Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Autosomal Recessive Sensorineural Hearing Impairment and Goiter, DFNB 4 Nonsyndromic Hearing Loss and Deafness]
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Authors:
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Richard JH Smith, MD
Guy Van Camp, PhD |
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Initial Posting:
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Last Update:
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Disease characteristics. Pendred syndrome and DFNB4 comprise a phenotypic spectrum of hearing loss with or without other findings. Pendred syndrome is characterized by severe to profound bilateral sensorineural hearing impairment that is usually congenital and non-progressive, vestibular dysfunction, temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood. Variability of findings is considerable, even within the same family. DFNB4 is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and temporal bone abnormalities. Thyroid defects are not seen in DFNB4.
Diagnosis/testing. Pendred syndrome and DFNB4 are diagnosed clinically in individuals with (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; and (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia (the presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia). In addition, individuals with Pendred syndrome have either an abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout could not be performed). SLC26A4 is the only gene associated with Pendred syndrome/DFNB4, although SLC26A4 mutations are not always found in individuals with Pendred syndrome/DFNB4, making it likely that the condition is genetically heterogeneous. Sequence analysis identifies disease-causing mutations in about 50% of affected individuals from multiplex families and 20% of individuals from simplex families; such testing is clinically available.
Management. Treatment for Pendred syndrome/DFNB4 includes hearing habituation, hearing aids, and educational programs designed for the hearing impaired. If present, abnormal thyroid function is treated in the standard manner. Surveillance includes semiannual or annual examination for hearing impairment and endocrine function. Also recommended are repeat audiometry initially every three to six months for progressive hearing loss and consideration of cochlear implantation in individuals with severe to profound deafness. Activities such as weightlifting and contact sports should be avoided.
Genetic counseling. Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the mutations causing Pendred syndrome/DFNB4 are detected in one affected family member, carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible.
Pendred syndrome and DFNB4 comprise a phenotypic spectrum caused by mutations in SLC26A4 [Campbell et al 2001].
Pendred syndrome is diagnosed clinically in individuals with the following:
Sensorineural hearing impairment that is usually congenital, non-progressive, and severe to profound as measured by auditory brain stem response testing (ABR) or pure tone audiometry. For evaluation of hearing loss, see Hereditary Deafness and Hearing Loss Overview .
Bilateral dilation of the vestibular aqueduct (DVA) (also called enlarged vestibular aqueduct [EVA]) with or without cochlear hypoplasia, in which the labyrinth has one and one-half cochlear turns as opposed to the normal two and three-quarters turns. The presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia.
An abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout cannot be performed). Perchlorate discharge tests have a false-negative rate of approximately 5%.
DFNB4 is diagnosed clinically in individuals with the following:
Sensorineural hearing impairment that may be congenital, is often progressive and may become severe to profound as measured by auditory brain stem response testing (ABR) or pure tone audiometry
DVA (EVA) with an otherwise normal bony labyrinth
Normal thyroid function
Perchlorate discharge testing. In individuals with Pendred syndrome, serum thyroglobulin levels may be elevated and a perchlorate challenge shows excessive release of iodine from the thyroid gland. The test uses perchlorate to displace intravenously infused radiolabeled iodide, which accumulates in the thyrocyte secondary to abnormal function of pendrin, the protein encoded by SLC26A4. Normally, iodide is transported into the colloid where it is rapidly bound to thyroglobulin; discharge of unincorporated iodide is less than 10% two hours after administration of perchlorate. In individuals with Pendred syndrome, discharge is greater than 15% and may be as high as 80%.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. SLC26A4 is the only gene known to be associated with Pendred syndrome/DFNB4.
Other loci. The fact that SLC26A4 mutations are identified in only 50% of probands from multiplex families (i.e., more than one affected child) suspected on clinical findings of having Pendred syndrome/DFNB4 suggests genetic heterogeneity for the condition. To date, no other genes or loci have been identified.
Clinical uses
Clinical testing
Targeted mutation analysis. Three recurrent mutations: p.Leu236Pro (26%), p.Thr416Pro (15%), and 1001+G>A (14%) account for 50% of the Pendred syndrome/DFNB4 alleles in Caucasians of northern European descent who have a confirmed diagnosis of Pendred syndrome [Coyle et al 1998 , Campbell et al 2001]. The recurrent mutation H723R accounts for 53% of alleles among Japanese [Tsukamoto et al 2003].
Mutation scanning. The sensitivity of mutation scanning for disease-causing mutations is technique dependent. Denaturing high-performance liquid chromatography (DHPLC) has been shown to detect 100% of allelic variants in an SLC26A4 panel of 41 different mutations. Single-strand conformational polymorphism analysis (SSCP) detected only 63% of the same allelic variants, with detection of two of the most common mutations (p.Leu236Pro, IVS8+1G>A) being inconsistent [Prasad et al 2004].
