Pendred syndrome
A hereditary disorder most commonly characterized by profound bilateral hearing loss due to vestibular and cochlear abnormalities and also associated with adolescent development of a goiter, Pendred syndrome is estimated to account for up to 10% of all hereditary hearing loss [1].
This web page was produced as an assignment for the Genetics 564 course in the Spring 2014 semester at UW-Madison
Pendred syndrome
Pendred syndrome is a hearing loss spectrum disorder with a large range of severity of symptoms that varies between individuals. Pendred Syndrome is a heritable genetic disorder in which an individual are homozygous mutant copies of the SLC26A4 gene, historically referred to as the PDS gene in research and media. An affected individual inherits two copies of a disease-causing mutation in the SLC26A4 gene, one copy inherited from the mother and another mutant copy from the father [1]. A variety of different mutations in the SLC26A4 gene have been linked to Pendred syndrome, with specific mutations having higher prevalence in different populations as well as correlations with varying symptom severity. Pendrin is the transmembrane protein encoded by the SLC26A4 gene, that functions primarily in anion transport across the membranes of the cell. Expressed in a variety of epithelial cells of the inner ear, thyroid, and kidney the pendrin protein is integral to inner ear formation [2]. The altered protein form of pendrin encoded by homozygous recessive mutant SLC26A4 genes displays significant loss of function and decreased ability to perform the anion transportation function typical of pendrin. Inability to transport anions such as chloride, iodide, and bicarbonate across cell membranes results in abnormal concentrations of anions in epithelial cells [3,4].
The reduced functional capabilities of mutant pendrin result in severe enlargement of the membraneous vestibular labyrinth, an elaborate system of interconnected canals ands membranous sacs within the temporal bone that are filled with endolymph. The abnormally enlarged vestibular aqueduct (EVA) results in a malformation of the temporal bone, however the abnormal temporal bone formation is not the underlying cause of the hearing loss associated with Pendred syndrome [5]. EVA and subsequent temporal malformation, is however, an indication of abnormal enlargement of the endolymphatic duct epithelium in embryonic development [6].
Pendred syndrome is characterized by progressive, asymmetric, bilateral hearing loss. In other words, individuals with Pendred will typically experience an increasing severity of hearing loss as they age, and while individuals typically experience hearing impairment in both ears, one ear may be more profoundly affected than the other [7].
Identifiable by striking inner ear malformations of the endolymphatic duct, EVA, cochlear displasia, and a condition termed Mondini dysplasia (in which the dilated vestibular aqueduct is seen in association with dilation of the apical turn of the cochlea). Dilation of the vestibular aqueduct results in an abnormal one-and-a-half turn in the cochlea, instead of the normal two-and-a-half turns [8].
Extensive research conducted on phenotypic manifestation of SLC26A4 mutant homozygosity in individuals with a clinical diagnosis of Pendred Syndrome yielded consistent but not invariable results. Hearing loss incurred through the inheritance of mutant SLC26A4 varies in severity by individual. Results with variation in hearing loss other manifesting symptoms of Pendred Syndrome, including Modini dysplasia, bilateral dialted vestibular aqueduct, and goiter formation also vary by individual. While Pendred syndrome is estimated to account for up to 8% of congenital deafness, phenotypic heterogeneity however makes diagnosis difficult without definitive genetic test confirmation [9].
Pendred syndrome is characterized by progressive, asymmetric, bilateral hearing loss. In other words, individuals with Pendred will typically experience an increasing severity of hearing loss as they age, and while individuals typically experience hearing impairment in both ears, one ear may be more profoundly affected than the other [7].
Identifiable by striking inner ear malformations of the endolymphatic duct, EVA, cochlear displasia, and a condition termed Mondini dysplasia (in which the dilated vestibular aqueduct is seen in association with dilation of the apical turn of the cochlea). Dilation of the vestibular aqueduct results in an abnormal one-and-a-half turn in the cochlea, instead of the normal two-and-a-half turns [8].
Extensive research conducted on phenotypic manifestation of SLC26A4 mutant homozygosity in individuals with a clinical diagnosis of Pendred Syndrome yielded consistent but not invariable results. Hearing loss incurred through the inheritance of mutant SLC26A4 varies in severity by individual. Results with variation in hearing loss other manifesting symptoms of Pendred Syndrome, including Modini dysplasia, bilateral dialted vestibular aqueduct, and goiter formation also vary by individual. While Pendred syndrome is estimated to account for up to 8% of congenital deafness, phenotypic heterogeneity however makes diagnosis difficult without definitive genetic test confirmation [9].
Axial CT section of the petrous temporal bones at the level of the lateral semicircular canal and internal auditory meatus showing enlarged vestibular aqueduct (arrow)
Treatment
While the mutations in an individual's SLC26A4 gene cannot be normalized to alleviate the effects of Pendred syndrome, modern medical technology has rendered the symptoms of the disorder manageable. The primary symptom of congenital hearing loss can be combatted with hearing aids, cochlear implants, and treatment that involves the individual learning communication skills such as sign language and cued speech [8].
In a study evaluating hearing outcome in Pendred syndrome with cochlear implant recipients, researchers evaluated the anatomical, audiological, and surgical complications associated with Pendred and the hearing outcome of the cochlear device implantation [6]. Despite the difficulties of implantation due to the challenging phenotype associated with Pendred syndrome, including goiter, hearing loss, and inner-ear dysplasias the recipients of the cochlear implants all expressed satisfaction in their hearing rehabilitation following implantation.
