Etiologic and Audiologic Characteristics of Patients With Pediatric-Onset Unilateral and Asymmetric Sensorineural Hearing Loss | Genetics and Genomics | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Figure.  Representative Inner Ear Malformations on Temporal Bone High-Resolution Computed Tomography
Representative Inner Ear Malformations on Temporal Bone High-Resolution Computed Tomography

A, Axial view showing common cavity deformity of cochlea (c). B, Axial view showing incomplete partition type 1 of cochlea (c), accompanied by an enlarged cystic vestibule (v). C, Axial view showing dilated vestibule (v). D, Axial view showing stenosis of the cochlear aperture (ca).

Table 1.  Demographic Characteristics of the Patientsa
Demographic Characteristics of the Patientsa
Table 2.  Comparison of Audiologic Features Among Different Groups
Comparison of Audiologic Features Among Different Groups
Table 3.  Comparison of HRCT Findings Among Different Groups
Comparison of HRCT Findings Among Different Groups
Table 4.  Comparison of Genetics Results Among Different Groups
Comparison of Genetics Results Among Different Groups
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Original Investigation
September 2017

Etiologic and Audiologic Characteristics of Patients With Pediatric-Onset Unilateral and Asymmetric Sensorineural Hearing Loss

Author Affiliations
  • 1Department of Otolaryngology, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
  • 2Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
  • 3Department of Otolaryngology, Taichung Tzu-Chi Hospital, Taichung, Taiwan
  • 4Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  • 5Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
  • 6Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
JAMA Otolaryngol Head Neck Surg. 2017;143(9):912-919. doi:10.1001/jamaoto.2017.0945
Key Points

Question  What are the etiologic and audiologic features of patients with pediatric-onset unilateral and asymmetric hearing loss?

Findings  In this cohort study of 133 patients, inner ear malformations were detected at a higher rate in patients with unilateral hearing loss than in those with asymmetric hearing loss, whereas common genetic mutations were detected at a higher rate in patients with asymmetric hearing loss than in those with unilateral hearing loss.

Meaning  During the general etiologic workup, imaging studies might be prioritized for patients with unilateral hearing loss; genetic testing might be prioritized for patients with asymmetric hearing loss.

Abstract

Importance  Pediatric-onset unilateral and asymmetric sensorineural hearing loss (SNHL) is a common condition, but in most patients, the cause remains unclear; thus, determination of the hearing outlook is difficult.

Objective  To analyze the etiologic and audiologic characteristics of pediatric-onset unilateral and asymmetric SNHL.

Design, Setting, and Participants  In this retrospective cohort study performed from January 1, 2008, through December 31, 2016, patients at a tertiary referral center who were diagnosed with pediatric-onset unilateral or asymmetric SNHL were divided into 3 groups according to their hearing levels: unilateral hearing loss with scaled-out levels (UHL-SO), unilateral hearing loss with residual hearing (UHL-RH), and asymmetric hearing loss (AHL).

Main Outcomes and Measures  Basic demographic data, family and medical histories, audiologic results, imaging findings, and genetic results were ascertained and compared among patients of the 3 groups.

Results  A total of 133 patients (mean [SD] age, 9.1 [10.9] years; 63 [47.4%] male and 70 [52.6%] female), including 50 with UHL-SO, 42 with UHL-RH, and 41 with AHL, were enrolled for analyses. Of 50 patients with UHL-SO, 49 (98.0%) had stable hearing levels with time, whereas 10 of 42 patients with UHL-RH (23.8%) and 18 of 41 patients with AHL (43.9%) revealed progressive or fluctuating hearing loss. Inner ear malformations detected with temporal bone high-resolution computed tomography, particularly cochlear aperture stenosis, were detected at higher rates in patients with UHL-SO (9 of 31 [29.0%]) and UHL-RH (6 of 24 [25.0%]) than in those with AHL (1 of 30 [3.3%]). In contrast, screening for mutations in 3 common deafness genes—GJB2, SLC26A4, and MTRNR1—achieved definite diagnosis in a higher percentage of patients with AHL (10 of 37 [27.0%]) than patients with UHL-SO (0 of 33) and UHL-RH (1 of 25 [4.0%]).

