Microtia-Anotia

Description

Microtia-anotia (M-A) can occur either as an isolated defect or in association with other defects. Only in a minority of cases has a genetic or environmental cause been found; in these cases, M-A is usually part of a specific pattern of multiple congenital anomalies. For instance, M-A is an essential component of isotretinoin embryopathy (243440), is an important manifestation of thalidomide embryopathy, and can be part of the prenatal alcohol syndrome and maternal diabetes embryopathy. M-A occurs with a number of single gene disorders, such as Treacher Collins syndrome (154500), branchiotorenal/branchiootic syndromes (see 113650 and 602588), oculoauricular syndrome (612109), microtia with hearing impairment and cleft palate (612290), or chromosomal syndromes, such as trisomy 18. M-A also occurs as part of seemingly nonrandom patterns of multiple defects, such as Goldenhar syndrome (164210) (Mastroiacovo et al., 1995).

Alasti and Van Camp (2009) reviewed the genetics of microtia and microtia-associated syndromes and discussed their clinical aspects in relation to the causative genes. They stated that the estimated prevalence of microtia is 0.8 to 4.2 per 10,000 births, that it is more common in males, and that it can have a genetic or environmental predisposition.

Inheritance

Mastroiacovo et al. (1995) studied the epidemiology and genetics of microtia-anotia (M-A) using data collected from the Italian Multicenter Birth Defects Registry (IPIMC) from 1983 to 1992. Among 1,173,794 births, they identified 172 with M-A, a rate of 1.46/10,000; 38 of the 172 infants (22.1%) had anotia. Of the 172 infants, 114 (66.2%) had an isolated defect, 48 (27.9%) were multimalformed infants (MMI) with M-A, and 10 (5.8%) had a well defined syndrome. The frequency of bilateral defects among nonsyndromic cases was 12% compared to 50% of syndromic cases. Among the MMI, only holoprosencephaly was preferentially associated with M-A; 4 cases were observed versus 0.7 expected (p = 0.005). No geographic variation in the prevalence of nonsyndromic cases was observed nor was there evidence of time trends. Mothers with parity 1 had a higher risk of giving birth to an MMI with M-A. Mothers with insulin-dependent diabetes were at significantly higher risk for having a child with M-A. Mastroiacovo et al. (1995) suggested autosomal dominant inheritance with variable expression and incomplete penetrance 'in a proportion of cases,' or multifactorial etiology. Three cases had consanguineous parents, but there were no other affected sibs to support recessive inheritance.

Hussain et al. (2004) reported a pair of monozygotic male twins, both of whom had right microtia with an atretic external ear and an absent external auditory canal, without evidence of facial asymmetry or other dysmorphic features or abnormalities. The left pinna was normal in both.

Artunduaga et al. (2009) ascertained 13 monozygotic and 22 dizygotic twin pairs in which at least 1 sib had severe nonsyndromic microtia requiring surgical repair. The concordance rate for all auricular malformations was higher in monozygotic than in dizygotic twins (61.5% and 4.5%, respectively; odds ratio, 33.4 and p = 0.003), as was concordance for microtia (38.5% and 4.5%, respectively; OR, 12.6 and p = 0.029). Combining their data with 37 twin pairs with microtia reported in the literature, the 72 sets of twins showed significant differences in the concordance rate for monozygotic (26.3%) and dizygotic (2.9%) twins (OR, 11.5; p = 0.023). Artunduaga et al. (2009) concluded that there is a strong genetic contribution to malformations of the external ear, and that the data are consistent with either an incompletely penetrant germline mutation or somatic mutation with epigenetic events occurring early in embryogenesis.