title: Etiology and pathogenesis of robin sequence in a large Dutch cohort.
abstract: Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.|Department of Plastic and Reconstructive Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Basart
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht/ Wilhelmina Children's Hospital, Utrecht, Netherlands.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Paes
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Maas
authors.affiliation: Department of Clinical Genetics, Utrecht Medical Center/Wilhelmina Children's Hospital, Utrecht, Netherlands.
authors.forename: Marie-Jose H
authors.initials: MJ
authors.lastname: van den Boogaard
authors.affiliation: Department of Clinical Genetics, VU Medical Center Amsterdam, Netherlands.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht/ Wilhelmina Children's Hospital, Utrecht, Netherlands.
authors.forename: Corstiaan C
authors.initials: CC
authors.lastname: Breugem
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Jan Maarten
authors.initials: JM
authors.lastname: Cobben
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, VU Medical Center, Amsterdam, Netherlands.
authors.forename: J Peter W
authors.initials: JP
authors.lastname: Don Griot
authors.affiliation: Department of Clinical Genetics, VU Medical Center Amsterdam, Netherlands.
authors.forename: Augusta M A
authors.initials: AM
authors.lastname: Lachmeijer
authors.affiliation: Department of Clinical Genetics, Utrecht Medical Center/Wilhelmina Children's Hospital, Utrecht, Netherlands.
authors.forename: Klaske D
authors.initials: KD
authors.lastname: Lichtenbelt
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht/ Wilhelmina Children's Hospital, Utrecht, Netherlands.
authors.forename: Daan P F
authors.initials: DP
authors.lastname: van Nunen
authors.affiliation: Department of Plastic and Reconstructive Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Chantal M
authors.initials: CM
authors.lastname: van der Horst
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D000402:Airway Obstruction / Q000209:etiology / Q000473:pathology; D001168:Arthritis / Q000209:etiology / Q000473:pathology; D002972:Cleft Palate / Q000473:pathology; D003240:Connective Tissue Diseases / Q000209:etiology / Q000473:pathology; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000209:etiology / Q000473:pathology; D006801:Humans; D008297:Male; D008844:Micrognathism / Q000209:etiology / Q000473:pathology; D010855:Pierre Robin Syndrome / Q000209:etiology* / Q000473:pathology*; D012163:Retinal Detachment / Q000209:etiology / Q000473:pathology
keywords: cause; genetic diagnosis; intellectual disability; pathogenesis; robin sequence; stratification; syndrome; treatment