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Pendred Syndrome/DFNB4

Synonyms: Autosomal Recessive Sensorineural Hearing Impairment, Enlarged Vestibular Aqueduct and Goiter; DFNB 4 Nonsyndromic Hearing Impairment and EVA; DFNB 4 Nonsyndromic Hearing Loss and Deafness

, PhD, , PhD, and , MD.

Author Information
, PhD
Post-Doctoral Fellow, Department of Otolaryngology
University of Iowa
Iowa City, Iowa
, PhD
Department of Genetics
University of Antwerp
Antwerp, Belgium
, MD
Professor of Internal Medicine, Division of Nephrology
Sterba Hearing Research Professor of Otolaryngology
Director, Molecular Otolaryngology Research Laboratories
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: May 29, 2014.

Summary

Disease characteristics. Pendred syndrome (PDS) 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 (or prelingual) 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 enlarged vestibular aqueduct (EVA). Thyroid defects are not seen in DFNB4.

Diagnosis/testing. PDS 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 PDS have either an abnormal perchlorate discharge test or goiter. Pathogenic variants in three known genes account for approximately half of PDS/DFNB4 cases: SLC26A4 (~50% of affected individuals), FOXI1 (<1%), and KCNJ10 (<1%), suggesting further genetic heterogeneity. Sequence analysis of SLC26A4 identifies pathogenic variants in approximately 50% of affected individuals from either simplex or multiplex families. These persons are usually compound heterozygotes for disease-causing variants in SLC26A4, although not infrequently only a single pathogenic variant is detected.

Management. Treatment of manifestations: Hearing habituation, hearing aids, and educational programs designed for the hearing impaired; consideration of cochlear implantation in individuals with severe-to-profound deafness; standard treatment of abnormal thyroid function.

Surveillance: Semiannual or annual assessment of hearing and endocrine function. Baseline ultrasound of the thyroid with periodic ultrasound surveillance to monitor volumetric changes. Repeat audiometry initially every three to six months if hearing loss is progressive.

Agents/circumstances to avoid: Weightlifting and contact sports.

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. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible when the family-specific pathogenic variants are known.

Diagnosis

Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum caused by biallelic pathogenic variants in SLC26A4 [Campbell et al 2001, Park et al 2003, Albert et al 2006, Wang et al 2007, Pera et al 2008, Anwar et al 2009] (the most common cause), or double heterozygosity in either SLC26A4 and FOXI1 [Yang et al 2007] or SLC26A4 and KCNJ10 [Yang et al 2009].

Clinical Diagnosis

Pendred syndrome (PDS) is diagnosed clinically in individuals with the following:

  • Sensorineural hearing impairment that is usually congenital (or prelingual), 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 Deafness and Hereditary 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. The perchlorate discharge 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 should be 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%. Perchlorate discharge tests have a false-negative rate of approximately 5%.
  • In individuals with PDS, serum thyroglobulin levels may be elevated.

DFNB4 (also called nonsyndromic enlarged vestibular aqueduct [NS-EVA]), is diagnosed clinically in individuals with the following:

  • Sensorineural hearing impairment that is often congenital (or prelingual) but can be progressive or fluctuating, often eventually becoming severe to profound as measured by auditory brain stem response testing (ABR) or pure tone audiometry
  • DVA (EVA) with a normal bony labyrinth
  • Normal thyroid function

Confirming the Diagnosis

The diagnosis of PDS/DFNB4 can be confirmed by identification of biallelic pathogenic variants in SLC26A4 [Campbell et al 2001, Park et al 2003, Yang et al 2007, Yang et al 2009] (see Table 1).

Digenic inheritance, in which an affected individual has double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in FOXI1 [Yang et al 2007] or double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in KCNJ10 [Yang et al 2009], has also been observed (see Table 1) and is discussed in more detail in Molecular Genetics. Digenic inheritance has not been supported by other studies, suggesting that pathogenic variants in FOXI1 and KCNJ10 are an extremely rare cause of PDS/DFNB4 [Jonard et al 2010, Wu et al 2010, Mercer et al 2011, Chen et al 2012, Cirello et al 2012, Chai et al 2013, Song et al 2013, Landa et al 2013].

