Auriculocondylar Syndrome 1

A number sign (#) is used with this entry because of evidence that auriculocondylar syndrome-1 (ARCND1) is caused by heterozygous mutation in the GNAI3 gene (139370) on chromosome 1p13.

Description

Auriculocondylar syndrome (ARCND) is an autosomal dominant disorder of the first and second pharyngeal arches and is characterized by malformed ears (question mark ears), prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia (summary by Masotti et al., 2008).

Genetic Heterogeneity of Auriculocondylar Syndrome

Auriculocondylar syndrome-2 (ARCND2; 614669) is caused by mutation in the PLCB4 gene (600810) on chromosome 20p12.3-p12.2. ARCND3 (615706) is caused by mutation in the EDN1 gene (131240) on chromosome 6p24.

See also 612798 for isolated question mark ears.

Clinical Features

Uuspaa (1978) reported a mother and 2 sons with bilateral external ear malformations and hypoplastic mandible.

Jampol et al. (1998) described a family in which several individuals in at least 5 generations had prominent, malformed ears, abnormality of the temporomandibular joint and condyle of the mandible, and microstomia, but normal hearing and normal ossicles of the middle ear. The ear deformity was referred to as 'prominent, constricted ears.' This may be the same as that called 'question mark ear,' by Brodovsky and Westreich (1997). The question mark ear had been noted in 2 sibs with unaffected parents by Takato et al. (1989). In the kindred reported by Jampol et al. (1998), the ear deformity was present in the father of the propositus and in a paternal aunt and her daughter, a paternal uncle, the paternal grandmother, and the paternal grandmother's father, as well as the paternal grandmother's paternal grandmother. None of these affected relatives was known to have had other birth defects. When the propositus was examined at the age of 8 years, the prominent ears were described as narrowing at the junction of the lower third and upper two-thirds and had no antihelix. The mandible was prognathic with type III malocclusion. This anomaly is presumably inherited as an autosomal dominant.

Guion-Almeida et al. (1999) reported a patient with strikingly malformed ears, abnormalities of the condyle of the mandible, micrognathia, small mouth, and cleft uvula. The parents were nonconsanguineous, with normal phenotype and normal radiologic findings of the mandible and temporomandibular joint. The authors concluded that this patient may be affected with the condition reported by Jampol et al. (1998). They suggested that the absence of findings in the parents supports the possibility of a new mutation in this case.

Guion-Almeida et al. (2002) described several members with auriculocondylar syndrome in 3 generations of a family. At 5 months of age the proband had microstomia with severely limited opening of her mouth, marked micrognathia, glossoptosis, and low-set ears with atretic external auditory canals and constriction at the junction of the upper two-thirds and lower third of the pinna. A CT scan excluded abnormalities of the bones of the middle ear. X-ray films showed condylar agenesis. The proband's father had similar facial features and ears but also had a history of cleft palate and sensorineural hearing loss.

Guion-Almeida et al. (2002) compared the findings in reported patients with auriculocondylar syndrome with those in the mother and daughter reported by Erlich et al. (2000) as having the dysgnathia complex (202650). They concluded that the patients of Erlich et al. (2000) actually had auriculocondylar syndrome.

In a literature review of 14 patients, Storm et al. (2005) reported the most common clinical signs of ARCND: abnormalities of the TMJ/condyle (100%), ear constriction (96.8%), micrognathia (71%), abnormal palate (62.5%), prominent cheeks (57.1%), microstomia (51.9%), glossoptosis (45.5%), respiratory distress (36.4%), stenotic ear canals (30%), and hearing loss (21%). Some patients may need orthodontic treatment, speech therapy, or orthognathic surgery. Storm et al. (2005) noted that the phenotype is highly variable, even within families.

Nezarati and Aftimos (2007) reported a 26-year-old man, born of first-cousin parents, with severe micrognathia, absence of the upper portion of the helices, atresia of the external meatus and absence of the middle ear ossicles, mildly downslanting palpebral fissures, and a highly arched palate with a submucous cleft. The authors suggested that this constellation of findings might represent a more severe manifestation of the auriculocondylar syndrome or a previously undescribed syndrome.

