Clinical characteristics.

Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL) that is usually congenital and often severe to profound (although mild-to-moderate progressive hearing impairment also occurs), vestibular dysfunction, and temporal bone abnormalities (bilateral enlarged vestibular aqueduct with or without cochlear hypoplasia). PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not.

Diagnosis/testing.

In at least 50% of probands with Pendred syndrome and/or NSEVA, the molecular diagnosis is established by identification of biallelic pathogenic variants in SLC26A4 or double heterozygosity for one pathogenic variant in SLC26A4 and one pathogenic variant in either FOXI1 or KCNJ10.

The clinical diagnosis of Pendred syndrome is established in a proband with SNHL, characteristic temporal bone abnormalities identified on thin-cut CT, and euthyroid goiter. In comparison, the clinical diagnosis of nonsyndromic enlarged vestibular aqueduct (NSEVA) is established in a proband with SNHL and the temporal bone finding of enlargement of the vestibular aqueducts. It is important to note that in PDS, the temporal bone abnormality can include both EVA and cochlear hypoplasia, an anomaly in which the cochlea has only 1.5 turns instead of the expected 2.75 turns. In NSEVA, the temporal bone abnormality is restricted to EVA, defined as a vestibular aqueduct that exceeds 1.5 mm in width at its midpoint. This distinction is relevant because thyroid enlargement is variably present, depending on methods used to assess thyroid size and nutritional iodine intake. Some studies have suggested that a goiter is present in only 50% of affected individuals.

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: Repeat audiometry every three to six months initially if hearing loss is progressive, then semiannually or annually. Baseline ultrasound examination of the thyroid with periodic physical examination and/or ultrasonography to monitor volumetric changes; thyroid function tests every two to three years.

Agents/circumstances to avoid: Some evidence suggests that dramatic increases in intracranial pressure can be associated with a sudden drop in hearing. For this reason, advisability of weightlifting and/or contact sports should be discussed with a physician/health care provider prior to participation.

Genetic counseling.

PDS/NSEVA 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 family-specific pathogenic variants are known, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) spectrum is suggested by the following clinical, temporal bone imaging, and endocrine findings.

Temporal Bone Imaging Findings

The identification and interpretation of temporal bone defects require both the appropriate test (i.e., thin-cut CT as a routine CT of the temporal bones typically will not suffice) and detailed familiarity with cochlear anatomy:

• Mondini malformation or dysplasia (bilateral enlarged vestibular aqueduct [EVA] with cochlear hypoplasia) is detected on thin-cut CT of the temporal bones. The cochlea is hypoplastic and has 1.5 cochlear turns instead of the expected 2.75 turns, and the vestibular aqueduct is enlarged, with a midpoint width exceeding 1.5 mm. The presence of both cochlear hypoplasia and EVA is known as a Mondini malformation or dysplasia.
• While the temporal bones are abnormal radiologically in all persons with PDS [Goldfeld et al 2005], a range of findings can be present. In a study of individuals homozygous for the same SLC26A4 pathogenic variant, high-resolution CT revealed that 100% had deficiency of the modiolus (i.e., the bony polyhedral structure centered on the cochlea was not apparent on a mid-modiolar section); 80% had EVA (i.e., width in the middle portion of the descending limb of the vestibular aqueduct >1.5 mm); and 75% had absence of the upper turn of the cochlea (i.e., the interscalar septum was not seen between the upper and middle turns) [Goldfeld et al 2005] (Figure 1).
• Note: A radiologic diagnosis of EVA with or without cochlear hypoplasia does not equate to a clinical diagnosis of Pendred syndrome as there are other causes of these types of temporal bone malformations without associated thyroid abnormality (see Differential Diagnosis).
• Nonsyndromic enlarged vestibular aqueduct (NSEVA) is detected on thin-cut CT of the temporal bones. The vestibular aqueduct is enlarged when its midpoint width exceeds 1.5 mm.

Figure 1.

Computed tomography in a proband with PDS shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular aqueduct, (more...)

Establishing the Diagnosis

The clinical diagnosis of PDS is established in a proband with SNHL, characteristic temporal bone abnormalities identified on thin-cut CT and euthyroid goiter; the clinical diagnosis of NSEVA is established in a proband with SNHL and the temporal bone finding of enlargement of the vestibular aqueducts (see Suggestive Findings).

The molecular diagnosis of PDS/NSEVA is established by identification of biallelic pathogenic (or likely pathogenic) variants in SLC26A4 or double heterozygosity for one pathogenic (or likely pathogenic) variant in SLC26A4 and one pathogenic (or likely pathogenic) variant in either FOXI1 or KCNJ10 (Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

The outcome of testing varies by ethnicity and phenotype.