Table 1. Summary of Molecular Genetic Testing Used in Pendred Syndrome/DFNB4

Gene 1Proportion of PDS/DFNB4 Attributed to Pathogenic Variants in This GeneTest Method
SLC26A450% 2Targeted mutation analysis 3
Sequence analysis 4
Deletion/duplication analysis 5, 6
FOXI1<1% 7Sequence analysis 4
Deletion/duplication analysis 5, 8
KCNJ10<1% 9Sequence analysis 2
Deletion/duplication analysis 5, 8
Unknown 10NANA

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. SLC26A4 pathogenic variants are identified in 50% of either simplex or multiplex families segregating a Pendred syndrome or DFNB4 phenotype. In one third of such families, only one variant is found (1/6 of all individuals with a Pendred syndrome / DFNB4 phenotype) [Campbell et al 2001, Park et al 2003]. In a study of 144 Chinese individuals who had EVA with or without Mondini dysplasia, more than 50% had either one or two pathogenic SLC26A4 disease-causing variants [Huang et al 2011].

3. Testing for specific SLC26A4 pathogenic variants (e.g., p.Leu236Pro, p.Thr416Pro, c.1001+1G>A), which account for 50% of the disease-causing alleles in individuals with a confirmed diagnosis of Pendred syndrome who are of northern European descent. Note: Other variants common in affected persons of Chinese, Japanese/Korean, and Pakistani origin are discussed in Molecular Genetics.

4. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, heterozygous whole-exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies whole-exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Deletons and duplications of SLC26A4 are extremely rare. The authors identified one partial-exon deletion in a study of 686 patients screened for genetic deafness [Authors, unpublished data], and Pera et al [2008] characterized a multiexon 14-kb deletion spanning intron 3 to intron 6 of SLC26A4 in a patient with nonsyndromic EVA. In addition, a patient with dup(10p)del(8q) (SLC26A4 is not located in this region) and multiple congenital anomalies including Pendred syndrome has been described [van Wouwe et al 1986].

7. In two families, persons with DVA had double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in FOXI1 [Yang et al 2007].

8. No deletions or duplications in FOXI1 or KCNJ10 have been reported in association with PDS/DFNB4 or any other disease.

9. In two families, affected persons had double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in KCNJ10 [Yang et al 2009].

10. Linkage studies have identified additional genomic intervals for candidate EVA/PDS-associated genes [Ito et al 2011, Mercer et al 2011, Cirello et al 2012].

Testing Strategy

In a child with severe-to-profound congenital hearing loss in whom the clinical history and physical examination are consistent with the diagnosis of autosomal recessive nonsyndromic hearing loss:

  • Single-gene testing. The first test that should be ordered is molecular genetic testing of GJB2 (see Nonsyndromic Hearing Loss and Deafness, DFNB1).
  • If GJB2 molecular genetic testing does not identify two pathogenic variants, the following strategies can be considered:
    • High-resolution computed tomography (CT) or magnetic resonance imaging (MRI) of the temporal bones 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 with PDS, thyroid enlargement will NOT be present.
      OR
    • Sequence analysis and deletion/duplication analysis of SLC26A4 without obtaining CT or MRI of the temporal bones. This approach can be considered because pathogenic variants in SLC26A4 are the second most frequent cause of autosomal recessive nonsyndromic hearing loss (most frequent cause: GJB2 pathogenic variants).
      Note: In individuals with a single identified SLC26A4 pathogenic variant, molecular genetic testing of FOXI1 and KCNJ10. This may be considered based on rare reports of double heterozygosity with a heterozygous pathogenic variant in SLC26A4 and a heterozygous pathogenic variant in FOXI1 [Yang et al 2007] or KCNJ10 [Yang et al 2009].
  • Multi-gene panel. If the above evaluations are not diagnostic, further genetic testing of other genes associated with nonsyndromic hearing loss can be pursued [Shearer et al 2010].

Clinical Description

Natural History

Pendred Syndrome (PDS)

PDS 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 [Tsukamoto et al 2003, Napiontek et al 2004].

Hearing impairment. The degree of hearing impairment and its presentation vary. Classically, the hearing loss is bilateral, severe to profound, and congenital (or prelingual). However, hearing loss may be later in onset and progressive. The progression can be rapid in early childhood [Stinckens et al 2001] and may be associated with head injury, infection, or delayed secondary hydrops [Luxon et al 2003]. Vertigo can precede or accompany fluctuations in hearing [Sugiura et al 2005a, Sugiura et al 2005b]. The often-observed low-frequency air-bone gap in combination with normal tympanometry may represent a “third window” effect caused by the dilated vestibular aqueduct [Merchant et al 2007].