SLC26A4
The SLC26A4 is located on the long arm of the 7th autosomal chromosome, in the 31st position. [7] The gene belongs to a family of genes termed solute carriers (SLC). The solute carrier gene family is made up of about 300 genes that encode for proteins that function in the transport of solutes into and out of the cell as well as transport between different components of the cell. SLC26A4 encodes the anion transporting protein pendrin.
Inheritance pattern
Pendred syndrome and the SLC26A4 mutations that encode for the mutant form of pendrin are inherited in an autosomal recessive pattern.
Genes that are not located on the sex chromosomes,like the SLC26A4 gene, are termed autosomal. As a recessive gene, in order for the syndrome to manifest a child needs have two copies of the mutant gene, one copy inherited from each parent. Therefore both parents of an afflicted individual must have at least one mutant copy of the gene. There is no gender preference in autosomal inheritance as the gene is not located on the sex chromosomes. A child receives one copy of the two copies of the autosomal gene in each parent's genome, therefore if a parent is heterozygous and has one mutant copy and one dominant copy there is a 50% chance the child will inherit the mutant allele from that parent.
Genes that are not located on the sex chromosomes,like the SLC26A4 gene, are termed autosomal. As a recessive gene, in order for the syndrome to manifest a child needs have two copies of the mutant gene, one copy inherited from each parent. Therefore both parents of an afflicted individual must have at least one mutant copy of the gene. There is no gender preference in autosomal inheritance as the gene is not located on the sex chromosomes. A child receives one copy of the two copies of the autosomal gene in each parent's genome, therefore if a parent is heterozygous and has one mutant copy and one dominant copy there is a 50% chance the child will inherit the mutant allele from that parent.
Final presentation file
| |||
References
Header Image Credit
[1] Borck, G., et al. (2006). Congenital Deafness and Goiter: Pendred Syndrome. Dtsch Arztebl, 103(46). doi: 10.1210/jc.2006-0142
[2] Ito, T., et al. (2011). SLC26A4 Genotypes and Phenotypes Associated with Enlargement of Vestibular Aqueduct. Cellular Physiol Biochem 2011; 28(3):545-52.
doi: 10.1159/000335119
[3] Genetics Home Reference: Pendred Syndrome
Inner Ear Diagram Credit
[4] Chattaraj, P., et al. (2013). Use of SLC26A4 Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct. JAMA Otolaryngol-Head Neck Surg. 2013;139(9):907-913.
doi: 10.1001/jamaoto.2013.4185
[5]. King KA, et al. (2010) SLC26A4 genotype, but not cochlear radiologic structure, is correlated with
hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope 120: 384–389.
doi: 10.1002/lary.20722
[6] Li X, Sanneman JD, Harbidge DG, Zhou F, Ito T, et al. (2013) SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice. PLoS Genet 9(7): e1003641.
doi: 10.1371/journal.pgen.1003641
[7] National Institute on Deafness and other Communicative Disorders: Pendred Syndrome.
[8] EVA Image Credit: Reardon, W., et al. (1999). Enlarged vestibular aqueduct; a radiological marker of Pendred syndrome, and mutation of the PDS gene. QJM (2000) 93(2): 99-104. .
doi: 10.1093/qjmed/93.2.99
[8] Genetics Home Reference: SLC26A4
[9] Dror AA, et. al. (2014). Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness. Mamm Genome. doi: 10.1007/s00335-014-9515-1
[1] Borck, G., et al. (2006). Congenital Deafness and Goiter: Pendred Syndrome. Dtsch Arztebl, 103(46). doi: 10.1210/jc.2006-0142
[2] Ito, T., et al. (2011). SLC26A4 Genotypes and Phenotypes Associated with Enlargement of Vestibular Aqueduct. Cellular Physiol Biochem 2011; 28(3):545-52.
doi: 10.1159/000335119
[3] Genetics Home Reference: Pendred Syndrome
Inner Ear Diagram Credit
[4] Chattaraj, P., et al. (2013). Use of SLC26A4 Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct. JAMA Otolaryngol-Head Neck Surg. 2013;139(9):907-913.
doi: 10.1001/jamaoto.2013.4185
[5]. King KA, et al. (2010) SLC26A4 genotype, but not cochlear radiologic structure, is correlated with
hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope 120: 384–389.
doi: 10.1002/lary.20722
[6] Li X, Sanneman JD, Harbidge DG, Zhou F, Ito T, et al. (2013) SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice. PLoS Genet 9(7): e1003641.
doi: 10.1371/journal.pgen.1003641
[7] National Institute on Deafness and other Communicative Disorders: Pendred Syndrome.
[8] EVA Image Credit: Reardon, W., et al. (1999). Enlarged vestibular aqueduct; a radiological marker of Pendred syndrome, and mutation of the PDS gene. QJM (2000) 93(2): 99-104. .
doi: 10.1093/qjmed/93.2.99
[8] Genetics Home Reference: SLC26A4
[9] Dror AA, et. al. (2014). Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness. Mamm Genome. doi: 10.1007/s00335-014-9515-1
Site produced by Erin Tapper, in the Spring 2014 semester, as an assignment for the Genetics 564 undergraduate course at the University of Wisconsin-Madison
