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Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex.

ABSTRACT: The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current understanding of PR phenotypes, the proposed pathogenetic processes underlying them, select genes associated with PR, and available animal models that could be used to better understand the genetic basis and phenotypic variation of PR.

SUBMITTER: Motch Perrine SM

PROVIDER: S-EPMC7768358 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex.

Motch Perrine Susan M SM Wu Meng M Holmes Greg G Bjork Bryan C BC Jabs Ethylin Wang EW Richtsmeier Joan T JT

Journal of developmental biology 20201205 4

The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current und ...[more]

PMID: 33291480

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BMPR1B mutation causes Pierre Robin sequence.

Project description:We investigated a large family with Pierre Robin sequence (PRS).This study aims to determine the genetic cause of PRS.The reciprocal translocation t(4;6)(q22;p21) was identified to be segregated with PRS in a three-generation family. Whole-genome sequencing and Sanger sequencing successfully detected breakpoints in the intragenic regions of BMRP1B and GRM4. We hypothesized that PRS in this family was caused by (i) haploinsufficiency for BMPR1B or (ii) a gain of function mechanism mediated by the BMPR1B-GRM4 fusion gene. In an unrelated family, we identified another BMPR1B-splicing mutation that co-segregated with PRS.We detected two BMPR1B mutations in two unrelated PRS families, suggesting that BMPR1B disruption is probably a cause of human PRS.GTG banding, comparative genomic hybridization, whole-genome sequencing, and Sanger sequencing were performed to identify the gene causing PRS.

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Pierre robin sequence and the pediatric dentist.

Project description:This article on the dental management of a neonate with Pierre Robin sequence describes the clinical and laboratory procedures for construction of a feeding plate due to the presence of a cleft palate. Emphasis has also been laid on a few literatures to describe medical complications associated with this condition. A 56-day-old neonate had been referred to the outpatient department with the complaint of difficulty in feeding, description, and management of which has been described in the case report.

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Genetic Mutations Associated with Pierre Robin Syndrome/Sequence: A Systematic Review.

Project description:Pierre Robin syndrome/sequence (PRS) is associated with a triad of symptoms that includes micrognathia, cleft palate, and glossoptosis that may lead to respiratory obstruction. The syndrome occurs in 2 forms: nonsyndromic PRS (nsPRS), and PRS associated with other syndromes (sPRS). Studies have shown varying genetic mutations associated with both nsPRS and sPRS. The present systematic review aims to provide a comprehensive collection of published literature reporting genetic mutations in PRS. Web of Science, PubMed, and Scopus were searched using the keywords: "Pierre Robin syndrome/sequence AND gene mutation." The search resulted in 208 articles, of which 93 were excluded as they were duplicates/irrelevant. The full-text assessment led to the further exclusion of 76 articles. From the remaining 39 articles included in the review, details of 324 cases were extracted. 56% of the cases were sPRS, and 22% of the cases were associated with other malformations and the remaining were nsPRS. Genetic mutations were noted in 30.9% of the 300 cases. Based on the review, SOX9 was found to be the most common gene associated with both nsPRS and sPRS. The gene mutation in sPRS was specific to the associated syndrome. Due to the lack of original studies, a quantitative analysis was not possible. Thus, future studies must focus on conducting large-scale cohort studies. Along with generating data on genetic mutation, future studies must also conduct pedigree analysis to assess potential familial inheritance, which in turn could provide valuable insights into the etiopathogenesis of PRS.

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Project description: Not available

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16p13.3 duplication associated with non-syndromic pierre robin sequence with incomplete penetrance.

Project description:BackgroundPierre Robin sequence (PRS) is a condition present at birth. It is characterized by micrognathia, cleft palate, upper airway obstruction, and feeding problems. Multiple etiologies including genetic defects have been documented in patients with syndromic, non-syndromic, and isolated PRS.Case presentationWe report a 4-year-old boy with a complex small supernumerary marker chromosome (sSMC) who had non-syndromic Pierre Robin sequence (PRS). The complex marker chromosome, der(14)t(14;16)(q11.2;p13.13), was initially identified by routine chromosomal analysis and subsequently characterized by array-comparative genomic hybridization (array CGH) and confirmed by fluorescence in situ hybridization (FISH). Clinical manifestations included micrognathia, U-type cleft palate, bilateral congenital ptosis, upslanted and small eyes, bilateral inguinal hernias, umbilical hernia, bilateral clubfoot, and short fingers and toes. To our best knowledge, this was the first case diagnosed with non-syndromic PRS associated with a complex sSMC, which involved a 3.8 Mb gain in the 14q11.2 region and an 11.8 Mb gain in the 16p13.13-pter region.ConclusionsWe suggest that the duplicated chromosome segment 16p13.3 possibly may be responsible for the phenotypes of our case and also may be a candidate locus of non-syndromic PRS. The duplicated CREBBP gene within chromosome 16p13.3 is associated with incomplete penetrance regarding the mandible development anomalies. Further studies of similar cases are needed to support our findings.

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Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2.

Project description:BackgroundThe Pierre Robin sequence (PRS), consisting of cleft palate, micrognathia and glossoptosis, can be seen as part of the phenotype in other Mendelian syndromes--for instance, campomelic dysplasia (CD) which is caused by SOX9 mutations--but the aetiology of non-syndromic PRS has not yet been unravelled.ObjectiveTo gain more insight into the aetiology of PRS by studying patients with PRS using genetic and cytogenetic methods.Methods10 unrelated patients with PRS were investigated by chromosome analyses and bacterial artificial chromosome arrays. A balanced translocation was found in one patient, and the breakpoints were mapped with fluorescence in situ hybridisation and Southern blot analysis. All patients were screened for SOX9 and KCNJ2 mutations, and in five of the patients expression analysis of SOX9 and KCNJ2 was carried out by quantitative real-time PCR.ResultsAn abnormal balanced karyotype 46,XX, t(2;17)(q23.3;q24.3) was identified in one patient with PRS and the 17q breakpoint was mapped to 1.13 Mb upstream of the transcription factor SOX9 and 800 kb downstream of the gene KCNJ2. Furthermore, a significantly reduced SOX9 and KCNJ2 mRNA expression was observed in patients with PRS.ConclusionOur findings suggest that non-syndromic PRS may be caused by both SOX9 and KCNJ2 dysregulation.