Sequence analysis. Sequencing of all 21 exons (20 coding exons) and splice sites identifies 100% of disease-causing mutations in SLC26A4. In one third of families segregating a disease-causing mutation in SLC26A4, only one mutation is found (one sixth of all individuals with a Pendred syndrome phenotype) [Campbell et al 2001 , Park et al 2003].
Table 1
summarizes molecular genetic testing for Pendred syndrome/DFNB4.
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1. Proportion of affected individuals with a mutation(s) as classified by test method
2. Results of mutation scanning by DHPLC. Other techniques are less sensitive. 3. SLC26A4 mutations are identified in 50% of multiplex families segregating a Pendred syndrome phenotype. |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
In a child with severe-to-profound congenital deafness in whom the clinical history and physical examination are consistent with the diagnosis of autosomal recessive nonsyndromic hearing loss, the first test that should be ordered is mutation screening of GJB2 (see Nonsyndromic Hearing Loss and Deafness, DFNB1).
If GJB2 mutation screening does not identify two disease-causing mutations, computed tomography or magnetic resonance imaging of the temporal bones should be considered to evaluate for DVA and Mondini dysplasia. The presence of either of these temporal bone anomalies warrants molecular genetic testing of SLC26A4. In most children, thyroid enlargement will not be present. Perchlorate testing is not widely available and with molecular genetic testing, not essential to diagnose Pendred syndrome.
High-resolution computed tomography or magnetic resonance imaging of the temporal bones should be completed in all children with progressive sensorineural hearing loss to evaluate for DVA. If an enlarged vestibular aqueduct is observed, molecular genetic testing of SLC26A4 is warranted.
The only phenotypes known to be associated with mutations in SLC26A4 are Pendred syndrome and DFNB4.
That Pendred syndrome and DFNB4 should be considered together is supported by numerous studies reporting variable expressivity of Pendred syndrome and, in particular, its thyroid manifestations [Reardon et al 1997].
Pendred syndrome is characterized by sensorineural hearing impairment, temporal bone anomalies, and the development of euthyroid goiter in late childhood to early adulthood. Variability in hearing loss and thyroid disease is considerable, even within the same family [Napiontek et al 2004].
Hearing impairment. The degree of hearing impairment and its presentation can vary. Classically, the hearing loss is bilateral, severe to profound, and congenital (or prelingual). However, in some instances, hearing loss may be later in onset and progressive [Reardon et al 1997]. In a number of individuals reported, progressive postlingual hearing impairment has developed following head injury [Reardon et al 1997 , Luxon et al 2003]. The association with head injury suggests that these individuals may have had an inner-ear malformation such as a dilation of the vestibular aqueduct (DVA). In some individuals, vertigo can precede or accompany fluctuations in hearing [Sugiura et al 2005].
Vestibular dysfunction. Objective evidence of vestibular dysfunction can be demonstrated in 66% of individuals with Pendred syndrome and ranges from mild unilateral canal paresis to gross bilateral absence of function. Vestibular dysfunction should be suspected in infants with normal motor development who episodically experience difficulty walking.
Temporal bone abnormalities. The temporal bones are abnormal radiologically in most, if not all, persons with Pendred syndrome [Reardon et al 1997 , Goldfeld et al 2005]; however, universal agreement as to the type of abnormality is lacking. This ambiguity reflects imprecision in defining the bony anatomic defect. In a study of individuals homozygous for the same mutation in SLC26A4, high-resolution computed tomography was used to assess temporal bone anatomy. Absence of the upper turn of the cochlea (diagnosed when the interscalar septum could not be seen between the upper and middle turns) and deficiency of the modiolus (diagnosed when a bony polyhedral structure centered on the cochlea was not apparent on a midmodiolar section) were reported by Goldfeld and colleagues (2005) in 75% and 100% of ears, respectively. DVA, defined by width in the middle portion of the descending limb of the vestibular aqueduct of greater than 1.5 mm, was observed 80% of the time [Goldfeld et al 2005].
These findings suggest that deficiency of the modiolus is the most common anomaly in Pendred syndrome. Affected siblings may be discordant for temporal bone anomalies [Reardon et al 1997 , Goldfeld et al 2005].
Goiter. Approximately 75% of individuals have evidence of goiter on clinical examination. Goiter develops in late childhood or early puberty in about 40% of individuals, and in the remainder it develops in early adult life. Marked intrafamilial variability exists [Reardon et al 1997 , Van Hauwe et al 1998]. While many individuals with Pendred syndrome are started on thyroxine, only about 10% have abnormal thyroid function as defined by a raised serum TSH level (>5 mU/L). Abnormal thyroid function studies in the absence of a goiter have not been reported [Reardon et al 1997].