Ethnicity:

• In Korean and Japanese probands, more than 80% have two pathogenic variants in SLC26A4, slightly more than 10% have one pathogenic variant, and fewer than 10% have no pathogenic variants [Tsukamoto et al 2003, Park et al 2005].
• In North American or northern Europeans with PDS/NSEVA only about 25% have two pathogenic variants in SLC26A4, as would be expected for autosomal recessive inheritance [Pryor et al 2005, Ito et al 2011]. About half have no detectable SLC26A4 pathogenic variants, and in 25%, only one pathogenic variant is found [Choi et al 2009a].

Phenotype:

• The number of pathogenic variants in people of northern European descent is strongly correlated with the auditory and thyroid phenotypes: those with PDS are more likely than those with NSEVA to have biallelic pathogenic variants [Azaiez et al 2007].
• The degree of hearing loss in persons with NSEVA is greater if two (as opposed to 1 or 0) SCL26A4 pathogenic variants are identified [King et al 2010, Rose et al 2017].

An explanation for these molecular findings has been described by Chattaraj et al [2017], who identified a haplotype "Caucasian EVA" (CEVA) – comprising 12 variants upstream of SLC26A4 – which is frequently found in persons with NSEVA in trans with a coding or splice site variant.

Approach to molecular genetic testing. For all persons with hearing loss, the use of a multigene panel for hearing loss and deafness maximizes the diagnostic rate while minimizing the diagnostic expense.

Hearing loss and deafness multigene panels typically include SLC26A4, FOXI1, KCNJ10, and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in panels of this type and the diagnostic sensitivity of the testing vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: Comprehensive genome sequencing (i.e., exome sequencing and genome sequencing) is currently not justified as a primary screen for genetic causes of deafness [Sloan-Heggen et al 2016].

Clinical Description

Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL), vestibular dysfunction, and temporal bone abnormalities. PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not.

Genotype-Phenotype Correlations

An understanding of the relationship between genotype and phenotype in the PDS/NSEVA spectrum is helpful in patient care.

The phenotypes PDS and NSEVA are distinguishable based on the presence of thyroid dysfunction in PDS. The thyroid phenotype is dependent on the degree of residual iodide transport function in pendrin, the protein encoded by SLC26A4 [Pryor et al 2005, Pera et al 2008].

The correlation between variant type (missense vs nonsense) and development of thyroid enlargement is not robust and individuals who have biallelic pathogenic/likely pathogenic variants in SLC26A4 are at increased risk of developing thyroid-related manifestations regardless of variant type [Pryor et al 2005, Ladsous et al 2014, Suzuki et al 2007]. (See Management.)

Pathogenic variants can occur anywhere in the 780-amino-acid protein. If a novel missense pathogenic variant is identified, it can be very difficult to predict the phenotype (i.e., hearing loss, whether moderate, severe, or profound; thyroid enlargement) in the absence of additional in vitro functional testing.

Nomenclature

Pendred syndrome (PDS) and nonsyndromic enlarged vestibular aqueduct (NSEVA) should be considered part of a disease continuum [Reardon et al 1999, Azaiez et al 2007].

PDS is also referred to as autosomal recessive sensorineural hearing impairment, enlarged vestibular aqueduct, and goiter.

NSEVA is also referred to as:

• Nonsyndromic enlarged vestibular aqueduct hearing loss;
• Autosomal recessive nonsyndromic deafness 4 (DFNB4);
• DFNB4 nonsyndromic hearing impairment and EVA.

EVA is also referred to as dilated vestibular aqueduct (DVA).

Prevalence

When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high as pathogenic variants in SLC26A4 are the third most frequent cause of hearing loss (Figure 2).

Figure 2.

In an unbiased screen of 2434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic pathogenic variants in SLC26A4 was the third most (more...)

Evaluations Following Initial Diagnosis

To establish the extent of involvement in an individual with molecularly confirmed Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) or clinically confirmed Pendred syndrome, the following evaluations are recommended if they have not already been completed:

• Assessment of auditory acuity (ABR emission testing, pure tone audiometry)
• Thyroid ultrasonography to measure the size of the thyroid and thyroid function tests (T3, T4, and TSH)
• Consultation with an endocrinologist as needed
• Consultation with a clinical geneticist and/or genetic counselor

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
• Medical and/or surgical treatment of thyromegaly and/or abnormal thyroid function (requires consultation with an endocrinologist)

Surveillance

Surveillance includes the following:

• Lifelong monitoring of hearing and thyroid function
• Annual examination by a physician familiar with hereditary hearing impairment
• Repeat audiometric testing initially every three to six months and then annually
• Annual or biennial examination by an endocrinologist familiar with PDS
• Assessment of thyroid size by physical examination and/or ultrasonography to monitor volumetric changes
• Thyroid function tests (T3, T4, and TSH) every 2-3 years [Choi et al 2011b]

Agents/Circumstances to Avoid

Based on anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, some physicians recommend avoiding activities like weightlifting and contact sports. The value of this approach is debatable and should be considered on an individual basis.

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 (see Evaluations Following 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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) is typically inherited in an autosomal recessive manner.

