Pierre Robin Sequence

Definitions

The Pierre Robin sequence (PRS) is a triad of congenital micrognathia (small lower jaw), glossoptosis (retraction of the tongue into the pharynx), and airway obstruction.

• Pierre Robin is a sequence, not a syndrome!
  • Sequence = a series of sequential developmental malformations produced by a single cause
  • Syndrome = a group of signs and symptoms that occur together and that underlie a particular abnormality or condition
• Sequence progression: micrognathia → glossoptosis → airway obstruction
• Presents in an isolated form or as part of another syndrome (syndromic PRS), such as:
  • Stickler syndrome
  • DiGeorge syndrome
  • Fetal alcohol spectrum disorder
  • Treacher-Collins syndrome: Patients with this syndrome also have mandibular hypoplasia but to different degrees than PRS.
  • Patau syndrome
  • Velocardiofacial syndrome
  • Beckwith-Wiedemann syndrome
  • CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities, and Ear anomalies) syndrome
  • Cleft lip and/or palate

Epidemiology and Etiology

Epidemiology: 1 in 8,500–14,000 live births in the United States

Etiology:

• Deletions in the loci 4p, 4q, 6q, and 11q have been associated with micrognathia, which is believed to be the first step in this sequence of malformations. 
• Duplications in loci 10q and 18q have also been linked to micrognathia. 
• Some external factors during intrauterine life (e.g., oligohydramnios) may play a role in micrognathia. 
• Isolated PRS is believed to arise sporadically via de novo mutations in the SOX9 gene/protein, which plays a critical role in skeletal development.
  • Familial cases of isolated PRS are rare and inherited autosomal dominantly.
• Syndromic PRS follows the same inheritance pattern as the associated syndrome.

Clinical Presentation

• Pierre Robin sequence consists of a triad:
  1. Micrognathia:
     • Hypoplastic abnormalities of the mandible
     • Radiographic findings of micrognathia are the basis of the diagnosis
  2. Glossoptosis: abnormal placement of the tongue in the posterior part of the mouth/pharynx
  3. Airway obstruction:
     • The abnormal position of the tongue is responsible for airway obstruction.
     • Severe airway obstruction may result in hypoxia, cerebral impairment, and failure to thrive. 
• Suprasternal retractions and the use of accessory muscles of respiration are common findings in infants with PRS, and are activated in an attempt to forcefully relieve the airway obstruction. 
• Pierre Robin sequence is also commonly associated with feeding difficulties, which lead to failure to thrive and malnutrition.
• Commonly, the glossoptosis can produce a U- or V-shaped cleft palate, as it impedes the fusion of the 2 palatal shelves.

Diagnosis and Management

Diagnosis

• Mainly based on the clinical assessment and radiographic findings of micrognathia
• Genetic testing (e.g., fluorescence in situ hybridization) is important to determine if PRS is isolated or associated with another syndrome.

Management

• Patients with PRS may be treated non-surgically. 
  • Placement in the prone or lateral position will resolve the airway obstruction in two-thirds of cases. 
  • A nasopharyngeal tube can be inserted to avoid frequent oxygen desaturation.
  • A nasogastric tube can be inserted for feeding assistance.
• Patients who do not respond to these conservative measures should undergo surgical procedures to relieve the airway obstruction. 
  • Tongue-lip adhesion
  • Distraction osteogenesis or mandibular distraction
  • Tracheostomy (in severe cases)
• Patients with cleft lip and/or palate may also require corrective surgical interventions.

Differential Diagnosis

The following conditions are differential diagnoses for isolated or syndromic Pierre Robin sequence:

• Velocardiofacial syndrome (Shprintzen-Goldberg syndrome): also called chromosome 22q11.2 deletion syndrome, a disorder presenting with congenital heart disease, palate abnormalities, immunologic dysfunction (e.g., autoimmune disease), hypocalcemia, endocrine conditions (e.g., growth hormone deficiency), gastrointestinal problems, feeding difficulties, kidney malformations, hearing loss, seizures, minor facial abnormalities, and learning disabilities. 
• Stickler syndrome: a rare connective tissue disorder that presents as myopia, retinal detachment, hearing loss, a characteristic facial appearance with mid-facial flatness, and joint pain. Affected individuals may also have features of PRS (micrognathia, glossoptosis, and cleft palate).
• Treacher-Collins syndrome (mandibulofacial dysostosis): a rare autosomal dominant condition characterized by significant craniofacial deformities and conductive hearing loss. Treacher-Collins syndrome is strictly a physical disease; it does not affect cognition or other spheres of development. 
• Beckwith-Wiedemann syndrome: a cancer-predisposition disorder caused by changes on chromosome 11p15.5. Associated features include above-average birth weight (large for gestational age), macrosomia, macroglossia, organomegaly, omphalocele, umbilical hernia, and/or diastasis recti.
• CHARGE syndrome: a rare genetic disorder in children that affects almost all body systems due to impaired gene expression as a result of inherited mutations.
• Childhood sleep apnea: a sleep disorder in which a pediatric patient’s breathing is partially or completely obstructed repeatedly during sleep. While adult sleep apnea usually presents with fatigue and daytime sleepiness and is due to obesity, childhood sleep apnea is more likely to present with behavioral disorders and is usually due to an enlargement of the adenoids and tonsils.
• DiGeorge syndrome: a condition caused by a microdeletion at location q11.2 of chromosome 22. DiGeorge syndrome is associated with defective development of the 3rd and 4th pharyngeal pouches, leading to thymic and parathyroid hypoplasia. Features also include congenital heart defects, characteristic facial features, cleft palate, frequent infections, developmental delay, learning problems, and psychiatric disorders.
• Fetal alcohol spectrum disorders: a group of conditions that can occur in neonates whose mothers consumed heavy amounts of alcohol during their pregnancy. Problems may include characteristic craniofacial changes, short height, low body weight, small head size, poor coordination, low intelligence, behavior problems, and problems with hearing or seeing. 
• Pectus excavatum: a congenital malformation of the rib cage featuring a sternal depression usually beginning at the manubrium and progressing down to the xiphoid process. Can occur sporadically or be associated with connective tissue disorders (e.g., Marfan syndrome).
• Cleft lip and palate: a congenital defect of the face that can include the upper lip and/or the palate and that can be unilateral, bilateral, complete, or incomplete. A cleft lip is caused by the failure of fusion of the maxillary prominence with the medial nasal prominence, while a cleft palate is caused by the failure of fusion of the palatine prominences. Presents as difficulty with speech development, feeding, swallowing, and tooth eruption, as well as visible malformation of the face.