Developmental and genetic perspectives on Pierre Robin sequence

Abstract

Pierre Robin sequence (PRS) is a craniofacial anomaly comprising mandibular hypoplasia, cleft secondary palate and glossoptosis leading to life-threatening obstructive apnea and feeding difficulties during the neonatal period. The respiratory issues require careful management and in severe cases may require extended stays in neonatal intensive care units and surgical intervention such as lengthening the lower jaw or tracheotomy to relieve airway obstruction. These feeding and respiratory complications frequently continue well into childhood, affecting not only growth and development but also impacting on long term educational attainment. The diagnosis of PRS depends on readily recognizable clinical features but the phenotypic similarity of many PRS individuals conceals considerable etiological heterogeneity. Defects in the growth of the mandible sit at the core of PRS and the natural history of PRS can be classified into two major streams: primary defects of mandibular outgrowth and elongation and issues that are external to the mandibular skeleton but that secondarily impact on its growth. These altered developmental trajectories appear to be driven by a range of influences including defects in cartilage growth, neuromuscular function and fetal constraint. Various genetic and cytogenetic associations have been made with PRS and the diversity of these associations highlights the fact that there are numerous ways to arrive at this common phenotypic endpoint.

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

“…Here we present an animal model with 100% phenotype penetrance, ideal for the analysis of this developmental disorder with the ultimate goal of elucidating its pathogenesis and generating preventive approaches and/or early and more effective therapies. This is relevant from a clinical perspective because PRS in humans has a relatively high incidence of 1:8500-14,000 live births and it frequently leads to lifethreatening obstructive apnea and feeding difficulties during the neonatal period (Tan et al, 2013).…”

“…In humans, cleft palate due to mechanical interference with palatal shelf elevation by a malpositioned tongue and small jaw is clinically classified as Pierre Robin sequence or syndrome (PRS) (Rangeeth et al, 2011). Studies of human patients have shown that mutations in SATB2, SOX9, BMP2 and the collagens lead to PRS-like clefting (Melkoniemi et al, 2003;Tan et al, 2013). The etiology of PRS has also been associated with a range of syndromes and chromosomal anomalies plus extrinsic fetal deformational forces, but the developmental mechanisms causing this condition are unclear, in part because of the lack of an animal model (Tan et al, 2013).…”

Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate

“…For example, palatal elevation depends on mandibular elongation. 4 As the mandible elongates, the tongue is drawn forward and the palatal shelves are able to elevate and orientate horizontally. Therefore, the cleft palate can arise from primary defects of mandibular outgrowth, or from problems that are external to the mandibular skeleton but secondarily restrict its growth (eg, intrauterine constraint due to oligohydramnion).…”

“…Therefore, the cleft palate can arise from primary defects of mandibular outgrowth, or from problems that are external to the mandibular skeleton but secondarily restrict its growth (eg, intrauterine constraint due to oligohydramnion). 4 This triad of mandibular hypoplasia, glossoptosis and cleft secondary palate is referred to as Pierre-Robin sequence (PRS). Isolated PRS was found to be associated with variants in non-coding elements upstream of the SOX9 gene, 5 whereas common genetic causes for syndromic PRS include Stickler syndrome (COL2A1, COL11A1, COL11A2), Campomelic Dysplasia (SOX9), trisomy 18 and 22q11 microdeletion syndrome.…”

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

“…Clinically, it is referred to as the Pierre Robin sequence (PRS), which is comprised of mandibular hypoplasia (micrognathia or retrognathia), displaced tongue position, and cleft secondary palate (5). Previous studies from a few mutant mouse strains, including deficiencies in Hoxa2, Snail1/2, Prdm16, Alk2, Sox9, and Erk2, have shown that the cleft secondary palate resulting from the failed palatal elevation is a consequence of the physical obstruction by a malpositioned tongue (6 -12), partially mimicking the clefting of PRS in humans (2,13,14).…”