Biallelic pathogenic variants in SLC26A4 are causative in about 50% of affected individuals and double heterozygosity in SLC26A4 and either FOXI1 or KCNJ10 occurs in fewer than 1% of affected individuals.

Risk to Family Members of a Proband with Biallelic SLC26A4 Pathogenic Variants

Parents of a proband

• The parents of a child with biallelic SLC26A4 pathogenic variants are obligate heterozygotes (i.e., carriers of one SLC26A4 pathogenic variant).
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib has a 25% probability of having PDS/NSEVA, a 50% probability of being an asymptomatic carrier, and a 25% probability of being unaffected and not a carrier.
• Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with biallelic SLC26A4 pathogenic variants are obligate heterozygotes (carriers) for an SLC26A4 pathogenic variant.

Other family members. Each sib of the proband's parents has a 50% probability of being a carrier of an SLC26A4 pathogenic variant.

Risk to Family Members – Digenic Inheritance

Parents of a proband. One parent may be heterozygous for an SLC26A4 pathogenic variant and the other parent heterozygous for a FOXI1 or KCNJ10 pathogenic variant or, alternatively, one parent may have two pathogenic variants. Both parents should undergo confirmatory genetic testing.

Sibs of a proband. Assuming that each parent has one pathogenic variant, at conception each sib has a 25% probability of having PDS/NSEVA, a 50% probability of being an asymptomatic carrier, and a 25% probability of being unaffected and not a carrier.

Offspring of a proband. The risk to offspring of inheriting one pathogenic variant is 50%; the risk to offspring of inheriting two pathogenic variants is 25%.

Other family members. Each sib of the proband's parents will have zero, one, or two pathogenic variants depending on the genetic status of the proband's parent.

Carrier Detection

Carrier testing for relatives of an individual with PDS/NSEVA requires prior identification of the SLC26A4, FOXI1, or KCNJ10 pathogenic variants in the family.

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 members of the Deaf community and who sign requires the services of a skilled interpreter.
• Members of the Deaf community 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."
• 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.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.

Family planning

• The optimal time for clarification of carrier status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling to young adults who are deaf or who may be carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once both pathogenic variants have been identified in a family member with PDS/NSEVA, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Loss of the endocochlear potential is the cause of deafness in Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) [Wangemann et al 2004]. Normal endolymphatic K⁺ concentrations suggest that absent or dysfunctional pendrin results in a secondary loss of KCNJ10 protein expression and the endocochlear potential.

The thyroid phenotype (PDS and NSEVA) depends on the degree of residual iodide transport function in pendrin, the protein encoded by SLC26A4 [Pryor et al 2005, Pera et al 2008].Biallelic loss-of-function variants in SLC26A4 are invariably associated with thyroid dysfunction resulting from impaired iodide organification and reduced iodide efflux into the thyroid follicle. In the absence of pendrin, expression of the chloride channel-5 (ClC-5) will also be increased and will transiently compensate 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].

However, the correlation between variant type (missense vs nonsense) and the development of thyroid enlargement is not robust and individuals who are biallelic for pathogenic/likely pathogenic variants in SLC26A4 are at increased risk of developing thyroid-related manifestations regardless of variant type.

In persons with PDS/NSEVA 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/NSEVA [Yang et al 2009]. Data from Yang et al [2007] are also consistent with a dosage-dependent model for the molecular pathogenesis of PDS/NSEVA that involves not only SLC26A4 but also FOXI1, which regulates its transcriptional regulatory machinery.

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 enlarged vestibular aqueduct (EVA) demonstrated double heterozygosity with a pathogenic variant in SLC26A4 and a pathogenic variant in FOXI1. In support of the pathogenic 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/NSEVA, 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 PDS/NSEVA. The KCNJ10 pathogenic variants reduce K(+) conductance activity, which is critical for generating and maintaining the endocochlear potential [Yang et al 2009].

Pathogenic variants in FOXI1 or KCNJ10 are a rare cause of EVA [Jonard et al 2010, Wu et al 2010].

Author Notes

Hereditary Hearing Loss Home Page

Author History

Fatemeh Alasti, PhD; University of Iowa (2011-2017)
Lorraine A Everett, MD; National Institutes of Health (1998-2001)
Eric D Green, MD, PhD; National Institutes of Health (1998-2001)
Yoichiro Iwasa, MD, PhD; University of Iowa (2020-present)
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Amanda M Schaefer, MS, LGC; University of Iowa (2020-present)
Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD; University of Antwerp (1998-2017)
Peter Van Hauwe; University of Antwerp (1998-2001)

Revision History

• 18 June 2020 (rjhs) Revision: added authors Iwasa and Schaefer, citations Ladsous et al [2014] and Suzuki et al [2007]; updated thyroid surveillance recommendations
• 19 October 2017 (bp) Comprehensive update posted live
• 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

Published Guidelines / Consensus Statements

• 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 6-27-23.
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 6-27-23.

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