Alternative titles; symbols
ORPHA: 141074;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q22.3 | Aural atresia, congenital | 607842 | Autosomal dominant | 3 | TSHZ1 | 614427 |
A number sign (#) is used with this entry because of evidence that congenital aural atresia (CAA) is caused by heterozygous mutation in the TSHZ1 gene (614427) on chromosome 18q22.
Altmann (1955) was the first to describe a congenital aural atresia (CAA) classification, which has been modified over the years (Cremers et al., 1988; Schuknecht, 1989; Jahrsdoerfer et al., 1992). In CAA type I, there is bony or fibrous atresia of the lateral part of the external auditory canal and an almost normal medial part and middle ear. CAA type II is the most frequent type and is characterized by partial or total aplasia of the external auditory canal. CAA type IIA involves an external auditory canal with either complete bony atresia of the medial part or partial aplasia that ends blindly in a fistula leading to a rudimentary tympanic membrane. CAA type IIB is characterized by bony stenosis of the total length of the external auditory canal. CAA type III involves bony atresia of the external auditory canal and a very small or absent middle-ear cavity (summary by Feenstra et al., 2011).
Feenstra et al. (2011) studied 2 unrelated families with congenital aural atresia due to point mutations in the TSHZ1 gene. In the first family, the mother had isolated congenital conductive hearing loss due to CAA type IIA, for which she underwent bilateral surgical treatment at 3 years of age. Her hearing declined slowly over the following decades, and she underwent placement of a bone-anchored hearing aid (BAHA) at age 42. Her affected monozygotic twin daughters, who both had CAA type IIA, each underwent canalplasty on one ear and BAHA placement on the other. In the second family, the proband was a 10-year-old boy in whom impaired speech and delayed language development were noticed at age 3 to 4 years; pure-tone audiometry at age 5 showed a 42-dB bilateral conductive hearing loss due to CAA type IIA, and the boy underwent BAHA placement. His unaffected mother, from whom he inherited the mutation, had no abnormalities of the external auditory canal or tympanic membrane and no hearing difficulties. None of the affected individuals in either family exhibited dysmorphic features or any other features associated with the 18q deletion syndrome.
After finding that mice with conditional deletion of the Tshz1 gene showed hypoplasia of the olfactory bulb and had severe olfactory deficits, Ragancokova et al. (2014) performed olfactory testing in the families with TSHZ1 point mutations reported by Feenstra et al. (2011). All 5 mutation carriers exhibited hyposmia, with substantial decreases in odor sensitivity and impaired odor discrimination compared to controls; however, odor identification did not differ significantly between patients and controls.
Congenital aural atresia is a rare anomaly, occurring in approximately 1 in 10,000 live births (Melnick et al., 1979).
Congenital aural atresia has been reported frequently in patients with chromosomal anomalies, especially terminal deletions starting at chromosome 18q23 (see chromosome 18q deletion syndrome, 601808). Veltman et al. (2003) stated that CAA occurs in approximately 66% of all patients who have a terminal deletion of 18q. They reported a series of 20 patients with CAA, of whom 18 had microscopically visible 18q deletions. The extent and nature of the chromosome 18 deletions were studied in detail by array-based comparative genomic hybridization. A critical region of 5 Mb on chromosome 18q22.3-q23 was deleted in all patients. Veltman et al. (2003) concluded that this region can be considered a candidate region for aural atresia.
The transmission pattern of congenital aural atresia in the patients reported by Feenstra et al. (2011) was consistent with autosomal dominant inheritance.
Feenstra et al. (2011) performed SNP-array analysis in affected individuals with syndromic congenital aural atresia from 2 families with 18q22.3-q23 microdeletions and found a 459-kb deletion overlap, a region containing a single known gene, TSHZ1. Sequencing of TSHZ1 in 6 sporadic and 5 familial patients with an isolated bilateral form of CAA type IIA and normally shaped pinnae revealed heterozygous loss-of-function mutations in a mother and 2 daughters (614427.0001) and in a boy and his unaffected mother (614427.0002). The mutation-positive individuals had no facial dysmorphism or other features associated with 18q deletion syndrome (see 601808). Whole-gene deletion in the remaining 7 patients was excluded by whole-genome array analysis, and screening of the TSHZ1 gene in a cohort of 24 individuals with a unilateral form of CAA type I, IIB, or III, 10 of whom also had mild to severe developmental malformation of the external ears (microtia or anotia), revealed no mutations, suggesting genetic heterogeneity.
Altmann, F. Congenital atresia of the ear in man and animals. Ann. Otol. Rhinol. Laryng. 64: 824-858, 1955. [PubMed: 13259384] [Full Text: https://doi.org/10.1177/000348945506400313]
Cremers, C. W. R. J., Teunissen, E., Marres, E. H. M. A. Classification of congenital aural atresia and results of reconstructive surgery. Adv. Otorhinolaryng. 40: 9-14, 1988. [PubMed: 3389235] [Full Text: https://doi.org/10.1159/000415666]
Feenstra, I., Vissers, L. E. L. M., Pennings, R. J. E., Nillessen, W., Pfundt, R., Kunst, H. P., Admiraal, R. J., Veltman, J. A., van Ravenswaaij-Arts, C. M. A., Brunner, H. G., Cremers, C. W. R. J. Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans. Am. J. Hum. Genet. 89: 813-819, 2011. [PubMed: 22152683] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.008]
Jahrsdoerfer, R. A., Yeakley, J. W., Aguilar, E. A., Cole, R. R., Gray, L. C. Grading system for the selection of patients with congenital aural atresia. Am. J. Otol. 13: 6-12, 1992. [PubMed: 1598988]
Melnick, M., Myrianthopoulos, N. C., Paul, N. W. External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig. Art. Ser. 15: 1-140, 1979. [PubMed: 393325]
Ragancokova, D., Rocca, E., Oonk, A. M. M., Schulz, H., Rohde, E., Bednarsch, J., Feenstra, I., Pennings, R. J. E., Wende, H., Garratt, A. N. TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction. J. Clin. Invest. 124: 1214-1227, 2014. Note: Erratum: J. Clin. Invest. 132: e163087, 2022. [PubMed: 24487590] [Full Text: https://doi.org/10.1172/JCI72466]
Schuknecht, H. F. Congenital aural atresia. Laryngoscope 99: 908-917, 1989. [PubMed: 2770382] [Full Text: https://doi.org/10.1288/00005537-198909000-00004]
Veltman, J. A., Jonkers, Y., Nuijten, I., Janssen, I., van der Vliet, W., Huys, E., Vermeesch, J., Van Buggenhout, G., Fryns, J.-P., Admiraal, R., Terhal, P., Lacombe, D., Geurts van Kessel, A., Smeets, D., Schoenmakers, E. F. P. M., van Ravenswaaij-Arts, C. M. Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am. J. Hum. Genet. 72: 1578-1584, 2003. [PubMed: 12740760] [Full Text: https://doi.org/10.1086/375695]