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.

Health‐related quality of life in children with Robin sequence

“…RS is a very heterogenic entity. It can be seen isolated but is part of a syndrome in two‐third of patients [Basart et al, ]. There is currently limited insight in RS pathogenesis.…”

The ontogeny of Robin sequence

“…Interestingly, Ednra signaling is stimulated by endothelin 1 (Edn1), expressed in the overlying pharyngeal arch ectoderm (Clouthier et al, ). The EDN1 gene has been identified as the causative gene for recessive auriculocondylar syndrome (OMIM #615706) and dominant isolated question‐mark ears (OMIM #612798) (Gordon et al, ), which can present with features of RS, like micrognathia and glossoptosis (Basart et al, ). Clouthier et al () reported that several familial cases of auriculocondylar syndrome were very mildly affected and may present with isolated micrognathia, suggesting that some sporadic cases of more frequent mandibular dysplasias such as RS may actually have an underlying genetic cause in common with that of auriculocondylar syndrome.…”

“…Mutations in the SOX9‐regulated collagen genes COL2A1 , COL11A1 , and COL11A2 are associated with, respectively, Stickler syndrome type 1 (OMIM #108300), type 2 (OMIM #604841), and type 3 (OMIM #184840) and reported as a common cause of RS (Basart et al, ; Izumi et al, ). Stickler syndrome is characterized by ocular findings, mainly myopia, mild spondyloepiphyseal dysplasia, and early‐onset osteoarthritis and is the syndrome most commonly associated with RS, consistent with a Meckel's cartilage‐based etiology.…”

“…Mutations in the TBX1 ‐gene disturb normal migration of the cervical neural crest cells into the derivatives of the pharyngeal arches and cause the phenotypes Velocardiofacial syndrome (OMIM #192430) and DiGeorge syndrome (OMIM #188400). However, two recent studies that investigated large cohorts of RS‐patients on genetic diagnosis reported low frequencies of 22q11.2 deletions (1.5% and 1%), indicating the importance of genetic re‐evaluation of syndromic, isolated, and RS‐plus patients (Basart et al, ; Gomez‐Ospina & Bernstein, ).…”

MED13L loss‐of‐function variants in two patients with syndromic Pierre Robin sequence

“…Pierre Robin sequence (PRS), when defined by the triad of micrognathia, glossoptosis and posterior U‐shaped cleft palate, has an estimated prevalence of about 1:8,500–14,000 (Tan, Kilpatrick, & Farlie, ). It is a highly heterogeneous condition in which a clinical or molecular diagnosis can be made in 35–40% of cases (Basart et al, ; Holder‐Espinasse et al, ; Izumi, Konczal, Mitchell, & Jones, ), with Stickler syndrome, 22q11.2 deletion syndrome, Treacher Collins syndrome and teratogenic exposure reported as the four most common diagnoses (Holder‐Espinasse et al, ).…”