopy may be helpful in evaluation of patients with PRS, although these are infrequently needed. Performing a jaw thrust maneuver during endoscopy is helpful in evaluating whether advancement of the jaw would help in treatment of the patient. If required, respiratory support should be undertaken in order to provide sufficient oxygenation. Positioning alone is sometimes sufficient to decrease airway obstruction, and other techniques such as nasopharyngeal airways or intubation are usually considered before any surgical therapy.

A sleep study should be performed on all children with PRS, including those children who are not snoring, as more than half of the children with PRS and sleep apnea did not snore as newborns.

Feeding should also be evaluated. Special attention should be given to respiratory capability during feeding. If the patient is not getting adequate nutrition and/or food intake, food should be fortified or an intervention considered. Nasogastric tubes or gastrostomy can be helpful in patients who are unable to maintain appropriate intake.

Definitive treatment – If airway obstruction is persistent and unrelieved by positioning and/or nasopharyngeal airway, surgery is the next step to consider. Other causes of airway obstruction (such as hypotonia, central apnea, and laryngomalacia) should be considered and can also be seen in PRS; a sleep study and feeding evaluation should be performed prior to surgery. Surgical treatments include glossopexy/tongue-lip adhesion, mandibular distraction osteogenesis, and tracheotomy.

Counseling may include the need to monitor for airway and feeding difficulty along with a discussion of the natural course of jaw development and the likelihood for catch up growth in the first 2 years of life. If symptoms are mild, growth and prone positioning alone may be reasonable. However, moderate or severe airway obstruction or feeding difficulty will prompt a discussion of further options.

What are the adverse effects associated with each treatment option?

See Table I for treatment options and associated adverse effects.

Table I.
Reported frequency of success(%) Possible indications Potential Adverse Effects
NonsurgicalPositioning 49-77 Mild, intermittent airway obstruction Increased risk of sudden infant death syndrome (SIDS)
Nasopharyngeal airway 36-100 Single level of airway obstruction at tongue base Nasal stenosis; positional; may effect occlusion
Endotracheal intubation 43 Temporary airway stabilization Minimal in the short-term. Increased risk of subglottic stenosis in the medium to long-term.
SurgicalTongue-lip adhesion 33-100 Single level of airway obstruction at tongue base not responsive to nonsurgical interventions Dehiscence of adhesion; injury of salivary structures; minimal longterm effects on speech production and development except with late release; Concern for feeding issues unclear.
Mandible distraction osteogenesis 88-100 Single level of airway obstruction at tongue base not responsive to nonsurgical interventions Disruption of permanent teeth; dislodgement or failure of appliance; premature consolidation; nerve injury (inferior alveolar, marginal mandibular); pin-site/ wound infection; scarring; bony malunion
Tracheotomy 5-22 Definitive airway treatment option if >1 level of obstruction exists or if not a candidate for other interventions. Especially useful in children with other comorbidities including neurologic impairment. Air leak (pneumomediastinum); tracheitis; bleeding; obstruction; stomal granulation; accidental decannulation; tracheomalacia; subglottic stenosis

*Table adapted from PMID:21464188

What are the possible outcomes of Pierre Robin Sequence?

Prognosis: As PRS typically affects airway and feeding, success in managing these two aspects determines prognosis. Sometimes obstruction decreases with age due to catch-up growth of the mandible but PRS may require long-term surveillance and treatment in the outpatient setting. Special attention should be paid to cognitive development, orthodontic care, speech, and any signs of obstructive sleep apnea. Prognosis is good once feeding issues and airway obstruction are treated.

Depending on the severity of the patient’s airway obstruction and feeding difficulty, treatment options range from minimal risk of sudden infant death syndrome to permanent consequences, including dental issues, external scarring, dependent on the treatment chosen. However, the treatments are generally successful in ensuring normal development and growth of the child.

What causes this disease and how frequent is it?

  • Epidemiology of PRS:

    PRS is relatively uncommon (estimates range from 1:8500 to 1:20,000 live births) and can occur as an isolated condition (most common), within a syndrome, or with other associated anomalies.

    There is consistent evidence of modest risk associated with heavy maternal smoking and PRS with cleft palate. There are also case reports tying exposure to agents such as tamoxifen and isotretinoin in utero to PRS.

  • There is evidence suggesting a genetic basis for PRS. Candidate genes include SOX9, GAD67, KCNJ2, and PVRL1.

  • When PRS exists in the context of other syndromes and conditions, there are other suspected genes implicated, such as RBM10 in the X-linked TARP syndrome.

How do these pathogens/genes/exposures cause the disease?

This is a sequence that is a consequence of an initial insult that results in micrognathia. The causes of micrognathia development are unclear, but may be related to genetic and/or environmental stimuli.

What complications might you expect from the disease or treatment of the disease?

Hypoxia due to airway obstruction and inadequate nutrition due to feeding difficulties are the main complications caused by PRS. Complications from hypoxia range from poor growth to cognitive difficulty but are avoidable with proper treatment and follow-up. Complications due to treatment are varied and specific for each intervention; see Table I.

Are additional laboratory studies available; even some that are not widely available?

Not currently, but these may arise as the genetic basis of this disease is better understood.

How can Pierre Robin Sequence be prevented?

As the etiology of PRS is not fully understood, there are currently no prevention strategies that have been shown to reduce the risk of PRS beyond limiting exposure to maternal smoking, tamoxifen, and isotretinoin in utero.

Genetic Counseling:

Is commonly focused on identification of coexisting genetic syndromes, as 80% of cases may be part of a multiple anomaly syndrome.

In children with deletion of 22q11, recurrence risk has been reported to be 50% if one parent has the deletion.

For isolated Pierre Robin Sequence:

Risk of recurrence with one child with a cleft palate is 3-5%.

Risk of recurrence with two children with a cleft palate is 10-12%.

Affected children have a 3-5% chance of having a child with cleft palate themselves.

What is the evidence?

(Incidence of PRS described in 1985.)

(PRS and its relationship to other syndromes in a series of consecutive cases.)

(Obstructive sleep apnea and snoring in infants with PRS.)

(Fetal alcohol syndrome and its relationship to PRS.)

(Tongue-lip adhesion as a treatment for obstructive sleep apnea in patients with micrognathia.)

(Stickler syndrome, a syndrome tied to PRS, reviewed.)

(Velocardiofacial syndrome [also known as DiGeorge syndrome or chromosome 22q11.2 deletion syndrome], a syndrome tied to PRS, reviewed.)

(Marshall syndrome, a syndrome tied to PRS, reviewed.)

(Auriculocondylar syndrome, a syndrome tied to PRS, reviewed.)

(Craniofacial microsomia and Goldenhar syndromes, other syndromes linked to PRS, reviewed.)

(Weissenbacher-Zweymüller syndrome, a syndrome tied to PRS, reviewed.)

(Recent review of PRS diagnosis and management.)

(Syndromes of 1st/2nd branchial arches reviewed).

(Embryology of 1st/2nd branchial arch syndromes reviewed).

(Consistent evidence of modest risk associated with heavy maternal smoking and PRS with cleft palate.)

(Case reports tying exposure to agents such as tamoxifen and isotretinoin in utero to PRS.)

(Evidence suggesting a genetic basis for PRS. Candidate genes include SOX9, GAD67, KCNJ2, and PVRL1.)

(When PRS exists in the context of other syndromes and conditions, there are other suspected genes implicated, such as RBM10 in the X-linked TARP syndrome.)