Hearing loss in children with growth hormone deficiency

Transcription

1 Pediatr Med. 2017; 1(1): Journal of Pediatrics and Pediatric Medicine Mini Review Open Access Hearing loss in children with growth hormone deficiency John S. Muus 1, Forest W. Weir 1, Kathryn L. Kreicher 1, Deborah A. Bowlby 2, Christopher M. Discolo1, Ted A. Meyer 1 1 Department of Otolaryngology-Head & Neck Surgery, Medical University of South Carolina, Charleston, SC 2 Department of Endocrinology, Medical University of South Carolina, Charleston, SC Article Info Article Notes Received: October 05, 2017 Accepted: November 20, 2017 *Correspondence: Dr. John S. Muus, BS Medical University of South Carolina Department of Otolaryngology-Head & Neck Surgery 135 Rutledge Ave, MC550 Charleston, SC 29425, USA, muus@musc.edu 2017 Muus JS. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. ABSTRACT Objective: Although insulin-like growth factor 1 (IGF-1) has been shown to be important for inner-ear development in animal models, little is known about the otologic and audiologic findings of children with growth hormone deficiency (GHD). The goal of this study is to evaluate the prevalence, type, and severity of hearing impairment in children with GHD. Methods: Audiologic, otologic, and demographic data were recorded for children with a diagnosis of GHD in the AudGen database. Data for each patient were selected based on the first encounter with available complete audiometric data or the first encounter with a type of hearing loss documented. The patients were then stratified by type and severity of hearing loss, and otologic issues were documented. A separate cohort comprised of children with GHD without hearing loss was compared as a control. Results: 209 children with GHD met inclusion criteria. 173 (83%) of these patients had hearing loss. 79% of losses were bilateral and 21% were unilateral (309 total ears with hearing loss). 293 of the 309 ears with hearing loss had audiograms with ear-specific thresholds; 47 had conductive, 24 had sensorineural, 65 had mixed and 157 had undefined hearing loss with incomplete audiograms. Pure-tone averages (PTA) were higher among patients with mixed hearing loss compared to patients with all other loss types. Conclusion: Hearing loss is prevalent in children with GHD with a predisposition to be bilateral. These findings suggest the need for increased awareness and routine hearing screening for patients with GHD. Introduction Growth hormone deficiency (GHD) is a rare endocrine disorder characterized by short stature and diminished growth hormone production 1,2. The disease is synonymous with pituitary dwarfism and isolated growth hormone deficiency and is estimated to affect 1 in 4000 children 1. GHD is typically diagnosed during infancy or early childhood 1-3, presenting clinically with growth failure and delayed bone age 1. Insulin-like growth factor 1 (IGF-1) is the central mediator of growth hormone action and is typically present at low serum concentrations in patients with GHD 5,6. Multiple animal models have shown IGF-1 plays a critical role in otologic neurogenesis, maturation and survival 5,7,8. Additionally, clinical data have supported an association between adults with hearing loss and various symptoms of growth hormone deficiency, such as short stature and low IGF-1 concentration Page 11 of 17