DFNB4 is characterized by sensorineural hearing impairment in the absence of overt abnormalities (i.e., nonsyndromic hearing loss), although computed tomography or magnetic resonance imaging of the temporal bones reveals DVA. Thyroid defects are not seen.
Hearing impairment. The degree of hearing impairment and its presentation can vary. Many persons with DVA are born with normal hearing and progressively become hearing impaired during childhood. Although several reports describe a correlation between the size of the DVA and the degree of hearing loss, a strict correlation has not been established [Berrettini et al 2005].
Vestibular dysfunction. Persons with DVA may deny vestibular disturbances although vestibular deficits can be demonstrated by caloric testing. When DVA is unilateral, there is no strict correlation between the side of the vestibular deficit and the side of the vestibular enlargement [Berrettini et al 2005].
Temporal bone abnormalities. DVA is the most common imaging finding in persons with sensorineural hearing loss dating from infancy or childhood. In a study of families with a DFNB4 phenotype, Tsukamoto and colleagues reported SLC26A4 mutations in 75% of probands [Tsukamoto et al 2003]. In simplex cases (i.e., a single occurrence in a family), however, the prevalence of SLC26A4 mutations is much lower [Berrettini et al 2005]. DVA can be bilateral or unilateral.
Functional studies have suggested that some missense SLC26A4 mutations are more likely to be associated with DFNB4 than with Pendred syndrome as the translated protein retains residual iodide transport function [Scott et al 2000].
Frequency of episodes of vertigo and the rate of progression of hearing loss may be mutation dependent [Sugiura et al 2005].
Although the prevalence of Pendred syndrome is unknown, Fraser (1965) calculated that it accounts for 7.5% of all congenital deafness. If the data are representative, Pendred syndrome is a common cause of congenital hearing impairment. Some contemporary studies do not support this estimate [Newton 1985 , Arnos et al 1992] and most modern studies in deafness are striking for the dearth of reported cases of classic Pendred syndrome.
When Pendred syndrome and DFNB4 are considered part of the same disease spectrum, prevalence figures are very high. A study of 274 East Asians and 318 South Asians with deafness demonstrated mutations in SLC26A4 in about 5.5% of both groups [Park et al 2003].
Pendred syndrome may be more common than suspected, particularly among individuals with DVA [Cremers et al 1998].
In order to establish the importance of mutations in SLC26A4 as a cause of hearing impairment in individuals with nonsyndromic deafness, screening of a broader deaf population will be necessary.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Congenital inherited hearing impairment. Congenital (or prelingual) inherited hearing impairment affects approximately one of 2,000 newborns. Thirty percent of these babies have additional anomalies, making the diagnosis of a syndromic form of hearing impairment possible (see Hereditary Deafness and Hearing Loss Overview). Although dilation of the vestibular aqueduct (DVA) with or without cochlear hypoplasia is seen in 85% of individuals with Pendred syndrome, neither DVA nor cochlear hypoplasia is specific for Pendred syndrome; individually, therefore, they are of limited diagnostic value. Approximately 20% of children who represent simplex cases (i.e., the only affected individual in the family) have DVA and disease-causing mutations in SLC26A4 [Campbell et al 2001].
Abnormal perchlorate test. The perchlorate test is abnormal in a number of thyroid conditions, including Hashimoto's thyroiditis, total iodide organification deficiency, and I131-treated thyrotoxicosis [O'Mahoney et al 1996 , Reardon & Trembath 1996].
Congenital hypothyroidism with sensorineural hearing loss. Sporadic and endemic congenital hypothyroidism associated with sensorineural hearing impairment are clinically similar to Pendred syndrome but genetically distinct.
Resistance to thyroid hormone. Although the syndrome of resistance to thyroid hormone (RTH) is typically inherited in an autosomal dominant manner, one exceptional consanguineous kindred has been described in which RTH is inherited in an autosomal recessive manner. Two of six children had severe sensorineural hearing impairment and goiter and a large deletion (detected by karyotyping) on chromosome 3 that included the thyroid receptor β (TRM β) gene.
Autoimmune thyroid diseases. Autoimmune thyroid diseases (AITD), including Graves' disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, are caused by multiple genetic and environmental factors. Candidate genes involved in this group of diseases include genes that regulate immune response and/or thyroid physiology. A recent association study comparing alleles of D7S496 and D7S2459 with AITD phenotype suggests that SLC26A4 should be added to the list of susceptibility genes for GD [Hadj Kacem et al 2003].
