Pierre Robin Syndrome

Etiology

The etiology of PRS is typically separated into isolated and syndromic PRS. Non-syndromic PRS has been associated with mutations on chromosomes 2, 4, 11, or 17. Some evidence suggests SOX9 or KCNJ2 mutations (on chromosome 17) may affect the development of facial structures and cartilage development, leading to PRS.[2] Alternatively, syndromic PRS has been recently reported to account for 60% of PRS.[3] There have been 34 syndromes associated with syndromic PRS, the most common being Stickler syndrome.[4]

Associated Syndromes

Stickler syndrome is the most common syndrome associated with PRS. In one study, 47% of syndromic PRS patients were diagnosed with Stickler syndrome.[4] It is an autosomal dominant condition defined as a mutation of COL genes, affecting collagen formation. Clinical features include flat midface, epicanthal folds, retinal detachments, cataracts, joint hypermobility, and sensorineural hearing loss, in addition to the typical signs of PRS.[5]

Velocardiofacial syndrome is a 22q11 deletion syndrome or TBX1 gene resulting in abnormalities in heart, parathyroid, thymus, and facial development. Clinical features include long upper lip and philtrum, elongated face, slender digits, hypothyroidism, immune dysfunction, hearing loss, pulmonary atresia, ventricular septal defects (VSDs), and hypoplastic pulmonary arteries.[2]

Treacher Collins syndrome has mutations in TCOF1, POLR1C, and POLR1D genes. Clinical features include hypoplasia of zygomatic, maxillary, and mandibular bones, and anomalies of the temporomandibular joint (TMJ), cleft palate, and external ear.[5]

Epidemiology

Epidemiological data is sparse, but available evidence suggests that PRS affects approximately 1 in 8,500 to 1 in 14,000 newborns a year.[2]

Pathophysiology

Pierre Robin sequence (previously named Pierre Robin syndrome) is now correctly named a sequence because one initial malformation leads to a sequential chain of events causing the other anomalies. A syndrome, in contrast, is a set of anomalies that arise separately due to one underlying pathogenesis. In PRS, micrognathia is the first abnormality that leads to glossoptosis and, ultimately, airway obstruction and/or a cleft palate. The following are common theories behind the hypoplastic mandibular growth.

Mechanical Theory 

In the early first trimester, around the 7th week of gestation, the mandible typically grows ventrally and inferiorly. If mandibular growth is abnormal, the tongue is not able to follow the normal trajectory of growth and blocks the closure of the palatal cleft in the 11th week of gestation. The glossoptosis, due to abnormal mandibular growth, ultimately leads to upper airway obstruction.[5]

Neurological Maturation Theory

This theory proposes a delay in the neuromuscular development of the tongue, which in turn does not stimulate the mandible to grow appropriately or palatal shelves to fuse.[5]

Mandible Compression Theory

This theory proposes that external forces cause the fetal head to become flexed, compressing the mandible against the chest, rendering it unable to grow appropriately. This may be caused by multifetal gestation, uterine anomalies, or oligohydramnios. The tongue continues to grow normally and is ultimately displaced backward, causing potential obstruction of the upper airway. The tip of the tongue may also impede the fusion of the palatal shelves, leading to cleft palate.[5]

History and Physical

Micrognathia 

This is a clinical diagnosis of the underdeveloped mandible. This typically includes a shorter mandibular body length and a greater mandibular angle. Defined indexes for diagnosing micrognathia have been developed in the past. However, none have been useful in predicting patients who will experience respiratory problems.

Glossoptosis 

This is defined by the displacement of the base of the tongue towards the pharynx. There is a wide range of severity and therefore associated respiratory distress. There is no standard for diagnosing glossoptosis, but endoscopy and computed tomography (CT) imaging may be helpful in quantifying the level of obstruction present.

Airway Obstruction 

There is a wide range of clinical severity of airway obstruction, ranging from severe ventilatory compromise requiring intubation immediately after birth, to mild dysfunction not requiring any intervention. Clinical signs of airway obstruction may include abnormal breathing sounds, increased respiratory accessory muscle use, desaturations, difficulty feeding/swallowing, reflux, and aspiration. Long term signs of airway obstruction may include reduced weight gain, difficulty speaking, neurological deficits, and ultimately pulmonary hypertension and cor pulmonale. 

Cleft Palate 

While not one of the required triad of PRS, cleft palate is present in most cases. The most common type is a U-shaped cleft palate, though V-shaped have also been reported.[5]

Evaluation

During pregnancy, ultrasound findings of micrognathia raise concern for PRS.[1] Polyhydramnios may also be present if glossoptosis is significant enough to cause swallowing impairment.[1] Prenatal diagnosis is important for appropriate counseling of parents before delivery of expected short and long term complications and treatments for PRS. This also allows all team members to be prepared for intervention at delivery if needed, such as maternal-fetal medicine providers, neonatologists, pediatric anesthesia, and/or pediatric otolaryngologists. Alternatively, it allows the parents the option of terminating the pregnancy. Typically, presentations apparent on ultrasound during the prenatal period are more severe.[6] Amniocentesis with microarray should be offered to women with findings concerning for PRS, given its common association with genetic syndromes. Referral to a genetic counselor is also advised.