Conclusions and Relevance  The UHL-SO and UHL-RH conditions share a common or similar etiopathogenesis different from that of AHL. Imaging studies and genetic testing might be prioritized during the respective general etiologic workups for patients with UHL and AHL. Regular hearing checkups are warranted for patients with UHL and AHL because a certain proportion of patients might sustain progression in SNHL.

Introduction

Sensorineural hearing loss (SNHL) is the most common sensory deficit in children. The prevalence of bilateral SNHL in newborns is approximately 0.1% to 0.2%1-3 and approximately 0.1% in unilateral SNHL.3,4 Because some children develop hearing impairment later in childhood, it has been documented that the prevalence of bilateral SNHL might increase to 0.27% before the age of 5 years and to 0.35% during adolescence1 and that 3% to 6% of school-aged children might have some degree of unilateral hearing loss (UHL).5 Without timely intervention, bilateral SNHL may lead to delayed language development, resulting in poor academic performance, poor communication, and negative psychosocial development.6 Similarly, the lack of binaural auditory refinement in patients with unilateral SNHL might compromise sound localization and signal discrimination,7 contributing to behavioral problems and academic difficulties in affected children.8,9

For children with bilateral or unilateral SNHL, the parents are usually eager to know the causes and are concerned about the hearing outlook. The causes of bilateral SNHL in children have been well investigated, with more than 50% of cases attributable to genetic causes, followed by congenital infections, ototoxicity, prematurity, and asphyxiation.1,2 By contrast, relatively less clarification exists with regard to the causes of unilateral SNHL. Several risk factors have been related to unilateral or asymmetric SNHL in the literature, including inner ear malformations (IEMs), congenital cytomegalovirus (CMV) infection, meningitis, and temporal bone trauma.10-12 However, in more than 50% of children with unilateral SNHL, no identifiable risk factors were found despite comprehensive etiologic investigations7,12; thus, determination of the hearing outcomes in these patients is difficult. For a better determination of the hearing outlook, delineation and comparison of causes among different patient groups with specific audiologic features might be necessary. In this study, we analyzed the causes in patients with unilateral SNHL with or without residual hearing and in those with bilateral but asymmetric SNHL and then characterized the hearing loss patterns in each group of patients.

Methods
Patient Recruitment and Grouping

From January 1, 2008, through December 31, 2016, patients at National Taiwan University Hospital who were diagnosed with pediatric-onset unilateral SNHL or with asymmetric SNHL were included in this study. Diagnoses were based on audiometric data, and all patients were diagnosed with SNHL before 18 years of age. Patients older than 50 years, with conductive or mixed-type hearing impairment, or without complete history records were excluded. Basic demographic data, family history, birth history (including maternal history, possible birth trauma, and the patient’s Apgar score), and medical history of each patient were ascertained. Autoimmune profiles (including C3, C4, and antinuclear antibody levels) and thyroid function (including thyrotropin and free thyroxine levels) were also examined. This study was approved by the Research Ethics Committee of the National Taiwan University Hospital.

According to the audiologic results, patients were divided into 3 groups: UHL with scaled-out levels (UHL-SO), UHL with residual hearing (UHL-RH), and asymmetric hearing loss (AHL). Unilateral hearing loss was defined as SNHL that was confined to a single ear, with hearing levels of 25 dB or less in the better ear at all frequencies; AHL was defined as bilateral SNHL with hearing levels greater than 25 dB in the better ear at any frequency. Patients were recorded as having scaled-out levels if hearing levels of their worse ears exceeded maximal testable thresholds at all frequencies. Asymmetry was defined as a difference of greater than 15 dB in mean hearing levels between the 2 ears, with that in the better-hearing ear being greater than 25 dB10,13 (eFigure in the Supplement).

