Clinical, cytogenetic, and molecular outcomes in a series of 66 patients with Pierre Robin sequence and literature review: 22q11.2 deletion is less common than other chromosomal anomalies

Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.

The triad of micrognathia, glossoptosis, and resultant airway obstruction is known as Robin sequence (RS). Although RS is a well-recognized clinical entity, there is wide variability in the diagnosis and care of children born with RS. Systematic evaluations of treatments and clinical outcomes for children with RS are lacking despite the advances in clinical care over the past 20 years. We explore the pathogenesis, developmental and genetic models, morphology, and syndromes and malformations associated with RS. Current classification systems for RS do not account for the heterogeneity among infants with RS, and they do not allow for prediction of the optimal management course for an individual child. Although upper airway obstruction for some infants with RS can be treated adequately with positioning, other children may require a tracheostomy. Care must be customized for each patient with RS, and health care providers must understand the anatomy and mechanism of airway obstruction to develop an individualized treatment plan to improve breathing and achieve optimal growth and development. In this article we provide a comprehensive overview of evaluation strategies and therapeutic options for children born with RS. We also propose a conceptual treatment protocol to guide the provider who is caring for a child with RS.

To give an epidemiological description of the clinical entity given the name Pierre Robin sequence, defined by retro- and micrognathia, cleft palate, and respiratory distress and describe other malformations and possible intrauterine impairment. Using the inclusion criteria of micrognathia, cleft palate, and neonatal respiratory distress, a retrospective population-based study of all Danish live births during 1990 through 1999 were carried out. We found 50 children, 25 boys and 25 girls, fulfilling the inclusion criteria, giving an incidence of 1 in 14,000 live births. Two-thirds (n = 33) of the children had the classical U-shaped cleft palate. More than one-third (n = 19) had one or several other malformations, and in five patients the triad of Pierre Robin was a minor feature of a complex syndrome. The most common noncomplex syndrome was the Stickler syndrome found in 6 of the 50 patients. More than one-fourth (n = 17) had some kind of intrauterine impairment, with no specific obstetric diagnosis predominant. Consistent with this, the average birth weight was well below normal. Several authors have stated that the triad of Pierre Robin is not a nosological entity, in that it has diverse etiology and diverse pathogenesis. We conclude that the triad of Pierre Robin still can be regarded as a clinical entity, readily defined at birth, experiencing the same neonatal problems in varying degrees and hence the possibility of designing treatment protocols for later scientific evaluation.