Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.0.0
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: SLC26A4
• Condition: Pendred syndrome
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• SLC26A4 ⇔ 0010134 (pendred syndrome; pds): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: SLC26A4 ⇔ 0010134 (OMIM:274600)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Communication Deficit / Referral to multidisciplinary care team, as available, to facilitate communication development and discussion of other interventions (such as hearing aids, cochlear implants)	1	2C	3B	3	9CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Pendred syndrome (PDS) and nonsyndromic enlarged vestibular aqueduct (NSEVA or EVA) are considered part of the same disease spectrum. Pathogenic variants in SLC26A4 are one of the most frequent causes of hereditary deafness. The prevalence of PDS/NSEVA is estimated as 1-9:100,000. Although precise prevalence is unknown, PDS may account for between 1-15% of hereditary deafness. In an unbiased screen of 2434 persons who underwent comprehensive genetic testing for hearing loss, PDS/NSEVA caused by biallelic pathogenic variants in SLC26A4 was the third most common diagnosis of 79 different genetic diagnoses, comprising 6% of the total. [1, 2, 3, 4, 5]

Clinical Features

PDS/NSEVA comprises a phenotypic spectrum of sensorineural hearing loss (SNHL) that is classically congenital (prelingual), bilateral, non-progressive and often severe to profound (although later-onset, unilateral and/or mild-to-moderate progressive hearing impairment also occurs); vestibular dysfunction; and characteristic temporal bone abnormalities including EVA with or without cochlear hypoplasia. EVA is usually bilateral, but unilateral EVA may occur. When bilateral EVA with cochlear hypoplasia is present, it is referred to as Mondini dysplasia. PDS/NSEVA also includes variable development of goiter. Patients are usually euthyroid, but some have abnormal thyroid function, such as hypothyroidism. Abnormal thyroid function in the absence of goiter has not been reported. Thyroid nodules and carcinoma have been observed in rare cases. Intellectual disability has been reported in one multigenerational family. [1, 2, 3, 4, 5, 6, 7]

Natural History

Progression of hearing impairment can be rapid in early childhood and may be associated with head injury, infection, or delayed secondary hydrops. Occasionally the hearing loss develops later in childhood. Vertigo can precede or accompany fluctuations in hearing. The frequency of episodes of vertigo and the rate of progression of hearing loss may be pathogenic variant dependent. Progression of hearing loss is generally more common in patients with more severe inner ear anomalies. Vestibular dysfunction may manifest in infants with normal motor development who episodically have trouble walking.
Deafness is not typically associated with increased mortality. For children, deafness may have significant consequences for linguistic cognitive, emotional, educational, and social development. Children with hearing loss may have difficulty learning grammar, word order, idiomatic expressions, and other forms of verbal communication. Delayed language and speech, low educational attainment, increased behavior problems, decreased psychosocial well-being, and poor adaptive skills are all associated with hearing loss in children. Educational intervention is insufficient to completely remediate these deficiencies. Thus, early identification and timely intervention is essential for optimal cognitive development in children with prelingual deafness. Historically, children who are deaf or hard of hearing were not identified until two-to-three years of age, and those with hearing thresholds between ~25 and 40 dB hearing level were often undetected until school age.
Members of the Deaf community in the United States are deaf and use American Sign Language. As in other cultures, members are characterized by unique social and societal attributes. Members of the Deaf community (i.e., the Deaf) do not consider themselves to be hearing "impaired," nor do they feel that they have a hearing "loss." Rather, they consider themselves deaf. Their deafness is not considered to be a pathology or disease to be treated or cured. "Hard of hearing" is more functional than audiologic. It is used by the Deaf to signify that a person has some usable hearing – anything from mild to severe hearing loss.
"Hearing impairment" and "hearing loss" are often in guidelines and therefore this report will use the terms as used in the guidelines.
In PDS, goiter, can develop from late childhood into early adult life, generally appearing after age 10. Goiter enlargement continues to increase 2.6-fold with each decade. Development of hypothyroidism may by influenced by nutritional iodine intake. [1, 2, 3, 8, 9, 10, 11, 12, 13, 14]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/Hearing-Loss-ACT-Sheet.pdf

Referral to a multidisciplinary care center, when available, is recommended. A team approach that includes otolaryngologists, clinical geneticists, genetic counselors, audiologists, speech and language specialists, early hearing intervention and family support specialists (which may include other individuals who are deaf or hard of hearing or other parents of deaf or hard-of-hearing children), and other appropriate specialists offer optimal opportunity to provide ongoing management and support of deaf and hard-of-hearing individuals and their families as their needs change over time. (Tier 2) [10, 11, 13, 15]

Regardless of newborn hearing screening results, children diagnosed with PDS should have audiologic testing again between 9-30 months of age. (Tier 2) [10, 15]