Vestibular dysfunction. Objective evidence of vestibular dysfunction can be demonstrated in 66% of individuals with PDS 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 PDS [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 pathogenic variant in SLC26A4, high-resolution CT was used to assess temporal bone anatomy. Absence of the upper turn of the cochlea (diagnosed when the interscalar septum cannot be seen between the upper and middle turns) and deficiency of the modiolus (diagnosed when a bony polyhedral structure centered on the cochlea is not apparent on a mid-modiolar section) were reported by Goldfeld and colleagues in 75% and 100% of affected 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 PDS. Affected siblings may be discordant for temporal bone anomalies [Goldfeld et al 2005].

Goiter. Approximately 75% of individuals with PDS have evidence of goiter on clinical examination. Goiter is incompletely penetrant and develops in late childhood or early puberty in approximately 40% of individuals; in the remainder, it develops in early adult life. Marked intrafamilial variability exists [Reardon et al 1999, Madeo et al 2009], making the distinction between NS-EVA and PDS difficult during childhood. While many individuals with PDS are started on thyroxine, only approximately 10% have abnormal thyroid function as defined by a serum TSH level greater than 5 mU/L. Abnormal thyroid function studies in the absence of a goiter have not been reported.

DFNB4

DFNB4 is characterized by sensorineural hearing impairment in the absence of other obvious abnormalities (i.e., nonsyndromic hearing loss), although CT or MRI of the temporal bones reveals dilation of the vestibular aqueduct (DVA). Thyroid defects are not seen.

Hearing impairment. The degree of hearing impairment and its presentation vary. Many persons with DVA are born with normal hearing and progressively become hearing impaired during childhood. Several reports have described a correlation between the size of the DVA and the degree of hearing loss, but 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, SLC26A4 pathogenic variants were reported in 75% of probands [Tsukamoto et al 2003]. However, in simplex cases (i.e., a single occurrence in a family) the prevalence of SLC26A4 pathogenic variants is much lower [Berrettini et al 2005]. DVA can be bilateral or unilateral.

Genotype-Phenotype Correlations

An understanding of the relationship between genotype and phenotype in the PDS/NS-EVA spectrum would be helpful in patient management. Functional studies suggest that missense SLC26A4 pathogenic variants that retain residual iodide transport function are more likely to be associated with DFNB4 (NS-EVA) than with PDS [Scott et al 2000]; however, predicting the likely functional significance of a missense variant is difficult. The two parameters traditionally used, low incidence in a control population and substitution of an evolutionarily conserved amino acid, are not reliable. Pera and colleagues have shown that the addition or omission of proline or charged amino acids in the sequence of SLC26A4 is a better predictor of altered SLC26A4 function in the absence of direct functional tests [Pera et al 2008]. All truncating variants eliminate pendrin function.

The frequency of episodes of vertigo and the rate of progression of hearing loss may be pathogenic variant-dependent [Sugiura et al 2005b].

Thyroid phenotype is dependent on the degree of residual iodide transport function [Pryor et al 2005, Pera et al 2008]. Loss-of-function variants in SLC26A4 are associated with impaired iodide organification because iodide efflux into the follicular lumen is reduced. In the absence of pendrin, expression of chloride channel-5 (ClC-5) is increased and transiently compensates for apical iodide efflux. In more affected follicles, dual oxidase (Duox) and thyroid peroxidase (TPO) are relocated in the cytosol, leading to abnormal intracellular thyroid hormone synthesis, which results in cell destruction [Senou et al 2010].

Deleterious variants can occur anywhere in the 780 amino-acid protein, making it difficult to link the severity of any aspect of the phenotype (hearing loss, be it moderate, severe, or profound; thyroid enlargement) to specific pathogenic variants. For example, pathogenic variants with no transport activity or with reduced transport activity are equally identified in individuals with PDS and NS-EVA with hearing loss that ranges from moderate to profound [Taylor et al 2002, Pera et al 2008, Dossena et al 2009]. This degree of variability supports the existence of genetic, epigenetic, and/or environmental factors that modify the pendrin-induced phenotype [Pera et al 2008, Dossena et al 2009].