Audiologic Tests

The audiologic assessments were performed by experienced audiologists using pure tone audiometry or diagnostic auditory brainstem response depending on patients’ ages or neurologic status. The audiologic results were interpreted by 3 otologists (P.-H.L., C.-C.W., T.-C.L.) and were detailed in 4 parameters: the onset of hearing loss, hearing levels, hearing loss patterns, and the configurations of audiograms.14 The onset of hearing loss was divided as congenital, younger than 10 years, or 10 to 18 years of age. Congenital hearing loss was ascertained when a patient failed a newborn hearing screening that measured automated auditory brainstem response or otoacoustic emissions at birth. The hearing levels were determined by averaging the 4-tone thresholds (0.5, 1, 2, and 4 kHz). The hearing loss patterns were evaluated using serial audiologic tests or history and were categorized as stable, progressive, fluctuating, or other.14 During the follow-up period, patients with a repeated history of sudden hearing loss of more than 15 dB at any frequency were noted to have fluctuating hearing loss, those with a deterioration of 10 dB or more in mean hearing levels were classified as having progressive hearing loss, and those with a deterioration of less than 10 dB were noted as having stable hearing loss; otherwise, the hearing loss pattern was defined as other.14 The configurations of audiograms were classified as flat, sloping, high-tone hearing loss, or other.14

Imaging Studies

Noncontrast temporal bone high-resolution computed tomography (HRCT) with contiguous axial and coronal sections of 0.6-mm thickness was performed to investigate the structure of the inner ear. One pediatric neuroradiologist and 2 otologists (P.-H.L., C.-C.W.), who were masked to the laterality of the hearing loss, interpreted the images and determined the types of IEMs according to the morphologic features of cochlea, vestibule, semicircular canal, vestibular aqueduct, and cochlear aperture.15,16 In cases in which interpretations were inconsistent, the otologists reviewed the images together to achieve a consensus. Enlarged vestibular aqueduct (EVA) was characterized by a diameter of the vestibular aqueduct at the midpoint between the common crus and the external aperture that exceeded 2 mm,17 whereas cochlear aperture stenosis was defined as 1.5 mm or less in axial measurements.16,18

Genetic Examination

Genetic counseling was offered to all patients and/or their parents. Patients who agreed to undergo genetic testing with written informed consent had Sanger sequencing performed for the 3 common deafness genes: GJB2 (or CX26) (OMIM 121011), SLC26A4 (or PDS) (OMIM 605646), and MTRNR1 (mitochondrial 12S ribosomal RNA) (OMIM 561000).19 Both exons of GJB2, all 21 exons of SLC26A4, and the entire MTRNR1 gene were sequenced. Patients with biallelic GJB2 mutations, biallelic SLC26A4 mutations, or mitochondrial genetic mutations (in homoplasmy or heteroplasmy) were interpreted as having a definite genetic diagnosis by 2 clinical geneticists (Yin-Hung Lin and C.-C.W.).

Statistical Analysis

Categorical data were summarized as number (percentage) and analyzed by the χ2 or Fisher tests when appropriate; continuous data were analyzed by the analysis of variance test or unpaired, 2-tailed t test when appropriate. SPSS for Windows, version 22.0 (SPSS Inc) was used for all statistical analyses. P < .05 (2-sided) was interpreted as being statistically significant.

Results
Demographic Data

A total of 133 patients were included in this study (mean [SD] age, 9.1 [10.9] years; 63 [47.4%] male and 70 [52.6%] female), including 50 patients (37.6%) with UHL-SO, 42 patients (31.6%) with UHL-RH, and 41 patients (30.8%) with AHL. The demographic data of the patients are given in Table 1. No difference was found in the demographic data, family history, or birth history among the patients in the 3 groups. As for medical history, 5 patients (12.2%) with AHL had abnormal autoimmune profiles, and this percentage was higher than those in the other 2 groups (AHL vs UHL: odds ratio [OR], 12.6; 95% CI, 1.4-112.0).

Audiologic Features

The audiologic features of the patients are detailed in Table 2. Of the 50 patients with UHL-SO, 21 (42.0%) revealed hearing loss at birth, 28 (56.0%) developed hearing loss before 10 years, and 1 (2.0%) developed hearing loss after 10 years. Of the 42 patients with UHL-RH, 17 (40.5%) revealed hearing loss at birth, 18 (42.9%) developed hearing loss before 10 years, and 7 (16.7%) developed hearing loss after 10 years. Of the 41 patients with AHL, 9 (22.0%) had hearing loss at birth, 28 (68.3%) developed hearing loss before 10 years, and 4 (9.8%) developed hearing loss after 10 years. Patients diagnosed with UHL-SO or UHL-RH developed SNHL earlier than patients diagnosed with AHL.

