Auriculocondylar Syndrome 3

A number sign (#) is used with this entry because of evidence that auriculocondylar syndrome-3 (ARCND3) is caused by homozygous mutation in the EDN1 gene (131240) on chromosome 6p24. Heterozygous mutation in EDN1 causes isolated question mark ears (612798).

Description

Auriculocondylar syndrome (ARCND) is a rare craniofacial disorder involving first and second pharyngeal arch derivatives and includes the key features of micrognathia, temporomandibular joint and condyle anomalies, microstomia, prominent cheeks, and question mark ears (QMEs). QMEs consist of a defect between the lobe and the upper two-thirds of the pinna, ranging from a mild indentation in the helix to a complete cleft between the lobe and helix (summary by Gordon et al., 2013).

For a general phenotypic description and discussion of genetic heterogeneity of auriculocondylar syndrome, see ARCND1 (602483).

Clinical Features

Guion-Almeida et al. (2002) described a 9-year-old boy with auriculocondylar syndrome whose parents were consanguineous. He had characteristic ears, unique bilateral appendages emerging from the anterior tonsillar pillars almost into the tip of the normal uvula, and a hypoplastic mandibular condyle on x-ray films. He also had mild ptosis and mild developmental delay, which the authors noted was also present in the patient described by Priolo et al. (2000).

Gordon et al. (2013) studied a brother and sister ('case 10'), born to healthy first-cousin parents, who had auriculocondylar syndrome. The brother presented with bifid uvula, laryngeal cleft, short velum, retrognathia, a typical QME on the right, a severely dysmorphic left ear, and an aneurysm of the vein of Galen, while his sister displayed a left QME, over-folded helix on the right, glossoptosis, and mandibular hypoplasia requiring distraction. Gordon et al. (2013) restudied the consanguineous family originally reported by Gordon et al. (2013) and stated that the pedigree included 4 sibs, 3 affected and 1 unaffected. CT scan of the previously reported sister revealed hypoplasia of the mandibular ramus and a thickened zygomatic process of the right temporal bone. The previously unreported sister presented with micrognathia, QMEs, microstomia, full cheeks, several hamartomatous pedicles on the ventral surface of the tongue, bilateral paramedian submucosal cleft of the velum, and bifid uvula with adjacent ectopic tissue.

Molecular Genetics

In 2 affected sibs from a consanguineous family with auriculocondylar syndrome that was previously studied by Gordon et al. (2013) and found to be negative for mutation in the coding regions of the GNAI3 (139370), PLCB4 (600810), GNAQ (600998), and GNA11 (139313) genes and the catalytic domain exons of the PLCB3 gene (600230), Gordon et al. (2013) performed whole-exome sequencing and identified homozygosity for a missense mutation in the EDN1 gene (K91E; 131240.0002). The mutation was present in heterozygosity in the unaffected parents and an unaffected sib. Sanger sequencing of EDN1 in a 23-year-old man with auriculocondylar syndrome who was originally described by Guion-Almeida et al. (2002) (patient 2) revealed homozygosity for a missense mutation (P77H; 131240.0003); his unaffected mother was heterozygous for the mutation.