The presence of two pathogenic variants of SLC26A4 is correlated with bilateral EVA and Pendred syndrome, whereas unilateral EVA and NS-EVA correlate most closely with either one or no pathogenic variants of SLC26A4 [Ito et al 2011].

Nomenclature

PDS and DFNB4 (NS-EVA) should be considered part of a disease continuum [Reardon et al 1999, Azaiez et al 2007].

Prevalence

Although the prevalence of PDS is unknown, Fraser [1965] calculated that it accounts for 7.5% of all congenital deafness. If these data are representative, Pendred syndrome is a common cause of congenital hearing impairment.

When PDS and DFNB4 are considered part of the same disease spectrum, prevalence rates are very high (pathogenic variants in SLC26A4 are the second most frequent cause of nonsyndromic hearing loss) [Hilgert et al 2009]. A study of 274 East Asians and 318 South Asians with deafness demonstrated pathogenic variants in SLC26A4 in approximately 5.5% of both groups [Park et al 2003].

Differential Diagnosis

Congenital inherited hearing impairment. Congenital (or prelingual) inherited hearing impairment affects approximately one in 1,000 newborns. Thirty percent of these infants have additional anomalies, making the diagnosis of a syndromic form of hearing impairment possible (see Deafness and Hereditary Hearing Loss Overview). Although dilation of the vestibular aqueduct (DVA) with or without cochlear hypoplasia is seen in approximately 80% of individuals with Pendred syndrome (PDS), neither DVA nor cochlear hypoplasia is specific for PDS; 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 mutation of SLC26A4 [Campbell et al 2001].

Abnormal perchlorate test. The perchlorate test is abnormal in a number of thyroid disorders, including Hashimoto's thyroiditis, total iodide organification deficiency, and I-131-treated thyrotoxicosis.

Congenital hypothyroidism with sensorineural hearing loss. Sporadic and endemic congenital hypothyroidism associated with sensorineural hearing impairment is clinically similar to PDS 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 in which RTH was inherited in an autosomal recessive manner has been described. 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 hormone receptor β gene (THRB).

Autoimmune thyroid diseases. Autoimmune thyroid diseases, including Graves' disease, Hashimoto thyroiditis, 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.

See Deafness, autosomal recessive: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this condition, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of involvement in an individual diagnosed with Pendred syndrome (PDS)/DFNB4, the following evaluations are recommended:

  • Assessment of auditory acuity (ABR emission testing, pure tone audiometry)
  • Thin-cut CT of the temporal bones to identify structural abnormalities
  • Vestibular function studies
  • Thyroid ultrasonography and thyroid function tests (T3, T4, and TSH)
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Hearing habilitation (hearing aids as early as possible)
  • Consideration of cochlear implantation in individuals with severe to profound deafness
  • Educational programs designed for individuals with hearing impairment
  • Treatment of abnormal thyroid function (if present) using thyroid hormone replacement therapy

Surveillance

Surveillance includes:

  • Semiannual or annual examination by a physician familiar with hereditary hearing impairment
  • Semiannual or annual examination by an endocrinologist familiar with PDS
  • Repeat audiometry initially every three to six months if hearing loss is progressive
  • Since goiter is more common than hypothyroidism, volumetric baseline measurement of the thyroid, obtained by ultrasonography with periodic (every 2-3 years) reassessment [Choi et al 2011b]

Agents/Circumstances to Avoid

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 weightlifting and contact sports.

Evaluation of Relatives at Risk

At-risk relatives should be evaluated for hearing loss, vestibular dysfunction, and thyroid abnormality in the same manner as an affected individual at initial diagnosis.

If the pathogenic variants in the family are known, molecular genetic testing of sibs is indicated shortly after birth so that appropriate and early support and management can be provided to the child and family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

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 condition.

Genetic Counseling

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. —ED.

Mode of Inheritance

Pendred syndrome (PDS)/DFNB4 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Parents are obligate heterozygotes and therefore carry a single copy of a deafness-causing pathogenic variant.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% probability of having PDS/DFNB4, a 50% probability of being an asymptomatic carrier, and a 25% probability of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the probability of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with PDS/DFNB4 are obligate heterozygotes (carriers) for a deafness-causing pathogenic variant.