2 Although IGF-1 has been shown to be important for inner-ear development in animal and human studies, no studies have described the otologic and audiologic findings of children with growth hormone deficiency. We identified only one small-scale study to date characterizing audiologic outcomes of patients with GHD, where adults with lifetime, untreated GHD showed increased hearing thresholds compared to controls 6. Using the AudGen Database, this study provides what we believe to be the largest analysis of hearing outcomes and audiometric data in 173 children with GHD and hearing loss. Methods Subjects The AudGen Database is an NIH-funded resource with over 180,000 audiograms and encounters of patients between the ages 0 and 21. The patients in this study were drawn from a query for children with a diagnosis of GHD via ICD9 coding. Patients with GHD were then cataloged by age, gender, ethnicity, and availability of audiometric data. Audiologic Evaluation Pure-tone air and bone conduction audiometry as well as sound-field testing were used to evaluate hearing outcomes. For audiograms lacking complete information, the hearing loss was designated as undefined. The puretone average (PTA) was calculated for air conduction thresholds bilaterally using the four frequencies 0.5, 1.0, 2.0, and 4.0 khz. To analyze change in hearing loss over time, change in PTA was calculated from the patient s first audiogram to their last available audiogram in patients with at least one year between extremal dates. Cases were stratified by PTA Outcome (classified as improved, unchanged, or worse) with unchanged defined as an absolute change in PTA 5 db HL. We analyzed all available audiograms for each patient for evidence of elevated hearing thresholds at any frequency. Patients with greater than a 15 db HL threshold at any frequency by pure tone audiometry or greater than 20 db hearing level at any frequency by sound-field testing were classified as having hearing loss. The audiogram that demonstrated the earliest evidence of hearing loss was used to describe hearing loss type, severity and laterality for each patient. Hearing Loss Type and Severity For audiograms tested by pure-tone audiometry, type of hearing loss was classified as: 1. Conductive: Normal bone-conduction thresholds, air conduction thresholds greater than 15 db HL and an air-bone gap of 10 db HL or more at any recorded frequency 2. Sensorineural: Bone-conduction thresholds of greater than 15 db HL with an air-bone gap of less than 10 db HL at any recorded frequency 3. Mixed: Conductive and sensorineural hearing loss were present together at any recorded frequency or were both present but at different frequencies 4. Undefined: Air conduction thresholds greater than 15dB, however, insufficient bone-conduction thresholds to determine loss type For audiograms obtained in a sound-field using noise or warble tones, hearing loss was defined as any threshold greater than or equal to 20 db HL and the loss type was classified as undefined. The severity of the hearing loss was established using the pure-tone average (PTA) when possible, via the following guidelines: normal (PTA 15 db HL), slight (16-25 db HL), mild (26-40 db HL), moderate (41-55 db HL), moderately severe (56-70 db HL), severe (71-90 db HL), and profound (90+ db HL) Hearing loss was also described as unilateral or bilateral. Data describing loss type and severity was summarized by ear to more effectively characterize the sample population, as seen in previous studies evaluating hearing in patients with GHD 6. Throughout the text, N is used to denote number of patients and n is used to denote number of ears. Medical Conditions Various medical conditions are recorded in Audgen, populated from ICD-9 codes. Diagnoses typically prevalent in children with GHD were documented in the patient population. For each patient with GHD, various otologic factors were also documented. Statistical Analysis All statistical analyses were performed in R version Results Patient Population The initial query yielded 234 patients with GHD, of which 209 patients had audiometric testing. 173 of 209 children with audiometric testing had hearing loss (83%). Among children with hearing loss (103 male, 70 female), the average age at time of earliest audiometry was 8.4 ± 5.3 years with the large majority being of Caucasian ethnicity (79.2%) (Table 1). The 36 remaining children with GHD who were not diagnosed with hearing loss (17%) served as a comparison group. The average age of the comparison group (16 male, 20 female) at time of earliest audiometry was 8.7 ± 4.2 years with the large majority being of Caucasian ethnicity (75%). Page 12 of 17

