Auriculocondylar Syndrome 2

A number sign (#) is used with this entry because of evidence that auriculocondylar syndrome-2 (ARCND2) is caused by heterozygous or homozygous mutation in the PLCB4 gene (600810) on chromosome 20p12.

Description

Auriculocondylar syndrome (ARCND), also known as 'question-mark ear syndrome' or 'dysgnathia complex,' is an autosomal dominant craniofacial malformation syndrome characterized by highly variable mandibular anomalies, including mild to severe micrognathia, often with temporomandibular joint ankylosis, cleft palate, and a distinctive ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark. Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia (summary by Rieder et al., 2012).

For a discussion of genetic heterogeneity of auriculocondylar syndrome, see ARCND1 (602483).

Clinical Features

Storm et al. (2005) reported 20 individuals from 4 unrelated families with auriculocondylar syndrome. Common features in the probands included cupped ears with overfolding of the superior helices, a cleft at the junction of the lobule and the helix, and preauricular and postauricular tags. In 1 patient, the left lobule was completely separated from the remainder of the external ear and was attached to the skin inferior to the helix. Other common features included micrognathia, microstomia, and a round facial appearance with prominent cheeks. Two probands had low-set, posteriorly rotated ears, and 1 had absence of the mandibular condyle. One patient had ankylosis of the temporomandibular joint (TMJ) and a very posterior tongue overlying the more anterior larynx, requiring a permanent tracheostomy. All patients showed normal growth and development without hearing loss.

In a literature review of 14 patients, Storm et al. (2005) found that the most common clinical signs were 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.

Gerkes et al. (2008) reported a 4-week-old boy with question mark ears, postauricular tags, micrognathia, and a small mouth. The authors stated that review of the literature indicated that postauricular tags had not been described in other syndromes or as an isolated finding, in contrast to the more common preauricular tags. Gerkes et al. (2008) concluded that postauricular tags should be considered part of the primary question mark ear malformation.

Gordon et al. (2013) studied 8 ARCND probands with mutations in the PLCB4 gene (see MOLECULAR GENETICS). One was an Omani boy who presented with neonatal hypotonia, developmental delay, feeding difficulties, and upper airway obstruction. He was diagnosed with ARCND based on micrognathia, with hypoplastic mandibular ramus on CT scan, full cheeks, microstomia, difficulty opening his mouth, and low-set question mark ears. A skin tag anterior to the sternocleidomastoid muscle was believed to be a remnant of the completely detached left ear lobe. Another patient was a boy born to healthy second-cousin parents of Indian origin, who presented with typical features of ARCND, including micrognathia, microstomia, full cheeks, bilateral question mark ears, and a postauricular tag on the right ear. A CT scan demonstrated dysplastic condyles and shallow condylar fossae bilaterally. He also had a significantly enlarged penis with descended testes, bilateral hydroceles, and some hirsutism over his back. He had ongoing swallowing problems, with poor suck requiring a nasogastric tube and significant gastroesophageal reflux. Electromyography showed chronic neurogenic changes in the tongue suggestive of bulbar palsy. Sleep studies conducted due to recurrent profound apneic episodes showed central apnea to be more frequent than obstructive apnea. Gordon et al. (2013) also studied a 3-generation family segregating question mark ears in an autosomal dominant pattern; the proband and her paternal grandfather were bilaterally affected, whereas her father had only a right-sided deformity. Although the family had originally been reported by Shkalim et al. (2008) as representing isolated question mark ears (612798), Gordon et al. (2013) observed that the lower jaws of the proband and her father were mildly dysplastic, and that some degree of mandibular dysplasia may have been present in the paternal grandfather; however, permission was not granted to publish photographs and the authors were unable to assess x-rays or mandibular scans in this family.

Gordon et al. (2013) reviewed reports of sleep studies performed in ARCND patients and found evidence for central apnea in some cases after distraction surgery, a procedure that they noted should reduce obstructive apnea events and unmask central events, if present.

Molecular Genetics

By whole-exome sequencing, Rieder et al. (2012) identified heterozygous missense mutations in the PLCB4 gene (600810.0001 and 600810.0002) in 2 probands with auriculocondylar syndrome. Subsequent Sanger sequencing of PLCB4 gene-coding regions containing the conserved catalytic site (exons 11-26) in the probands from 3 unrelated multigenerational ARCND pedigrees, including 2 families previously reported by Storm et al. (2005), revealed 3 more heterozygous missense mutations (600810.0003-600810.0005). The mutations segregated with disease in 2 of the families, whereas in the third family, there was evidence of phenotypic variability and apparent incomplete penetrance.

Gordon et al. (2013) analyzed the PLCB4 and GNAI3 (139370) 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. They identified 6 heterozygous missense mutations in the PLCB4 gene in 6 patients with ARCND (600810.0003, 600810.0004, and 600810.0006-600810.0009), including patients previously reported by Gerkes et al. (2008), Stuffken and Tuinzing (2008), and Greig et al. (2012), as well as in a proband previously described as having isolated question mark ears by Shkalim et al. (2008). A homozygous deletion in the PLCB4 gene (600810.0010) was identified in a proband from a consanguineous Indian family; the unaffected status of his heterozygous parents was cited by Gordon et al. (2013) as further support for a dominant-negative mechanism of ARCND-associated point mutations rather than haploinsufficiency. A missense mutation was identified in the GNAI3 gene (139370.0002) in 1 ARCND patient (ARCND1; 602483). 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 patients. They concluded that despite intrafamilial variation in severity, the PLCB4/GNAI3-associated auricular phenotype is highly specific and distinguishable from other human ear dysplasias.