Other family members of a proband. Each sib of the proband's parents has a 50% probability of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known.

Carrier testing for reproductive partners of individuals whose pathogenic variant has been identified may be possible.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

The following points are noteworthy:

  • Communication with individuals who are deaf requires the services of a skilled interpreter.
  • Deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." In fact, having a child with deafness may be preferred over having a child with normal hearing.
  • Many deaf people are interested in obtaining information about the cause of their own deafness — including information on medical, educational, and social services — rather than information about prevention, reproduction, or family planning. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears and to ascertain and address the questions and concerns of the family/individual.
  • The use of certain terms is preferred: "probability" or "chance" vs "risk"; "deaf" and "hard-of-hearing" vs "hearing-impaired." Terms such as "affected," "abnormal," and "disease-causing" should be avoided.

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.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the deafness-causing variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Pendred syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the deafness-causing variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pendred Syndrome/DFNB4: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pendred Syndrome/DFNB4 (View All in OMIM)

274600PENDRED SYNDROME; PDS
600791DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT; DFNB4
601093FORKHEAD BOX I1; FOXI1
602208POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 10; KCNJ10
605646SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4

Molecular Genetic Pathogenesis

The relationship between pendrin, the protein encoded by SLC26A4, and deafness is incompletely understood. Using mouse models, it has been shown that pendrin is required between embryonic day 16.5 and postnatal day two for normal hearing. Pendrin is not required for maintenance of hearing [Choi et al 2011a]. Extensive studies in mouse mutants segregating a targeted deletion of Slc26a4 have also shown that endolymph volume in the 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 normally generated across the basal cell barrier of the stria vascularis by the potassium channel KCNJ10 and localizes to the intermediate cells. In addition, endolymph acidification and free radical oxidative damage are found [Wangemann et al 2007, Singh & Wangemann 2008]. 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 is the cause of deafness in Pendred syndrome (PDS)/DFNB4 [Wangemann et al 2004].

In persons with PDS/DFNB4 the identification of double heterozygosity for a single pathogenic variant in both SLC26A4 and KCNJ10 provides additional proof for the involvement of KCNJ10 in the pathogenesis of PDS-NS-EVA deafness [Yang et al 2009]. Data from Yang et al [2007] are also consistent with a dosage-dependent model for the molecular pathogenesis of PDS/DFNB4 that involves not only SLC26A4 but also FOXI1, which regulates its transcriptional regulatory machinery. Mutation of FOXI1 or KCNJ10 is a rare cause of EVA [Jonard et al 2010, Wu et al 2010].

Digenic inheritance. Rare reports of apparent digenic inheritance in which an affected individual is a double heterozygote (heterozygous in each of two of the involved genes) include:

  • In two families, persons with dilation of the vestibular aqueduct (DVA) demonstrated double heterozygosity with a pathogenic variant in SLC26A4 and a pathogenic variant in FOXI1. In support of the disease-causing nature of this genotype, the investigators showed that FOXI1 activates transcription of SLC26A4 by binding to a 5’-conserved cis-acting promoter element [Yang et al 2007].
  • In other families with PDS/DFNB4, Yang et al [2007] found pathogenic variants in the promoter site of SLC26A4 that abolished FOXI1-mediated activation of gene transcription.
  • In two other families, affected persons had double heterozygosity with a pathogenic variant in SLC26A4 and a pathogenic variant in KCNJ10. The identified SLC26A4 pathogenic variants have been previously implicated in EVA/PDS. The KCNJ10 pathogenic variants reduce K(+) conductance activity, which is critical for generating and maintaining the endocochlear potential [Yang et al 2009].

SLC26A4

Gene structure. SLC26A4 comprises 57,173 bp of the genome on the ‘+’ chromosomal strand of chromosome 7 (hg19: 107,277,779-107,334,951 bp). Of the 21 exons, exon 1 is non-coding and partially overlaps SLC26A4-AS1 (SLC26A4 antisense RNA 1), located on the ’–’ strand. The mRNA product is approximately 5 kb long, with an open reading frame of 2343 bases, producing the 780 amino acid protein pendrin. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 2 and Molecular Genetic Pathogenesis, Digenic inheritance. Approximately 200 pathogenic variants have been reported in SLC26A4 in association with either NS-EVA or PDS [Hilgert et al 2009] (Deafness Variation Database [DVD]). Of these pathogenic variants, the majority are seen only in single families [Campbell et al 2001, Prasad et al 2004, Dai et al 2009, Hilgert et al 2009].