Hearing loss patterns differed among the 3 groups. Almost all patients (49 of 50 [98.0%]) with UHL-SO had stable hearing levels. By contrast, only two-thirds of patients with UHL-RH (28 of 42 [66.7%]) and half of patients with AHL (22 of 41 [53.7%]) had stable hearing levels. Of note, 10 of the 42 patients with UHL-RH (23.8%) and 18 of the 41 patients with AHL (43.9%) experienced progressive or fluctuating hearing loss.

The configurations of the audiograms also demonstrated differences among the 3 groups. The configurations of the audiograms were flat in all patients with UHL-SO. By contrast, among patients with UHL-RH, only 13 patients (31.0%) had flat-shaped audiograms and 12 (28.6%) had sloping-shaped audiograms. Among patients with AHL, 26 (63.4%) had flat-shaped audiograms and 6 (14.6%) had sloping-shaped audiograms in the worse ear.

Imaging Findings

A total of 31 patients with UHL-SO, 24 with UHL-RH, and 30 with AHL underwent temporal bone HRCT (Table 3). No statistical differences were found in age, sex, or severity of hearing loss between patients who underwent HRCT and those who did not (eTable 1 in the Supplement). One patient with AHL (3.3%) was identified with common cavity (Figure, A), whereas 3 patients with UHL-SO (9.7%) were identified with incomplete partition type 1 (Figure, B) and 1 (3.2%) with incomplete partition type 2 of the cochlea. All other patients had normal cochlear structures. Four patients with UHL-SO (12.9%) and 1 patient with UHL-RH (4.2%) had dilated vestibule (Figure, C). Two patients with UHL-SO (6.5%), 1 patient with UHL-RH (4.2%), and 1 patient with AHL (3.3%) presented with semicircular canal dysplasia. Enlarged vestibular aqueduct was not identified in all 3 groups of patients who underwent temporal bone HRCT. No differences were found in cochlea, vestibule, and semicircular canal anomalies among the 3 groups.

In contrast, the percentages of cochlear aperture stenosis (Figure, D) were different among the 3 groups: 9 patients with UHL-SO (29.0%) and 6 patients with UHL-RH (25.0%) had cochlear aperture stenosis, but only 1 patient with AHL (3.3%) had cochlear aperture stenosis (UHL vs AHL: OR, 10.9; 95% CI, 1.4-87.0). In total, 11 patients with UHL-SO (35.5%) and 6 patients with UHL-RH (25.0%) had IEMs on HRCT, whereas only 1 patient with AHL (3.3%) had IEMs, indicating that IEMs were more prevalent among patients with UHL-SO and UHL-RH than among patients with AHL (UHL vs AHL: OR, 13.0; 95% CI, 1.6-103.2).

Fifteen patients, including 3 with UHL-SO, 3 with UHL-RH, and 9 with AHL, underwent posterior fossa magnetic resonance imaging. Positive magnetic resonance imaging findings were detected in 2 of 3 patients with UHL-SO (66.7%): one with cochlear nerve aplasia and the other with cochlear nerve hypoplasia.

Genetic Results

A total of 33 patients with UHL-SO, 25 with UHL-RH, and 37 with AHL underwent genetic testing for 3 common deafness genes (Table 4). No statistical differences were found in age, sex, or severity of hearing loss between patients who underwent genetic testing and those who did not (eTable 2 in the Supplement). Mutations were detected in a higher percentage of patients with AHL (21 of 37 [56.8%]) than in the other 2 groups (5 of 33 patients with UHL-SO [15.2%] and 7 of 25 patients with UHL-RH [28.0%]; AHL vs UHL: OR, 5.0; 95% CI, 2.0-12.5). Overall, definite genetic diagnosis was achieved in 1 patient with UHL-RH (4.0%) (GJB2 p.V37I/p.V37I) and in 10 patients with AHL (27.0%), including 6 with GJB2 p.V37I/p.V37I, 2 with GJB2 c.235delC/c.235delC, 1 with GJB2 c.235delC/p.E47X, and 1 with SLC26A4 c.919-2A>G/c919-2A>G. The percentages of patients with definite genetic diagnosis and definite GJB2 mutations in the AHL group were higher than the percentages in the other 2 groups (AHL vs UHL: OR, 18.3; 95% CI, 2.2-151.9). Patients with AHL are more likely to have a genetic cause, with GJB2 mutations being the predominant cause.