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Clinical and Molecular Characterisation of Children with Pierre Robin Sequence and Additional Anomalies.

Project description:Pierre Robin Sequence (PRS) is usually classified into syndromic and nonsyndromic groups, with a further subclassification of the nonsyndromic group into isolated PRS and PRS with additional anomalies (PRS-Plus). The aim of this research is to provide an accurate phenotypic characterisation of nonsyndromic PRS, specifically the PRS-Plus subgroup. We sought to examine the frequency of sequence variants in previously defined conserved noncoding elements (CNEs) in the putative enhancer region upstream of SOX9, the regulation of which has been associated with PRS phenotypes. We identified 141 children with nonsyndromic PRS at the Royal Children's Hospital, Melbourne from 1985 to 2012 using 2 databases. Clinical and demographic data were extracted by file review and children categorized as 'isolated PRS' or 'PRS-Plus'. A subset of children with PRS-Plus was selected for detailed phenotyping and DNA sequencing of the upstream SOX9 CNEs. We found 83 children with isolated PRS and 58 with PRS-Plus. The most common PRS-Plus malformations involved the musculoskeletal and ocular systems. The most common coexisting craniofacial malformation was choanal stenosis/atresia. We identified 10 children with a family history of PRS or cleft palate. We found a single nucleotide substitution in a putative GATA1-binding site in one patient, but it was inherited from his phenotypically unaffected mother. PRS-Plus represents a broad phenotypic spectrum with uncertain pathogenesis. Dysmorphology assessment by a clinical geneticist is recommended. SOX9 CNE sequence variants are rare in our cohort and are unlikely to play a significant role in the pathogenesis of PRS-Plus.

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A Giant Heart Tumor in Neonate with Clinical Signs of Pierre - Robin Syndrome.

Project description:Pierre Robin syndrome is a congenital condition of facial abnormalities in humans. The three main features are: cleft palate, retrognathia and glossoptosis. Rarely heart tumors are associated with syndromes, mostly are isolated.In this presentation we describe a 3-weeks-old girl with Pierre-Robin syndrome and giant left ventricle tumor, diagnosed initially by transthoracic echocardiography. The purpose of this report is to review the literature on the fetuses and neonates with cardiac tumors in an attempt to determine the various ways which cardiac tumors differ clinically and morphologically in this age group.

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A comprehensive scoring system in correlation with perioperative airway management for neonatal Pierre Robin Sequence.

Project description:To evaluate a comprehensive scoring system which combines clinical manifestations of Pierre Robin Sequence (PRS) including severity of breathing difficulties, body weight and preoperative Cormack-Lehane grade, for its correlation with perioperative PRS airway management decision.Forty PRS children were retrospectively recruited after surgery. Specialists examined all subjects and scored for clinical manifestations (1´ - 4´), weight gain (1´- 4´), dyspnea scores (1´- 4´), and Cormack-Lehane grade (1´- 4´). The correlation of the integrated scores and the necessity of endotracheal intubation or laryngeal mask application were analyzed. In addition, the score correlation with postoperative dyspnea and/or low pulse oxygen saturation (SPO2) levels after extubation was determined.In our study every individual patient had a score from 0´ to 16´, while the higher in the numbers represented higher risk of breathing difficulty. All patients with comprehensive scores <10 points underwent endotracheal intubation successfully. Patients scoring 10-12 points had an intubation success rate of 47%, whereas all patients scored >13 points required a laryngeal mask assisted airway management and were considered to have difficult airways. Dyspnea after extubation and postoperative low SPO2 occurred among patients who scored over 10 points.In PRS patients, preoperative weight gaining status and severity of dyspnea in combination with Cormack-Lehane classification provide a scoring system that could help to optimize airway management decisions such as endotracheal intubation or laryngeal mask airway placement and has the potential to predict postoperative dyspnea or low SPO2 levels.

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Conditional deletion of Bmp2 in cranial neural crest cells recapitulates Pierre Robin sequence in mice.

Project description:Bone morphogenetic protein (BMP) signaling plays a crucial role in the development of craniofacial organs. Mutations in numerous members of the BMP signaling pathway lead to several severe human syndromes, including Pierre Robin sequence (PRS) caused by heterozygous loss of BMP2. In this study, we generate mice carrying Bmp2-specific deletion in cranial neural crest cells using floxed Bmp2 and Wnt1-Cre alleles to mimic PRS in humans. Mutant mice exhibit severe PRS with a significantly reduced size of craniofacial bones, cleft palate, malformed tongue and micrognathia. Palate clefting is caused by the undescended tongue that prevents palatal shelf elevation. However, the tongue in Wnt1-Cre;Bmp2f/f mice does not exhibit altered rates of cell proliferation and apoptosis, suggesting contribution of extrinsic defects to the failure of tongue descent. Further studies revealed obvious reduction in cell proliferation and differentiation of osteogenic progenitors in the mandible of the mutants, attributing to the micrognathia phenotype. Our study illustrates the pathogenesis of PRS caused by Bmp2 mutation, highlights the crucial role of BMP2 in the development of craniofacial bones and emphasizes precise coordination in the morphogenesis of palate, tongue and mandible during embryonic development.

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