Pierre Robin Sequence
Pierre Robin described a group of patients with cleft palate, micrognathia, and glossoptosis in 1923. The meticulous docu- mentation of the triad of findings led to the recognition of the sequence that bears his name. Pierre Robin sequence is estimat- ed to affect approximately 1 in 8500 births.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Sporadic in most instances
b. May be familial with autosomal dominant mode of inheritance
2. Genetic basis a. Isolated form
i. Genetic basis unknown
ii. A report of unbalanced t(2;21) with an interstitial deletion of 2q32.3-q33.2 provides a candidate Pierre Robin sequence locus in chromosomal region 2q32.3-q33.2
iii. A report of a family over three generations with isolated Pierre Robin sequence cosegre- gates with a balanced reciprocal t(2;17) (q24.1;q24.3), suggesting that the translocation has disrupted a putative gene or a regulatory element of one or both translocation break- points
b. Syndromic form: etiologically heterogeneous i. Monogenic
a) Stickler syndrome (common cause) b) Beckwith-Wiedemann syndrome c) Camptomelic syndrome
d) Cerebrocostomandibular syndrome e) Congenital myotonic dystrophy
f) Distal arthrogryposis-Robin syndrome g) Mandibulofacial dysostosis
h) Miller-Dieker syndrome i) Otopalatodigital syndrome II j) Robin-oligodactyly syndrome ii. Chromosomal
a) Del(22q) velocardiofacial syndrome (com- mon cause)
b) Del(4q) syndrome c) Del(6q) syndrome d) Dup(11q) syndrome iii. Teratogenic
a) Fetal alcohol syndrome b) Fetal hydantoin syndrome c) Fetal trimethadione syndrome iv. Deformation
a) Oligohydramnios
b) Uterine structural anomalies c) Amniotic band syndrome v. Disruption: amniotic band disruption
vi. Unknown cause:
a) CHARGE syndrome b) Femoral dysgenesis c) Moebius sequence d) Robin/amelia association
3. Pathogenetically and phenotypically variable (Robin sequences and complexes)
a. Malformation sequence based on intrinsic mandibular hypoplasia that prevents the normal descent of the tongue interfering with palatal fusion. For example:
i. Treacher-Collins syndrome ii. Del(22q) syndrome
b. Deformation sequence based on extrinsic mandibular hypoplasia caused by intrauterine constraint
i. Oligohydramnios (reduced amniotic fluid results in compression of the chin against the sternum restricting mandibular growth and impacting the tongue between the palatal shelves)
ii. Mandibular catch-up growth expected after birth when intrauterine deforming forces are no longer acting since micrognathia is based upon intra- uterine molding
c. Neurogenic hypotonia leading to lack of mandibular exercise
d. Connective tissue dysplasia: Stickler dysplasia complex e. Spondyloepiphyseal dysplasia congenita complex
CLINICAL FEATURES
1. Classic triads
a. Posterior, U-shaped cleft palate b. Micrognathia/retrognathia
c. Glossoptosis (observed tendency of the tongue to move posteriorly obstructing the oropharynx) 2. Pierre robin sequence using different criteria
a. Mandibular deficiency b. Cleft palate
c. Upper airway obstruction 3. Respiratory difficulty
a. Often the first signs causing concern relating to feeding b. May not necessarily be present at birth
c. Upper airway obstruction and apnea
i. Glossoptosis associated with retrognathia ii. Upper airway collapse secondary to:
a) Hypotonic pharynx b) Laryngomalacia c) Laryngeal cleft d) Laryngeal web
d. Complications of continuing airway obstruction i. Failure to thrive
ii. Pectus excavatum
iii. Decreased pulmonary function iv. Sudden death
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4. Failure to thrive 5. Developmental delay
a. Usually not present in isolated Robin sequence b. May be present depending on the underlying syndrome 6. Middle ear diseases associated with cleft palate
a. Otitis media (80%) b. Auricular anomalies (75%)
c. Hearing loss, mostly conductive (60%) 7. Cleft palate associated problems
a. Speech defects
b. Velopharyngeal insufficiency 8. “Catch-up growth” of the mandible
a. Normal mandibular growth in patients with Robin sequence secondary to mechanical constraint b. Deficient mandibular growth in patients with intrinsic
mandibular anomalies
9. Other signs and symptoms and associated anomalies depending on the underlying conditions
DIAGNOSTIC INVESTIGATIONS
1. Assess respiratory sounds with stethoscope during feeding and at rest
2. Monitor developmental milestone achievement
3. Pulse oximetry monitoring to document drops in oxygen saturation
4. Flexible fiber optic nasopharyngoscopy
a. To identify exact mechanism of upper airway obstruction b. To assess pharyngeal, palatal, lingual, and laryngeal morphology and function during feeding and swal- lowing
5. Identify the underlying cause of the micrognathia 6. Orthodontic assessment
7. Hearing assessment 8. Cephalometric radiographs
a. Deformation sequence i. Mandible
a) Short body b) Short ramus
c) Increased gonial angle d) Incomplete catch-up growth ii. Cranial base angle: decreased b. Treacher-Collin syndrome
i. Mandible a) Short body b) Short ramus c) Characteristic shape d) Severely affected growth ii. Cranial base angle: decreased c. Del(22q11.2) syndrome
i. Mandible a) Retrognathia
b) Essentially normal in shape ii. Cranial base angle: increased d. Stickler dysplasia complex
i. Mandible a) Short ramus
b) Antegonial notching of body ii. Cranial base angle: decreased
e. Spondyloepiphyseal dysplasia congenita complex:
short body of mandible
10. Chromosome analysis: del(22q11.2) 11. Molecular diagnosis
a. Treacher-Collins syndrome: mutations in TCOF1 b. Stickler dysplasia complex
i. Mutations in COL2A1 ii. Mutations in COL11A1
c. Spondyloepiphyseal dysplasia congenita complex:
mutations in COL2A1
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: rare unless Pierre Robin sequence is a part of a syndrome
b. Patient’s offspring: rare unless Pierre Robin sequence is a part of a syndrome
2. Prenatal diagnosis by ultrasonography demonstrating micrognathia/retrognathia and cleft palate
3. Management
a. Prone positioning of infants believed to help prevent the tongue and mandible from obstructing the airway, leading to generally improved oxygen saturation b. Nasogastric tube placement for early feeding c. Occupational therapy directed toward management of
the palatal abnormality
d. Surgical intervention for airway obstruction
i. Glossopexy to bring tongue forward and attach it to an anterior structure to prevent the tongue from falling back into the airway
ii. Tracheotomy needed only in cases where con- servative treatments fail
iii. Mandibular distraction involving surgical inci- sion of the mandible followed by the application of traction to stimulate new bone growth iv. Repair of cleft palate
e. Treat middle ear infections i. Antibiotics
ii. Placement of tympanostomy tubes f. Speech therapy
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Fig. 1. Three infants with typical Pierre Robin sequence.
