Congenital deformities of the outer ear, referred to as microtia, occur in about 1 out of every 9000 births and can be either unilateral (one-sided) or bilateral (both sides). Most cases are unilateral, and interestingly, the right ear is more frequently affected in these cases. Additionally, microtia occurs more frequently in males.
The condition is divided into four grades depending on the severity of the deformity. Syndromic forms of microtia are seen in individuals in whom microtia occurs together with other congenital abnormalities. Among the associated malformations in these syndromic cases are cleft lip or palate, kidney abnormalities, cardiac defects, and others, in addition to hearing loss.
Syndromes associated with microtia include the following:
- Oculo-auriculo-vertebral spectrum (which includes hemifacial microsomia aka Goldenhar radial defect syndrome
- Treacher Collins syndrome
- CHARGE association
- Nager syndrome
A new paper published online in the American Journal of Human Genetics reports the identification of a gene involved in an autosomal recessive form of microtia. Fatemeh Alasti, Guy Van Camp, and colleagues studied a consanguineous Iranian family in which four cases of bilateral microtia were seen in association with hearing impairment (prelingual onset), and partial cleft palate.
The authors performed linkage analysis and localized the disease gene to chromosome 7p between 7p14.3-p15.3. Further fine mapping revealed an identical homozygous region that was approximately 10MB in length and contained >100 genes. The authors chose to sequence genes from the HOXA gene cluster (HOX genes are homeobox genes which play a very important role in development). A DNA sequence change in HOXA2 causing an amino acid change (Q186K) in the HOXA2 protein was found in the homozygous haplotype in all affected individuals in the family and in heterozygous fashion in the unaffected parents. The authors demonstrated that this variant DNA sequence was absent from 231 Iranian and 109 Belgian control individuals (without microtia).
Although the collective evidence from this study regarding the involvement of HOXA2 in ear malformations is very solid, ultimately further proof will be necessary from the identification of additional microtia patients with HOXA2 mutations and/or solid functional analysis of the mutant Q186K HOXA2 protein.
It is difficult to speculate at this point about the percentage of autosomal recessive microtia that might be secondary to HOXA2 mutations. Most likely, this will prove to be a fairly genetically heterogeneous condition with involvement of other genes (including other homeobox genes) in some cases.
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