Microtia, Hearing Impairment, And Cleft Palate

A number sign (#) is used with this entry because of evidence that microtia, hearing impairment, and cleft palate is caused by homozygous mutation in the HOXA2 gene (604685) on chromosome 7p15. One such family has been reported.

There is also evidence that microtia with or without hearing impairment is caused by heterozygous mutation in the HOXA2 gene.

Clinical Features

Alasti et al. (2008) examined 3 of 4 affected members of a consanguineous Iranian family who had bilateral microtia, mixed symmetric severe to profound hearing impairment, and partial cleft palate. The helix, tragus, and antitragus were seen in all patients. On otoscopy, the external auditory canal was short and severely narrowed bilaterally, appearing almost stenotic; the disease was categorized as microtia grade II. A partial cleft palate was found in all 3 patients, 1 of whom also had right-sided facial paresis. High-resolution CT scan of the ears confirmed severe narrowing in the cartilaginous part of the auditory canal and showed near-atresia in the bony portion, and in all 3 patients, the malformed ossicular chain appeared to be fixed by an incomplete atretic plate. The inner ear structures were normal in 2 patients, but the third had no inner ear structures on the left. MRI confirmed the left inner ear agenesis in that patient; the brain MRI of the patient with facial paresis was normal and hypoplasia of the right seventh cranial nerve was suspected, based on clinical examination. All 4 patients had prelingual onset of hearing impairment; audiometry revealed bilateral symmetric severe to profound mixed hearing impairment affecting all frequencies and leading to a flat audiometric shape.

Microtia with or without Hearing Impairment

Brown et al. (2013) studied a 3-generation family segregating autosomal dominant microtia with or without hearing loss. Five of the 7 affected family members were examined, all of whom exhibited small, malformed ears with a thickened helix and superficial postauricular sulcus. The external auditory canals were normally formed, and the palate was intact in all. Renal anatomy was normal in the 3 individuals who underwent imaging. Audiometry was performed in 3 of the 4 affected family members with hearing loss and showed mild to severe bilateral mixed hearing loss. Middle ear explorations previously performed on 2 affected individuals revealed abnormalities of the ossicular chain, with a thickened posterior crus and absent anterior crus and stapedial tendon in 1 patient, and a rigid ossicular chain in the other.

Piceci et al. (2017) reported a 5-generation nonconsanguineous Italian family segregating autosomal dominant nonsyndromic bilateral microtia. The male proband had overtly dysplastic ears showing decreased median longitudinal length in the presence of mildly sharp pointed superior portion of the helix, absent superior crus and triangular fossa of the antihelix, overfolded helix with an underdeveloped inferior crus, underdeveloped antitragus, serpiginous antihelix stem, deep incisura between tragus and antitragus with a laterally dislocated hypoplastic lobe. Other outer ear structures and canals were average. Otoacoustic emissions were bilaterally regular. No additional anomalies were found. The patient's mother and maternal grandfather had similar ear anomalies, and audiometric testing had unremarkable results. Extended family history disclosed dysplastic ears in a maternal second-degree aunt and the maternal great- and great-great-grandfathers.

Mapping

Alasti et al. (2008) performed genomewide linkage analysis in a consanguineous Iranian family segregating autosomal recessive microtia, hearing impairment, and cleft palate, and obtained a maximum multipoint lod score of 3.15 with markers D7S503, D7S629, and D7S2444 on chromosome 7p15.3-p14.3. Fine mapping revealed an identical homozygous haplotype in all 4 affected individuals, with a maximum multipoint lod score of 4.17 for all markers across the 13.7-cM interval delimited by D7S503 and D7S435.

Molecular Genetics

In a consanguineous Iranian family with microtia, hearing impairment, and cleft palate, Alasti et al. (2008) identified homozygosity for a missense mutation in the HOXA2 gene (604685.0001). The unaffected parents were heterozygous for the mutation, which was not found in 231 Iranian or 109 Belgian controls.

Microtia with or without Hearing Impairment

In a 3-generation family in which 7 members had microtia with or without hearing loss, Brown et al. (2013) identified a heterozygous nonsense mutation in HOXA2 (Q235X; 604685.0002) that segregated with disease and was not found in controls. Analysis of HOXA2 in 119 patients with unilateral or bilateral microtia from Colombia and Ecuador revealed 2 patients with unilateral microtia and a potentially pathogenic variant, but each variant was also present in 1 control.

In affected members of a 5-generation Italian family segregating isolated bilateral microtia without hearing loss, Piceci et al. (2017) identified a heterozygous nonsense mutation (E224X; 604685.0003) in the HOXA2 gene that segregated with the trait in the family. The mutation, which was found by sequencing the HOXA2 gene and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases.