Robin sequence without cleft palate: Genetic diagnoses and management implications

Abstract

Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases (“syndromic” RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.

Associated anomalies in Pierre Robin sequence

“…In this study, anomalies of the cardiovascular system were observed in 18.4% of the cases of PRS with MCA. Similar figures were reported in other studies with a percentage of anomalies of the cardiovascular system varying from 12.1 (Weaver et al, 2022) to 75.0 (Hsieh et al, 1999) with variations for the ventricular septum defects from 24.3 in Indianapolis (Costa et al, 2014) to 50.0 in Strasbourg (this study) and for atrial septum defect from 16.4 in Europe (Santoro et al, 2021) to 40.0 in Denmark (Printzlau & Andersen, 2004). For the anomalies of the central nervous system, the percentages of reported anomalies varied from 6.2 in Denmark (Printzlau & Andersen, 2004) to 19.6 in Indianapolis (Costa et al, 2014) with variation for Arnold Chiari anomaly from 12.1 in Indianapolis (Costa et al, 2014) to 20.0 in Cincinnati (Weaver et al, 2022).…”

“…Similar figures were reported in other studies with a percentage of anomalies of the cardiovascular system varying from 12.1 (Weaver et al, 2022) to 75.0 (Hsieh et al, 1999) with variations for the ventricular septum defects from 24.3 in Indianapolis (Costa et al, 2014) to 50.0 in Strasbourg (this study) and for atrial septum defect from 16.4 in Europe (Santoro et al, 2021) to 40.0 in Denmark (Printzlau & Andersen, 2004). For the anomalies of the central nervous system, the percentages of reported anomalies varied from 6.2 in Denmark (Printzlau & Andersen, 2004) to 19.6 in Indianapolis (Costa et al, 2014) with variation for Arnold Chiari anomaly from 12.1 in Indianapolis (Costa et al, 2014) to 20.0 in Cincinnati (Weaver et al, 2022). For the musculoskeletal system, the percentages of anomalies reported varied from 11.2 in this series to 34.4 in Europe (Santoro et al, 2021) with variation for syndactyly from 6.8 in Europe (Santoro et al, 2021) to 27.3 in this series, for polydactyly from 2.8 in Europe (Santoro et al, 2021) to 9.1 in Strasbourg (This study) and for limb deficiency from 16.6 in Denmark (Printzlau & Andersen, 2004) to 27.3 in this series, for hypospadias from 5.2 in Europe (Santoro et al, 2021) to 100.0 in Denmark (Printzlau & Andersen, 2004) and in Stanford (Gomez-Ospina &…”

“…In the previously reported series the most common chromosomal abnormalities were also 22q11.2 deletion, 30 out of 170 cases (17.6%) of PRS with chromosomal anomalies reported in the literature were 22q11.2 deletion, with a percentage ranging from 10.0 in Indianapolis (Costa et al, 2014) to 100.0 in Denmark (Printzlau & Andersen, 2004) and in Oslo (Filip et al, 2015). Trisomy 21 and trisomy 18 were less frequent with a percentage ranging for trisomy 21 from 3.4 in Cincinatti (Weaver et al, 2022) to 10 in Indianapolis (Costa et al, 2014) and for trisomy 18 from 3.4 in Cincinatti (Weaver et al, 2022) to 50.0 in Taiwan (Hsieh et al, 1999). Gomez‐Ospina and Bernstein (2016) studied the cytogenetic and molecular outcomes in a series of 66 patients with PRS ascertained in Stanford, California and performed a literature review.…”

“…Many non‐chromosomal syndromes were reported to be associated with PRS including syndromes with identified genes (Basart et al, 2015; Costa et al, 2014; Gomez‐Ospina & Bernstein, 2016; Logjes et al, 2018; Weaver et al, 2022). The vast majority of reported cases were single cases reports with a few cases series.…”

Epidemiology of Robin sequence in the UK and Ireland: an active surveillance study

“…The aetiology of RS is not fully understood and is likely to be multifactorial, including genetic disposition and exposure to environmental risk factors during embryogenesis. Proposed exposures include methadone6 18–20 and cigarette smoking 21. Geographical differences in birth prevalence may relate to variation in genetic profiles and environmental exposures, or a ‘latitude gradient’ as has been identified for several other diseases 22–24.…”