After birth, an initial evaluation in the delivery room is important to determine if the patient needs immediate airway intervention such as intubation or positive pressure ventilation.[5] There is no gold standard for evaluation and diagnosis of PRS. Continuous oxygen saturations help determine spontaneous desaturation, desaturations with feeding, sleep, and different positions. Polysomnography can be helpful in establishing the severity of obstructive apneic events and the need and timing of intervention. Nasoendoscopy or bronchoscopy can assess points of airway obstruction in the upper and lower respiratory tract. 

In newborns, assessment of feeding should be noted. Growth charts and weight gain should be utilized to determine if the infant needs nutritional/feeding support with a nasogastric tube.

Treatment / Management

Historically, cases of PRS have been classified into groups or grades based on severity. The most common classification system was developed by Cole et al. and reports grades 1-3 from mild to severe.[7] A new classification system by Li et al. describes a 4 group system to assist in the choice of intervention.[8] This system includes grade 0, a very mild form without respiratory or feeding dysfunction. 

Mild disease can often be treated using conservative management without surgery. This entails prone and lateral positioning to allow gravity to pull the tongue anteriorly and improve airway obstruction, resolving approximately 70% of cases of PRS.[9] Nasopharyngeal stenting has also been used as a temporary measure to keep the airway open, though special attention must be paid by parents for complications such as aspiration and obstruction of the tube. Continuous positive airway pressure (CPAP) is a useful intervention that has shown great benefit, but compliance is very difficult in this patient population. Preepiglottic baton plate (PEBP) have also been noted to decrease apneic events and improve weight gain in one study.[10]

The literature is very conflicted regarding the potential for catch up growth in the postnatal period. Some studies have shown that isolated PRS may reach normal mandibular growth in the years following birth, but others have reported persistently small mandibles at up to 5 years of age. There is good consensus, however, that syndromic PRS does not experience catch up growth of the mandible.[9]

More severe cases of PRS require surgical management. Syndromic PRS will typically require this treatment. It has been estimated that only approximately 10% of isolated PRS requires surgical management.[5] Surgical options include tongue-lip adhesion, mandibular distraction osteogenesis, and tracheostomy.(B3)

Tongue-lip adhesion is a procedure where the tongue is sutured to the mucous membrane and muscle of the lower lip to hold the tongue in an anterior position in an attempt to reduce the amount of airway obstruction. This is often employed in isolated PRS as a temporary measure while the mandible grows during the first few years of life. Complications include lacerations, dehiscence, Wharton’s duct injury, infection, and aspiration. 

Mandibular distraction osteogenesis is another surgical intervention that produces longer-term results. This procedure advances and elongates the jaw in 3 phases - latency, activation, and consolidation. Latency is the period of time after osteotomy, and before distraction begins with the rotation of an external device that elongates the distance between the bones at the site of the break. Consolidation is the time allowed for bone formation and healing at the site of the osteotomy. Complications include infection, osteomyelitis of the mandible, damage to the inferior alveolar nerve, bite deformities, and permanent dentition loss.[2][11]

Tracheostomy is a procedure where the trachea is directly cannulated through the anterior aspect of the neck. This is more likely to be performed on patients with syndromic PRS. This is also a good option for patients with airway obstruction in multiple areas. This remains the gold standard of treatment for airway protection.[2] Complications include infection, damage to the esophagus, damage to recurrent laryngeal nerve, blockages of the cannula, pneumothorax, pneumomediastinum, and longer intensive care unit (ICU) stays than other interventions.[11]

Differential Diagnosis

Many of the following conditions are associated with Pierre Robin sequence and may be present concurrently.

• Velocardiofacial syndrome
• DiGeorge syndrome 
• Stickler syndrome
• Treacher Collins syndrome
• CHARGE syndrome (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities)
• Fetal alcohol syndrome 
• Pediatric cleft lip and palate 
• Childhood sleep apnea

Prognosis

Obstructive episodes can lead to hypoxemia, hypoventilation, malnutrition, asphyxia, cor pulmonale, or even death. Patients with other anomalies or syndromic PRS have a higher mortality rate. A retrospective review of 181 infants was conducted in one study and found an overall mortality rate of 16.6%, but no deaths in isolated PRS. Mortality was associated with cardiac and central nervous system (CNS) anomalies or anomalies of two or more organ systems.[12]

Complications

The complications of Pierre Robin sequence are due to airway obstruction. Short term complications from airway obstruction include desaturations, difficulty feeding, and aspiration events. Long term complications may be attributed to hypoxic injury and inability to feed well. This may include cerebral impairment, pulmonary hypertension, cor pulmonale, and failure to thrive. Procedural complications relating to PRS are discussed in the treatment/management section. Early detection of PRS can help prevent long term complications of airway obstruction and hypoxemia.