Three pathogenic variants – p.Leu236Pro (26%), p.Thr416Pro (15%), and c.1001+1G>A (14%) – are seen more frequently than other pathogenic variants in persons of northern European descent and account for 50% of the PDS-causing alleles in individuals with a confirmed diagnosis of PDS in this ethnic group [Coyle et al 1998, Campbell et al 2001]. Each of these recurrent variants 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].

Other ethnic groups also have unique diverse pathogenic alleles reflecting a few prevalent founder mutations: c.919-2A>G, p.His723Arg, and p.Val239Asp are prevalent pathogenic variants among the Chinese, Japanese/Korean, and Pakistani populations [Tsukamoto et al 2003, Park et al 2005, Wu et al 2005, Anwar et al 2009, Choi et al 2009b]. p.Glu384Gly is frequently seen among northern Europeans [Coyle et al 1998] and p.Gln514Lys is common among the Spanish [Pera et al 2008].

Deletions of single exons and multiexons have been reported in SLC26A4 [Pera et al 2008].

Haplotype reconstruction based on SLC26A4-linked short tandem repeat markers that segregate with the EVA phenotype in multiplex families with EVA/PDS in which only one SLC26A4 pathogenic variant is found suggests the presence of additional disease-causing mutations in regulatory regions, perhaps in the FOXI1 binding sites that regulate SLC26A4 transcription [Choi et al 2009a]. See FOXI1, Pathogenic allelic variants.

Table 2. Selected SLC26A4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.707T>Cp.Leu236ProNM_000441​.1
NP_000432​.1
c.716T>Ap.Val239Asp
c.919-2A>G
c.1001+1G>A
(IVS8+1G>A)
--
c.1151A>Gp.Glu384Gly
c.1246A>Cp.Thr416Pro
c.1540C>Ap.Gln514Lys
c.2168A>Gp.His723Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. SLC26A4 encodes the 780-amino acid (86-kd) protein, pendrin, which functions as a chloride, iodide, bicarbonate, and formate transporter. The predicted amino acid sequence initially suggested a highly hydrophobic protein with 11 transmembrane domains; however, Royaux et al [2000] have shown that the carboxy terminus is intracellular, implying that an additional alpha helix spans the cell membrane. In an analysis of data from ten transmembrane prediction programs, eight to 13 transmembrane domains are predicted. Twelve transmembrane domains are predicted by four of the programs, including MEMSAT2, ranked by a review as one of the most accurate prediction programs [Simon et al 2001]. A 15-transmembrane model, which places the amino terminus extracellularly and the carboxy terminus in the cytoplasm, has also been proposed [Dossena et al 2009].

SLC26A4 belongs to the solute carrier 26 gene family and has significant homology to 13 other proteins. These sequences cross a large taxonomic span including animals, plants, and yeast, although the two closest relatives of SLC26A4 are human SLC26A3 (previously known as DRA [down-regulated in adenoma]) and SLC26A2 (previously known as DTD [diastrophic dysplasia]). SLC26A3 and SLC26A4 are positioned tail to tail and separated by only 48 kb, suggesting an evolutionary relationship. The human SLC26 family members are involved in a range of key anion transport activities including Cl-/HCO3-, I-/HCO3-, and SO42-/HCO3- exchange, and are associated with debilitating disorders including PDS/NS-EVA, chondrodysplasias, and congenital chloride diarrhea [Dawson & Markovich 2005, Kere 2006].

Abnormal gene product. A splice site variant (c.1001+1G>A) 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 PDS [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 amplification of RT-PCR from cDNA of lymphoblastoid cell lines has been unsuccessful, even by nested PCR [Van Hauwe & Van Camp, unpublished results].