3 Table 1. Prevalence, laterality, and demographic data of hearing loss in patients with GHD. Total Patients N % No Hearing Loss Hearing Loss (a) Hearing Loss - Patients by Test Method Sound Field 16 9 Insert earphones or headphones Laterality of Hearing Loss Bilateral Hearing Loss Unilateral Hearing Loss Hearing Loss Demographics Male Female White Black or African American Hispanic (b) Other (c) Average Age at Audiometry (years) 8.4 ± 5.3 N = # of patients a Threshold >15 db at any frequency b includes Hispanic or Latino Black and Hispanic or Latino Other c includes Indian, Other and Unknown Table 2. Prevalence, types of hearing loss and HL mean and standard deviation in patients with GHD and hearing loss and ear specific thresholds (293 ears). Hearing Loss Type n % PTA (db) SD (db) Pure Conductive Hearing Loss Pure Sensorineural Hearing Loss Mixed Hearing Loss Undefined Hearing Loss ear-specific thresholds sufficient to determine loss type, with undefined the most common hearing loss type (53.6%). The next largest subgroup was mixed hearing loss (22.1%), followed by pure conductive (16.0%) and pure sensorineural hearing loss (8.2%), as shown in Table 2. Analysis of Pure Tone Averages Post hoc comparisons using the Tukey HSD test indicated that the mean PTA for mixed hearing loss was significantly worse than all other types (F (3,270) = 13.69, p < 0.001), as shown in table 2 and figure 2. There was no significant difference in mean PTA for ears with unilateral hearing loss compared to the mean PTA for ears in the bilateral group. There were significant differences in mean PTA between children with and without heart conditions (46.6 ± 33.4 db vs ± 21.9 db, p < 0.05), although this is potentially skewed by the low number of ears with hearing loss in patients with heart conditions (n = 16). Ethnicity, gender, and age, did not have a significant impact on the severity of the hearing loss. Severity of Hearing Loss Of 293 ears with audiometric data, 274 had available ear-specific pure-tone averages sufficient to determine hearing loss severity. The highest percentage of ears with hearing loss (n = 70) fell into the slight hearing loss category (16-25 db PTA). Approximately 19.4% (n = 60) of the measurable audiograms showed moderate or worse hearing loss. Severity for the remaining 35 ears was unknown due to incomplete audiometric data. Patients without hearing loss showed normal thresholds all frequencies. These results are summarized in Table 3 and Figure 3. Of the 234 total patients with GHD, the 25 patients without audiometric data were excluded from the analysis. The patient selection process is described in figure 1. Type of Hearing Loss Figure of 173 children with GHD and documented hearing loss displayed bilateral hearing loss (79%). 293 of the 309 ears with hearing loss had audiograms with Medical Comorbidities Documented otolaryngologic conditions in the ears of patients with GHD included acute otitis media, chronic otitis media, Eustachian tube dysfunction, and tympanostomy tube placement. A summary of recorded medical conditions and their associated type of hearing loss is displayed in Table 4a. Compared to the group of patients with normal hearing, statistical testing revealed children with hearing loss were Page 13 of 17

4 more likely to have chronic otitis media (OR = 3.4, p < 0.05) and Eustachian tube dysfunction (OR = 2.7, p < 0.05). The prevalence of comorbidities common in patients with GHD or hearing loss was compared for both the normal hearing and hearing loss group in Table 4b and 4c. Hearing Loss over Time 173 of the 293 ears with ear specific thresholds from the hearing loss group had follow-up audiometric data available with at least one year between extremal dates. The mean time between first and last audiogram for these patients was 4.4 years and PTA increased by 0.5 ± 3.5 db on average per year. The PTA Outcome (improved, unchanged, worse) showed the majority of ears were classified as unchanged (87.8%), followed by worse (6.9%) and improved (5.2%) and was not influenced by type of hearing loss. Discussion The existing literature on otologic and audiologic outcomes in patients with GHD is scarce. The present study attempts to provide greater insight into the audiologic and otologic profile of children with GHD. 83% of the patients with GHD displayed some degree of hearing loss across the frequency spectrum. Mixed hearing loss was particularly common amongst these patients. Given that this is an audiological database, there is bias in our study for inclusion of patients with hearing difficulties. Therefore, these results likely overestimate the true prevalence of hearing loss in the GHD population. However, the larger Table 3. Hearing loss severity by PTA in 309 ears with hearing loss. Severity by Ear n % Normal Slight Mild Moderate Moderately Severe Severe Profound Undefined Figure 2. Mean PTA by type of hearing loss ANOVA revealed significant difference in average PTA between mixed hearing loss and all other types of hearing loss (p < 0.001). Post hoc comparisons indicated that the mean PTA for mixed hearing loss (43.4 ± 25.6 db) was significantly worse than conductive (21.4 ± 10.0 db, p < ), sensorineural (27.2 ± 13.5 db, p < 0.01), and undefined (24.4 ± 23.3 db, p < ). Error bars denote ± standard error. Table 4a. A description of common conditions associated with GHD and the hearing loss type associated with each (N= # of patients; n=number of ears). Condition N n Conductive Sensorineural Mixed Undefined Short Stature Hypothyroidism Asthma Speech Disability Diabetes Intellectual Disability Heart Condition Hypoglycemia Jaundice Page 14 of 17

