Paediatrics (RCH) - Theses

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    Defining the phenotype of a cohort of children with non-syndromic Pierre Robin Sequence
    XU, JESSIE ( 2015)
    Background Pierre Robin Sequence (PRS) is a common craniofacial anomaly comprising of micrognathia, cleft palate, glossoptosis and upper airway obstruction. It is a condition which affects 1 in 6000 neonates, often resulting in airway and feeding difficulties. Although it is a well-known condition, many aspects about the diagnosis, aetiology and management of Pierre Robin Sequence are contentious or unknown. Specifically, the exact phenotypic spectrum of this condition has been poorly studied. The major aim of this Master of Surgery is to provide an accurate phenotypic characterisation of a large cohort of non-syndromic Pierre Robin Sequence patients. A retrospective review of diagnosis and management of this cohort was also performed, along with a preliminary investigation into the possible genetic aetiology of a subset of patients. Methods A cohort of 141 non-syndromic PRS patients managed at the Royal Children’s Hospital in Melbourne from 1985 to 2012 was identified by cross-referencing two clinical databases. A detailed review of each patient’s medical file was performed and patients were categorised into either “Isolated PRS” or “PRS-Plus” groups. A subset of patients with a family history of cleft and/or a musculoskeletal anomaly were selected for targeted DNA sequencing of the non-coding elements of SOX9 (chromosome 17), a potential candidate gene for non-syndromic PRS. Results Our cohort comprised 83 Isolated PRS patients and 58 PRS-Plus patients. In the PRS-Plus group, the most common malformations beyond the craniofacial region involved were the musculoskeletal and ocular systems, with choanal stenosis/atresia being the single most common coexisting condition. PRS-Plus patients were found to have worse outcomes at birth as well as during the neonatal period, with a higher proportion being born small-for-gestational-age, have failure to thrive and require surgical intervention for airway and feeding. No significant genetic mutations were identified in the non-coding elements of SOX9 in the subset of patients who had DNA sequencing. A single nucleotide substitution was identified in the GATA1 transcription factor binding site, however the functional significance of this variant is yet to be determined. Summary Pierre Robin Sequence is a phenotypically diverse condition which contains a wide spectrum of features far beyond what was initially described. The results of this study supports the existence of a “PRS Spectrum” ranging from the mildest isolated PRS patients to the more complex syndromic PRS patients. Patients with additional anomalies outside of the craniofacial system had poorer outcomes at birth and during the neonatal period. Further studies are required to determine whether these differences can be explained by underlying biological causes such as genetic mutations, or whether this is a result of inadequate initial management.