Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Mandibulofacial dysostosis Bauru type: Refining the phenotype.

Mandibulofacial dysostosis (MFD) Bauru type (OMIM 604830) is a rare genetic condition characterized mainly by malar hypoplasia, orofacial cleft, and micrognathia. Here, we describe the clinical and radiographic sings of 13 individuals (12 female and 1 male) from eight unrelated kindreds with MFD Bauru type, including four previously reported cases, treated at the Hospital for Rehabilitation of Craniofacial Anomalies. The clinical phenotype was characterized by severe underdevelopment of mandible, midface hypoplasia, orofacial cleft, bitemporal narrowing, mild upper eyelid down slanting, high nasal bridge, thick and everted lower lip, minor ears abnormalities, and hearing loss. Radiographic aspects included downslanting of zygomatic arch, maxillary hypoplasia, microretrognathia, hypoplastic mandibular condyles, and ectopic external auditory canal. Recurrence was observed in two of eight families and the affected distribution pattern was compatible with autosomal dominant inheritance in one and autosomal recessive in another, indicating possible genetic heterogeneity for this condition. Clinical and radiographic findings in this report contribute to the delineation of this rare MFD.

Targeted molecular investigation in patients within the clinical spectrum of Auriculocondylar syndrome.

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome.

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

An unusual presentation of oculoauriculovertebral spectrum with a Tessier 30 cleft: report on two cases.

Oculoauriculovertebral spectrum (OAVS, OMIM 164210) is a complex condition characterized by defects in aural, oral, and mandibular development. Other craniofacial and extracranial anomalies can be present. With the exception of the Tessier number 7 cleft, atypical clefting has rarely been reported in association with OAVS. Here, we report on two unrelated cases with a typical phenotype of OAVS and a Tessier 30 associated cleft. One of them also had other atypical facial clefts. We discuss the association between atypical facial clefts and OAVS.