FOXI1

Gene structure. The forkhead box L1 gene, FOXI1 (previously FKHL10), located on chromosome 5 (hg19: 169,532,917-169,536,729), is a small gene (3,813 bp) with a single exon and a coding region of 1038 nucleotides (NM_005250.2). Its two transcript variants encode different isoforms (isoform “a” has 378 and isoform “b” has 283 amino acids). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, biallelic pathogenic variants in FOXI1 have not been identified. However, five nonsynonymous putative pathogenic variants have been identified, one of which was a single amino acid deletion in the forkhead DNA-binding domain [Yang et al 2007]. The transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1 comprises two adjacent FOXI1 binding sites in a head-to-head orientation. Termed FBS1 and FBS2, both binding sites – in this specific orientation – are required for FOXI1-mediated transcriptional activation of SLC26A4. Pathogenic variants in FBS1 or FBS2 in trans with pathogenic variants in the coding sequence of SLC26A4 are a rare cause of EVA/PDS [Yang et al 2007] (see Molecular Genetic Pathogenesis, Digenic inheritance).

Normal gene product. FOXI1 is an early otic vesicle-specific gene necessary for the development of the cochlea and vestibule. FOXI1 encodes a protein of 345 amino acids (NP_005241.1). The encoded protein, FOXI1, is an upstream regulator of pendrin; consistent with this function, mice homozygous for the targeted deletion of Foxi1 have sensorineural deafness and dilation of the vestibular aqueduct [Hulander et al 2003]. One function of FOXI1 protein is as a transcription factor that controls expression of SLC26A4 [Yang et al 2007].

Abnormal gene product. In vitro studies demonstrated that FOXI1 protein isoform constructs encoded by FOXI1 transcripts with one of the five putative pathogenic variants had compromised FOXI1 transactivation-mediated SLC26A4 expression. These data support the causal relationship between FOXI1 defects and EVA/PDS [Yang et al 2007].

KCNJ10

Gene structure. KCNJ10 located on chromosome 1 (hg19: 160,007,257-160,040,051) is 32,795 bp and comprises two exons (NM_002241.4), the first of which is noncoding. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, biallelic pathogenic variants in KCNJ10 have not been identified in persons with PDS. However, digenic inheritance of one mutant KCNJ10 allele and one mutant SLC26A4 allele has been reported as causally related to EVA/PDS in two affected individuals (see Molecular Genetic Pathogenesis) [Yang et al 2009].

See Genetically Related Disorders for other phenotypes resulting from mutation of KCNJ10.

Normal gene product. The protein has 379 amino acid residues (NP_002232.2). This gene encodes a member of the inward rectifier-type potassium channel family, characterized by an increased tendency to allow potassium to flow into (rather than out of) a cell (provided by RefSeq; 7/2008). It is expressed in the stria vascularis of the cochlea, in the distal convoluted tubule of the kidney, and in glial cells in the brain.

Abnormal gene product. In vitro functional assays demonstrated that the two KCNJ10 pathogenic variants identified in families with EVA/PDS encode proteins that are detrimental to channel activity and reduce K+ conductance by about 50% [Yang et al 2009].

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available online. 2002. Accessed 5-21-14.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 5-21-14.

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Suggested Reading

  1. Petit C, Levilliers J, Marlin S, Hardelin JP. Hereditary hearing loss. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 254. New York, NY: McGraw-Hill. Available online. 2013. Accessed 5-21-14.
  2. Kochhar A, Hildebrand MS, Smith RJH. Clinical aspects of hereditary hearing loss. Genet Med. 2007;9:393–409. [PubMed: 17666886]
  3. Refetoff S, Dumont J, Vassart G. Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 158. New York, NY: McGraw-Hill. Available online. 2013. Accessed 5-21-14.

Chapter Notes

Author History

Fatemeh Alasti, PhD (2011-present)
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)

Revision History

  • 29 May 2014 (me) Comprehensive update posted live
  • 20 December 2012 (cd) Revision: clinical testing available for FOXI1 and KCNJ10
  • 22 December 2011 (me) Comprehensive update posted live
  • 2 April 2009 (me) Comprehensive update posted live
  • 2 July 2008 (cd) Revision: deletion/duplication analysis available clinically
  • 31 August 2006 (me) Comprehensive update posted to live Web site
  • 15 July 2004 (rjhs) Revision: use of an interpreter
  • 28 June 2004 (me) Comprehensive update posted to live Web site
  • 2 July 2003 (rjhs) Revisions
  • 1 May 2001 (me) Comprehensive update posted to live Web site
  • 28 September 1998 (pb) Review posted to live Web site
  • 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe
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