To establish the extent of involvement in an individual diagnosed with Pendred syndrome/DFNB4, the following evaluations are recommended:
Based on anecdotal reports that increased intracranial pressure in individuals with dilation of the vestibular aqueduct (DVA) can trigger a decline in hearing, some physicians recommend avoiding activities like weightflifting and contact sports.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner.
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an individual with Pendred syndrome/DFNB4 are obligate heterozygotes (carriers) for a disease-causing mutation in the SLC26A4 gene.
Other family members of a proband. Each sib of the proband's parents has a 50% chance of being a carrier.
The following points are noteworthy:
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from cells obtained from amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal diagnosis of hearing status are uncommon and require careful genetic counseling.
Preimplantation genetic diagnosis (PGD)
may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
DFNB4 | SLC26A4 | 7q31 | Pendrin |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Gene Symbol | Locus Specific | Entrez Gene | HGMD |
SLC26A4 |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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The relationship between pendrin, the protein encoded by SLC26A4, and deafness has been investigated extensively in mouse mutants segregating a targeted deletion of Slc26a4. Endolymph volume in homozygous null mice (Slc26a4-/-) is increased and tissue mass in areas occupied by type I and II fibrocytes is reduced. Slc26a4-/- mice lack an endocochlear potential, which is generated across the basal cell barrier of the stria vascularis by the potassium channel KCNJ10 and localizes to the intermediate cells. Normal endolymphatic K+ concentrations suggest that absent or dysfunctional pendrin results in a secondary loss of KCNJ10 protein expression and the endocochlear potential. Loss of the endocochlear potential may be the direct cause of deafness in Pendred syndrome/DFNB4 [Wangemann et al 2004].
Normal allelic variants: SLC26A4 belongs to the solute carrier 26 gene family and has statistically significant homology to 13 other proteins that function as sulfate transporters. These sequences cross a large taxonomic span including animals, plants, and yeast, although the two closest relatives of pendrin are the human DRA (down-regulated in adenoma) and DTD (diastrophic dysplasia) genes. The DRA and SLC26A4 genes are positioned tail to tail and separated by only 48 kb, suggesting an evolutionary relationship [Everett et al 1997].
Pathologic allelic variants:
More than 70 mutations in
SLC26A4 have been reported as causing Pendred syndrome/DFNB4 [Prasad et al 2004]. Of these mutations, the majority are seen in only single families [Campbell et al 2001].
Three mutations (p.Leu236Pro, p.Thr416Pro, and 1001+1G>A) are seen more frequently than other mutations in the Caucasian population of northern European descent and account for 50% of the Pendred disease alleles in individuals with a confirmed diagnosis of Pendred syndrome in this ethnic group [Coyle et al 1998
, Campbell et al 2001]. Each of these recurrent mutations occurs on distinct but common haplotypes, supporting the notion for common founders in these independently ascertained families [Coyle et al 1998
,
Van Hauwe et al 1998
, Park et al 2003]. However, all ethnic groups have a unique diverse mutant allele series with a few prevalent founder mutations.
Normal gene product: The SLC26A4 gene encodes the 780-amino acid (86-kd) protein, pendrin, that functions as a chloride and iodide transporter. The mRNA product is about 5 kb long, with an open reading frame of 2343 base pairs distributed across 21 exons. The predicted amino acid sequence initially suggested a highly hydrophobic protein with 11 transmembrane domains [Everett et al 1997]; however, Royaux et al 2000 have shown that the carboxy terminus is intracellular, implying that an additional alpha helix spans the cell membrane [Royaux et al 2000]. In an analysis of data from ten transmembrane prediction programs, eight to 13 transmembrane domains are predicted; 12 transmembrane domains are predicted by four of the programs, including MEMSAT2, ranked by a recent review as one of the most accurate prediction programs [Simon et al 2001].
Abnormal gene product: A splice site mutation that causes a G-to-A transition at a position in the 5' splice consensus sequence that is 100% conserved has been identified in several families with Pendred syndrome [Coyle et al 1998 , Van Hauwe et al 1998]. This type of mutation almost always leads to aberrant splicing, either by exon skipping or by the use of a cryptic splice site. The exact effect on mRNA has not been determined because RT-PCR on cDNA from lymphoblastoid cell lines has been unsuccessful, even by nested PCR [Van Hauwe & Van Camp, unpublished results].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.
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Resources Printable Copy
Lorraine A Everett, MD; National Institutes of Health (1998-2001)
Eric D Green, MD, PhD; National Institutes of Health (1998-2001)
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD (1998-present)
Peter Van Hauwe; University of Antwerp (1998-2001)
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