Discussion

In this study, we found that IEMs were detected at a higher rate among patients with UHL than among those with AHL, whereas common genetic mutations were detected at a higher rate among patients with AHL than among those with UHL. Specifically, cochlear aperture stenosis was identified in greater proportions of patients with UHL-SO and UHL-RH compared with patients with AHL; biallelic GJB2 mutations were detected in a higher percentage of patients with AHL compared with patients with UHL-SO or UHL-RH. Taken together, our results indicate that UHL-SO and UHL-RH might share a common or similar etiopathogenesis that is different from that of AHL.

Of note, progressive or fluctuating hearing loss was experienced in 23.8% of patients with UHL-RH and 43.9% of patients with AHL. Of those, 3 patients (7.1%) who were initially diagnosed as having UHL-RH developed progressive hearing loss and later developed AHL. The percentage was consistent with previous studies,20-22 which reported that approximately 10% to 11% of patients with UHL develop SNHL in the contralateral ear and eventually progress to bilateral SNHL. Because deterioration of hearing levels might occur in the worse and better ears, regular hearing checkups are warranted in patients with UHL-RH or AHL.

Inner ear malformations have been reported in 28.9% to 40.8% of patients with unilateral SNHL.12,23,24 Cochlear aperture stenosis has been detected with HRCT in 17%25 to 46%26 of patients with UHL. Corresponding to the finding of cochlear aperture stenosis on HRCT in these studies, 33% of patients with UHL revealed cochlear nerve deficiency on magnetic resonance imaging in another study.11 In accordance with those previous reports,11,12,23-26 17 of 55 patients with UHL (30.9%) were identified as having IEMs in the present study, with cochlear aperture stenosis being the most prevalent IEM (15 of 55 patients with UHL [27.3%]).

In addition to cochlear aperture stenosis, EVA is an IEM commonly associated with UHL and could be detected in approximately 5% to 14% of patients with UHL.12,23 To our surprise, EVA was not identified in our patients with UHL-SO or UHL-RH. A possible explanation for that finding is that, compared with previous studies23,24 that defined EVA as the midpoint diameter of vestibular aqueduct that exceeds 1.5 mm, we adopted 2 mm as the cutoff point for EVA because ears without SNHL might have vestibular aqueducts that measure up to 2 mm.17 The more stringent criterion adopted in this study might have led to a lower detection rate of EVA in our patients.

In the present study, screening for mutations in 3 common deafness genes achieved definite diagnosis in 10 patients with AHL (27.0%), including 9 with biallelic GJB2 mutations and 1 with biallelic SLC26A4 mutations. Approximately 14% to 15% of patients with biallelic GJB2 mutations might have AHL with binaural hearing level differences greater than 15 dB,27,28 and 26% to 60% of patients with biallelic SLC26A4 mutations might have AHL with binaural hearing level differences greater than 10 dB.29,30 It is thus conceivable that GJB2 and SLC26A4 mutations might be important contributors to AHL clinically. Of the 9 patients with biallelic GJB2 mutations, 6 were homozygous for GJB2 p.V37I, which is highly prevalent in the general Taiwanese population.31,32 Therefore, the observation that patients with biallelic GJB2 mutations (n = 9) significantly outnumbered those with biallelic SLC26A4 mutations (n = 1) in our AHL cohort might have resulted from the higher allele frequency of GJB2 variants in the general population and the hearing impaired cohort.

By contrast, definite genetic diagnosis was achieved in 0 patients with UHL-SO and 1 patient with UHL-RH (4.2%). These findings are consistent with a previous study33 that found that genetic examination might not be valuable in determining the cause of UHL in children. To date, there are no genetic mutations reported to be specifically associated with UHL.10 The only patient with UHL-RH with a definite genetic diagnosis was homozygous for GJB2 p.V37I. This patient was diagnosed with congenital UHL, and his hearing levels deteriorated rapidly from 65 to 85 dB by 1 year of age. Because GJB2 p.V37I is highly prevalent in the Taiwanese population,31,32 the possibility that UHL resulted from causes other than p.V37I homozygosity in this patient could not be excluded.