To establish the extent of involvement in an individual with PDS/NSEVA, the following evaluations are recommended:
- 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. (Tier 4) [3, 14]

Early intervention should begin as soon as possible after confirming hearing loss, regardless of age of identification or the type of hearing loss. When possible, it is recommended that intervention begin within first year, optimally by the age of 6 months. Early intervention comprises evaluation for amplification or sensory devices, surgical and medical evaluation, and communication assessment and therapy. The purpose of early intervention is meet the individualized needs of the child and family, including acquisition of communication competence, social skills, emotional well-being, and positive self-esteem. (Tier 2) [10, 12, 13, 16]

Shorter duration of hearing loss was associated with better outcomes, as it meant upon detection of hearing loss children and families could be provided with intervention services. Eleven research studies reported on the influence of duration of hearing loss on outcomes for children with hearing loss. A wide range of speech and language measures were captured using different methodologies. Almost all studies included children who used cochlear implants. Children who had a shorter duration of hearing loss tended to do better in terms of speech and language measures compared to their peers with a longer duration of hearing loss. The impact of duration of hearing loss on other outcomes such as reading ability and play were poorly represented in the literature. The evidence indicates that a composite of interrelated constructs of a habilitation methodology contribute to optimal outcomes for children with hearing loss. (Tier 1) [17]

If the family chooses, fitting of hearing aid amplification no later than four months of age (or as soon as there is confirmation that the child is deaf or hard of hearing) is optimal, if not medically contraindicated (e.g., draining ear, local skin or ear canal condition, absent auditory nerves). The purpose of hearing aid amplification in infants who are deaf or hard of hearing is to facilitate timely and optimal auditory development as a precursor to development of spoken language. (Tier 2) [10, 13]

Age at fitting of hearing aids may influence outcomes for children who have hearing loss. Timely access to audition is likely to support the development of speech and language skills. Age at fitting of hearing aids interacts with other variables (such as age at diagnosis and commencement of intervention programs). This finding highlights the complex inter-relationship between variables and their influence on outcomes. (Tier 1) [17]

If the family’s goals for their child include development of spoken language, cochlear implants are the mainstay of treatment for most children with severe to profound hearing loss. Cochlear implants should only be considered after an assessment by a multidisciplinary team. As part of the assessment, children should also have had a valid trial of an acoustic hearing aid for at least 3 months (unless contraindicated or inappropriate). If there is failure to make expected progress with appropriately fitted amplification in those with severe to profound hearing loss, cochlear implants are indicated. Timing of the intervention remains critical, with better outcomes achieved for those receiving an implant by 2 years of age. Outcomes following cochlear implantation can be impacted by a number of variables that include: age at implantation, progression of hearing loss, duration of device use, cochlear morphology and cranial nerve VIII integrity, electrode placement, high qualify mapping of speech processor, parental educational level, and involvement in family centered, intensive-auditory based intervention. In general, device failure rates after successful implantation are low (less than 5% over 15 years). (Tier 2) [9, 10, 12, 13]

A child’s age at the time of cochlear implantation does influence outcomes for children who have hearing loss. The younger a child is when they receive a cochlear implant, the better the outcomes. However, there is no consensus regarding a minimum age or an optimum age for implantation. Success following implantation is dependent upon high quality intervention services. (Tier 1) [17]

A systematic review of outcomes of cochlear implantation in predominantly pediatric patients with PDS included 231 patients with at least 234 implants (22 studies), 154 of which (13 studies) were genetically confirmed. Regardless of the assessment method used, post-implantation hearing outcomes were generally good with patients experiencing useful functional improvement in auditory/speech and language performance. (Tier 1) [5]

To treat the thyroid manifestations of PDS/EVA standard medical and/or surgical treatment of thyromegaly and/or abnormal thyroid function is appropriate, and requires consultation with an endocrinologist. (Tier 4) [1, 2, 3]

Surveillance

Regular surveillance of hearing status is recommended for all children with hearing levels that fall outside the range of normal in one or both ears. Regular assessment of progress of communication development (receptive and expressive language, speech, and auditory skills) through appropriate protocols is recommended every 6 months in the infant/toddler period and annually thereafter. (Tier 2) [10, 16]

Thyroid surveillance includes the following:
- Lifelong monitoring thyroid function with T3, T4, and TSH tests every 2-3 years.
- Lifelong assessment of thyroid size by physical examination and/or ultrasonography to monitor volumetric changes. (Tier 3) [3]

