title: Respiratory and gastrointestinal dysfunctions associated with auriculo-condylar syndrome and a homozygous PLCB4 loss-of-function mutation.
abstract: Auriculo-Condylar Syndrome (ACS) is a craniofacial malformation syndrome characterized by external ear anomalies, hypoplasia of the mandibular condyle, temporomandibular joint abnormalities, micrognathia, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The clinical diagnosis is usually suggested by the pathognomonic ear appearance ("question mark ear"), consisting of a variable degree of clefting between the helix and earlobe. The genetic mechanisms underlying ACS have recently been identified. Both autosomal dominant and recessive inheritance of mutations in phospholipase C, beta 4 (PLCB4) and endothelin 1 (EDN1) have been reported along with autosomal dominant mutations in guanine nucleotide-binding protein (G protein) α inhibiting activity polypeptide 3 (GNAI3). We report 6 years of follow-up of a child with a clinical phenotype consistent with ACS due to a homozygous frameshift mutation in PLCB4. The baby presented feeding difficulties associated with failure to thrive and a complex sleep-related respiratory disorder, characterized by central and obstructive apnoeas. Our observations of this case further delineate the phenotype of ACS associated with autosomal recessive PLCB4 loss-of-function mutations, underscoring gastrointestinal dysfunction and severe sleep-related breathing abnormalities as additional features when compared to patients with heterozygous mutations with a presumed dominant negative effect. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, Center for Rare Diseases, Catholic University, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Leoni
authors.affiliation: INSERM UMR 1163 and Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: Department of Neurosciences, Catholic University, Rome, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Della Marca
authors.affiliation: Department of Pediatrics, Center for Rare Diseases, Catholic University, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.affiliation: Department of Pediatrics, Center for Rare Diseases, Catholic University, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Onesimo
authors.affiliation: Department of Pediatrics, Center for Rare Diseases, Catholic University, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Perrino
authors.affiliation: Neuroradiology-Neurocenter Southern Switzerland, Lugano, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cianfoni
authors.affiliation: Department of Neuroscience and Neurorehabilitation, Speech Language Pathology Unit, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cerchiari
authors.affiliation: INSERM UMR 1163 and Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.|APHP, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Department of Pediatrics, Center for Rare Diseases, Catholic University, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
mesh_terms: D002648:Child; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities* / Q000503:physiopathology; D004427:Ear Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D059785:Karyotype; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D054799:Phospholipase C beta / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C518042:PLCB4 protein, human; D054799:Phospholipase C beta
keywords: PLCB4; auriculo-condylar syndrome; condylar hypoplasia; gastrointestinal dysfunctions; polysomnography; question mark ear; sleep apnoeas