Strengths and Limitations

To our knowledge, this study represented the largest cohort study in the literature to analyze the audiologic, imaging, and genetic results in patients with UHL-SO, UHL-RH, and AHL. Our findings provide insights into the etiopathogenesis and hearing progression of UHL and AHL and inform strategies for assessment, management, and counseling in clinical practice. However, some limitations of this study deserve discussion. First, HRCT was not performed in 36.1% of patients because of the patients’ young age or parents’ concerns regarding radiation exposure, and 28.6% of the patients did not receive genetic examinations after being informed that UHL is less related to genetic causes. Nonetheless, it is unlikely that these factors led to significant selection biases because our analyses revealed no statistical differences in demographic data or hearing features between patients who underwent imaging or genetic examinations and those who did not. Second, the cause could only be ascertained in less than 50% of patients in each group. Thus, for most patients with UHL and AHL, the cause remained unclear. A previous study34 found that congenital CMV infection is an important cause of unilateral and bilateral SNHL in children. Although no patients in this study were confirmed to have congenital CMV infection based on birth history, it is still possible that SNHL in some patients was caused by congenital CMV infection. According to the literature, most cases of congenital CMV infection are asymptomatic at birth, but 8% to 15% of these asymptomatic newborns might develop late-onset SNHL.35-37 To confirm the diagnosis of congenital CMV infection–related SNHL, samples need to be collected from these patients within 3 weeks of birth.38,39 As such, it has been proposed that newborn CMV screening be integrated into the universal newborn hearing screening for earlier identification of at-risk patients.34,35,40 Theoretically, the implementation of newborn CMV screening will facilitate the etiologic investigation in patients with UHL or AHL. Third, the findings of this study might not be generalizable to other populations because they were obtained in a relatively homogenous Taiwanese population. It has been documented that causes of SNHL, such as genetic mutations, might differ across different populations.41 Additional investigations in other populations are needed to validate our findings.

Conclusions

Imaging and genetic analyses in this study demonstrated that UHL-SO and UHL-RH might share a common or similar etiopathogenesis different from that of AHL. Specifically, cochlear aperture stenosis was identified in 29.0% of patients with UHL-SO and 25.0% of patients with UHL-RH, whereas definite GJB2 and SLC26A4 mutations could be detected in 27.0% of patients with AHL, indicating that imaging studies and genetic testing might be prioritized during the respective general etiologic workups for patients with UHL and AHL. Meanwhile, because a certain proportion of patients with UHL or AHL might have progressive hearing loss, regular hearing checkups are warranted.

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Article Information

Corresponding Author: Chen-Chi Wu, MD, PhD, Department of Otolaryngology, National Taiwan University Hospital, Chung-Shan South Road, Taipei, Taiwan (chenchiwu@ntuh.gov.tw).

Accepted for Publication: May 3, 2017.

Published Online: July 6, 2017. doi:10.1001/jamaoto.2017.0945

Author Contributions: Drs P.-H. Lin and Wu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: P.-H. Lin, Hsu, Yi-Hsin Lin, Lee, Wu, Liu.

Acquisition, analysis, or interpretation of data: P.-H. Lin, Hsu, Yi-Hsin Lin, Yin-Hung Lin, Wu, Liu.

Drafting of the manuscript: P.-H. Lin, Lee, Wu.

Critical revision of the manuscript for important intellectual content: P.-H. Lin, Hsu, Yi-Hsin Lin, Yin-Hung Lin, Wu, Liu.

Statistical analysis: P.-H. Lin.

Obtained funding: Hsu, Wu.

Administrative, technical, or material support: Yi-Hsin Lin, Yin-Hung Lin, Lee, Wu.

Study supervision: Hsu, Wu, Liu.

Funding/Support: This study was supported by research grants 103-2628-B-002-009-MY4 from the Ministry of Science and Technology of the Executive Yuan of Taiwan (Dr Wu) and NHRI-EX105-10414PC from the National Health Research Institutes (Dr Wu).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: We thank all the patients and their parents for participating in the study.

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