In a prospective cohort study of 70 individuals with EVA and hearing loss, the sensitivity and specificity of thyroid ultrasonography for detecting enlargement (thyroid volume >97th percentile of sex- and age-specific normative data) for 2 SLC26A4 mutant alleles were 60% and 89%, respectively, for subjects 10 years or younger; and 78% and 57%, respectively, for subjects older than 10 years. No direct evidence on the effectiveness of thyroid surveillance in patients with SLC26A4 pathogenic variants was identified. Several reports have documented the presence of follicular thyroid carcinomas in patients with PDS. Follicular variant of papillary thyroid cancer has been documented in an adult patient from Japan, while his identical twin brother had a multinodular goiter. In a case series of 52 patients with PDS with evidence of abnormal thyroid function, 15 of the 43 with goiter (35%) progressed to surgical intervention. (Tier 5) [18, 19, 20]

Surveillance should also include annual or biennial examination by an endocrinologist familiar with PDS. (Tier 4) [3]

Circumstances to Avoid

Some providers recommend avoidance of head trauma, including activities like weightlifting and contact sports. The value of this approach is debatable and should be considered on an individual basis. (Tier 4) [3]

A meta-analysis of progressive hearing loss and head trauma (including blunt trauma, respiratory infection, barotrauma, exercise and undefined head trauma) in patients with EVA (SLC26A4 pathogenic variant status not determined) found no difference in the incidence of progression between patients with and without head trauma (2 retrospective studies, total of 72 ears) with 22% of ears with a history of head trauma showing long-term progression compared to 33% of ears with no history of head trauma showing long-term progression. (Tier 1) [8]

Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately. (Tier 4) [14]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive
There are rare reports of digenic inheritance, which are not included in this report. [1, 2, 3, 4, 6, 7, 14]

Prevalence of Genetic Variants

Approximately 40-90% of PDS/NSEVA cases are attributed to pathogenic variants in SLC26A4, which varies by ascertainment, inheritance, and ethnicity. In patients ascertained for inner ear malformations (specifically EVA with or without cochlear hypoplasia), the proportion of cases attributable to SLC26A4 is ~40%-50% in the European-American population and higher in multiplex families and Asian populations. (Tier 3) [2, 3, 4, 6]

A meta-analysis including 2294 cases and 3193 controls in multiethnic cohorts found that pathogenic variants in the SLC26A4 gene accounted for 73.64% (648/880) of patients with EVA. (Tier 1) [7]

Penetrance

The degree of hearing loss in persons with NSEVA is greater if two (as opposed to 1 or 0) SLC26A4 pathogenic variants are identified. (Tier 3) [3]

In a systematic review of progressive hearing loss in patients with EVA (SLC26A4 pathogenic variant status not determined), overall, 442 of 1115 (39.6%) of ears (23 studies) showed evidence of progressive hearing loss. (Tier 1) [8]

Objective evidence of vestibular dysfunction can be demonstrated in 66% of individuals with PDS, ranging from mild unilateral canal paresis to gross bilateral absence of function. (Tier 4) [3]

In clinical studies including patients from 4-55 years of age (2 familial studies of 23 and 36 patients, one study of 52 unrelated patients), between 48-83% were found to have goiter, and of those with goiter 11-44% had evidence of abnormal thyroid function. (Tier 3) [2, 3, 6]

Approximately 75% of individuals with PDS have evidence of goiter on clinical exam. However, some studies suggest that a goiter develops in only 40-50% of individuals with PDS. (Tier 3) [3]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Considerable phenotypic variability has been reported in PDS/NSEVA. Intra- and interfamilial variability in number of ears affected, severity and progression of hearing loss have been observed, even among affected siblings homozygous for the same SLC26A4 pathogenic variant. Affected siblings have been reported to be discordant for temporal bone anomalies. Thyroid enlargement is variably present, and depends partly on nutritional iodine intake. In 2 large families (total of 23 individuals) who all had profound congenital deafness and the same SLC26A4 pathogenic variant, goiter was present in less than half of the individuals and only 3 were found to have abnormal iodine uptake. (Tier 3) [2, 3, 6]

4. What is the Nature of the Intervention?

Nature of Intervention

Services for people who are deaf aim to improve their quality of life by maximizing their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. General risks and complications of cochlear implantation include risk of meningitis, infection, facial nerve paralysis, electrode migration and anesthesia risk; however, the overall risks of complications of screening and treatment are estimated to be small (less than 1%). Cerebral spinal fluid (CSF) outflow is another risk of cochlear implantation, particularly in patients with EVA with and without cochlear hypoplasia. Patients who experience rapid CSF outflow (known as a CSF gusher) may be at higher risk of developing postoperative otogenic meningitis. [9, 10, 12, 13]

One systematic review of cochlear implantation of 231 patients with PDS (148 with EVA and 36 with Mondini/cochlear dysplasia) reported intraoperative CSF leak in 46 patients (20%), with no reports of meningitis, compared to the 1-10% previously published in patients without inner ear dysplasia. [5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