McGowan et al. (2011) reported 9 ARCND patients from 6 families. Micrognathia, microstomia, and prominent cheeks were present in all of the patients, but there was a significant degree of phenotypic variability. Six patients, who all had the typical auricular deformities of ARCND, underwent imaging, and all had either mandibular hypoplasia or abnormalities of the mandibular condyle. Facial asymmetry was a common feature, occurring in 7 of the 9 patients. In addition, patients in this series had other clinical signs not previously reported in ARCND, including facial cleft and preauricular and cheek pits. Citing the delay in diagnosis of ARCND as well as the phenotypic spectrum of abnormalities observed in their series, McGowan et al. (2011) suggested that ARCND is largely unrecognized and might be more common than would appear from published reports.

Gordon et al. (2013) studied a father and daughter with ARCND. The daughter displayed asymmetric micrognathia, malocclusion, microstomia, and a notch between the lobe and helix of the right ear. She also displayed mildly hypoplastic first ribs on x-ray. Her father had normal ears but large cheeks and possible hypoplasia of the angle of the mandible. Mandibular x-rays were not available for the father.

Pathogenesis

Rieder et al. (2012) studied 8 probands with auriculocondylar syndrome and available affected relatives. In each case, mandibular ankylosis was progressive, of variable severity, and characterized by inconsistent fusion to the medial and lateral pterygoid plates. All cases demonstrated a similar phenotype, consisting of a lateral mandibular bony prominence with or without temporomandibular joint ankylosis, and had features consistent with classic ARCND. The anatomic features of these cases led Rieder et al. (2012) to hypothesize that the malformations observed in patients with ARCND are due to a homeotic transformation, with the mandible assuming a maxillary phenotype.

Mapping

After excluding 3 known loci associated with disorders of first and second branchial arches through segregation analysis, Masotti et al. (2008) conducted genomewide linkage analysis in 2 large families with auriculocondylar syndrome, 1 of which (family 'F2') was previously reported by Guion-Almeida et al. (2002). Masotti et al. (2008) obtained a maximum lod score of 3.01 on chromosome 1p21.1-q23.3 (at theta = 0.0) in family F2; haplotype reconstruction defined a 43-cM (60-Mb) critical region between D1S206 and D1S2878, which the authors stated contained at least 250 genes. This locus was not linked to the phenotype segregating in the other family, however, suggesting genetic heterogeneity for the disorder.

Molecular Genetics

By whole-exome sequencing followed by filtering of exome data, Rieder et al. (2012) identified a heterozygous missense mutation in the GNAI3 gene (139370.0001) on chromosome 1p13.3 in a mother and daughter with auriculocondylar syndrome, who were originally reported by Erlich et al. (2000), and in another unrelated ARCND proband. The unrelated proband inherited the mutation from her unaffected father, demonstrating incomplete penetrance. The mutation was not found in 10,758 control chromosomes.

Gordon et al. (2013) analyzed the GNAI3 and PLCB4 genes in 27 patients, including 8 with clinical ARCND, 5 with 'atypical' ARCND who were previously described by McGowan et al. (2011), 3 with isolated question mark ears (612798), 6 diagnosed with either oculoauriculovertebral syndrome (OAVS) or Goldenhar syndrome (see 164210), and 4 with nonsyndromic auricular dysplasia with or without mandibular dysplasia. In a female proband with ARCND and her affected father, a missense mutation was identified in the GNAI3 gene (S47R; 139370.0002). In addition, 7 mutations were found in the PLCB4 gene. Gordon et al. (2013) noted that of 15 reported mutation-positive ARCND patients, 12 (80%) had a mutation in PLCB4 and 3 (20%) had a mutation in GNAI3. Among the mutation-negative patients were the 5 probands with 'atypical' ARCND originally reported by McGowan et al. (2011) (cases 1, 3, 4a, 5, and 6a). Gordon et al. (2013) stated that none of these 5 probands exhibited the indentation or cleft between the helix and lobe that is characteristic of PLCB4/GNAI3 mutation-positive ARCND cases. They concluded that despite intrafamilial variation in severity, the PLCB4/GNAI3-related auricular phenotype is highly specific and distinguishable from other human ear dysplasias.