If 1-2:1000 infants are diagnosed as deaf or hard of hearing at birth, it is estimated that another 1-2:1000 will later be diagnosed with permanent hearing loss. This may reflect delayed-onset hearing loss as well as missed conductive, sensory, or neural hearing loss at the time of newborn hearing screen. (Tier 3) [10, 11]

Based on a study of 57 individuals with PDS, thyroid dysfunction is variable and inclusion of goiter as a diagnostic requirement will lead to under-ascertainment. (Tier 3) [2]

Detection of euthyroid goiter depends on the method used to assess thyroid size. Nutritional iodine intake may prevent thyroid enlargement. (Tier 4) [3]

Date of Search: 08.18.2020 (updated 01.12.2021)

Reference List

1. Pendred syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=705

2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. PENDRED SYNDROME; PDS. MIM: 274600: 2016 Feb 12. World Wide Web URL: http://omim.org.

3. Smith RJH, Iwasa Y, Schaefer AM. Pendred Syndrome/Nonsyndromic Enlarged Vestibular Aqueduct. GeneReviews®. (1993)

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT; DFNB4. MIM: 600791: 2019 Mar 07. World Wide Web URL: http://omim.org.

5. Biggs K, Lovett A, Metcalfe C, Muzaffar J, Monksfield P, Bance M. Outcomes of Cochlear Implantation in Patients with Pendred syndrome: A Systematic Review and Narrative Synthesis. J Int Adv Otol. (2020) 16(2148-3817):432-442.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4. MIM: 605646: 2019 Mar 07. World Wide Web URL: http://omim.org.

7. Lu YJ, Yao J, Wei QJ, Xing GQ, Cao X. Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis. Medicine (Baltimore). (2015) 94(1536-5964):e2248.

8. Alemi AS, Chan DK. Progressive Hearing Loss and Head Trauma in Enlarged Vestibular Aqueduct: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. (2015) 153(1097-6817):512-7.

9. National Institute for Health and Care Excellence (NICE). Cochlear implants for children and adults with severe to profound deafness. Technology appraisal guidance [TA566].. (2019) Accessed: 2021-01-12. Website: https://www.nice.org.uk/guidance/ta566

10. Joint Committee on Infant Hearing (JCIH). Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. Journal of Early Hearing Detection and Intervention. (2019) Accessed: 2021-01-25. Website: https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=1104&context=jehdi

11. Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, Rehm HL, Robin NH, Scott DA, Yoshinaga-Itano C. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. (2014) 16(1530-0366):347-55.

12. . Universal screening for hearing loss in newborns: US Preventive Services Task Force recommendation statement. Pediatrics. Pediatrics. (2008) 122(1098-4275):143-8.

13. New York State Department of Health, Division of Family Health, Bureau of Early Intervention. Clinical Practice Guideline: Report of the Recommendations - Hearing loss, Assessment and Intervention for Young Children. (2007) Accessed: 2021-01-25. Website: https://www.health.ny.gov/community/infants_children/early_intervention/docs/guidelines_hearing_loss_recommendations.pdf

14. Shearer AE, Hildebrand MS, Smith RJH. Hereditary Hearing Loss and Deafness Overview. GeneReviews®. (1993)

15. Trinidad-Ramos G, de Aguilar VA, Jaudenes-Casaubón C, Núñez-Batalla F, Sequí-Canet JM. Early hearing detection and intervention: 2010 CODEPEH recommendation. Acta otorrinolaringologica espanola. (Acta) 61(1988-3013):69-77.

16. American Academy of Pediatrics (AAP) / Joint Committee on Infant Hearing (JCIH). Supplement to JCIH 2007 Position Statement: Principles and Guidelines for Early Intervention After Confirmation That a Child Is Deaf or Hard of Hearing. Pediatrics. (2013) Accessed: 2021-01-25. Website: https://pediatrics.aappublications.org/content/pediatrics/131/4/e1324.full.pdf

17. Centre for Allied Health Evidence. Kumar et al. A systematic review of the literature on early intervention for children with permanent hearing loss. Volumes 1 and 2.. (2008) Accessed: 2020-03-21. Website: https://www.unisa.edu.au/cahe

18. Madeo AC, Manichaikul A, Reynolds JC, Sarlis NJ, Pryor SP, Shawker TH, Griffith AJ. Evaluation of the thyroid in patients with hearing loss and enlarged vestibular aqueducts. Arch Otolaryngol Head Neck Surg. (2009) 135(1538-361X):670-6.

19. Reardon W, Coffey R, Chowdhury T, Grossman A, Jan H, Britton K, Kendall-Taylor P, Trembath R. Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome. J Med Genet. (1999) 36(0022-2593):595-8.

20. Wémeau JL, Kopp P. Pendred syndrome. Best Pract Res Clin Endocrinol Metab. (2017) 31(1878-1594):213-224.