5 Figure 3. Hearing loss thresholds across various frequencies by hearing loss type. size of our hearing loss population allowed us to more fully characterize the profile of hearing loss in these children, enabling future research for exploration of this topic Our study showed that mixed hearing loss was more prevalent than all other measurable types of hearing loss. Mixed hearing loss is potentially overrepresented by minor Page 15 of 17

6 Table 4b. Common conditions associated with GHD in hearing loss group vs control (N= # of patients). Hearing Loss N total = 173 No Hearing Loss N total = 36 Condition N (HL) % N (Non HL) % Odds Ratio Short Stature *0.4 Hypothyroidism *4.1 Asthma Speech Disability Diabetes Intellectual Disability Heart Condition Hypoglycemia Jaundice * p < 0.05 Table 4c. Prevalence of otologic conditions in group with hearing loss and group with normal hearing (N= # of patients). Hearing Loss N total = 173 No Hearing Loss N total = 36 Condition N % N % Odds Ratio Chronic Otitis Media *3.4 Eustachian Tube Dysfunction *2.7 Acute Otitis Media Tympanostomy Procedures *p < 0.05 and temporary otitis media-related conductive hearing loss. Our study showed 33.3% of patients with mixed hearing loss were diagnosed with chronic or acute otitis media some point (N =13). However, prevalence of either acute or chronic otitis media diagnoses was greater in children with conductive loss compared to mixed losses (OR = 15.3, p < 0.001). Further research is needed to analyze the seasonal distribution of otitis media-related conductive hearing loss in children with GHD. This study was also limited by the lack of data on therapies received such as hormone therapy for GHD or hypothyroidism. The standard of care for children diagnosed with GHD is administration of subcutaneous injections of growth hormone in the patient s home, with the injection frequency varying by case, age and response 1,2,20. Without information regarding treatment, we were not able to compare hearing loss in patients that were treated for GHD using different medications or injection schedules. Additionally, we cannot control for other possible causes of hearing loss such as ototoxic medications or noise exposure. Children diagnosed with GHD face numerous physiological difficulties. However, with no existing recommendations for hearing screenings in this patient population, hearing loss is potentially underdiagnosed. Since the literature shows that even minimal-to-mild hearing impairment of db can have a significant impact on speech and communication abilities in children 21, we recommend all patients with GHD to be screened regularly for hearing loss. Conclusion This study represents the largest audiological evaluation of children with GHD to date, showing that hearing loss is prevalent in children with growth hormone deficiency. Mixed hearing loss was particularly common amongst these patients. Additional research focusing on longerterm outcomes should help physicians better understand progression of hearing loss over time in children with GHD. Since hearing loss has been shown to impact speech and academic performance in children, we recommend all children with GHD be referred to an otolaryngologist and routinely screened for hearing loss. Therefore, early intervention using hearing aids or special classroom seating is highly recommended for this patient population. References 1. Murray PG, Dattani MT, Clayton PE. Arch Dis Child. 2016; 101: Society GHR. The Journal of clinical endocrinology and metabolism. 2000; 85: Society LWPE. The Journal of pediatrics. 1995; 127: Gluckman PD, Gunn AJ, Wray A, et al. J Pediatr. 1992; 121: Camarero G, Villar MA, Contreras J, et al. Hearing research. 2002; 170: Prado-Barreto VM, Salvatori R, Santos Junior RC, et al. Otolaryngology- -head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2014; 150: Varela-Nieto I, Morales-Garcia JA, Vigil P, et al. Hearing research. 2004; 196: Varela-Nieto I, Murillo-Cuesta S, Rodriguez-de la Rosa L, et al. Pediatric endocrinology reviews : PER. 2013; 10: Welch D, Dawes PJ. Pediatric research. 2007; 62: Page 16 of 17

7 10. Woods KA, Camacho-Hubner C, Savage MO, et al. The New England journal of medicine. 1996; 335: Attias J, Zarchi O, Nageris BI, et al. European archives of oto-rhinolaryngology : official journal of the European Federation of Oto-Rhino- Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2012; 269: Weir FW, Hatch JL, Muus JS, et al. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2016; 37: Weir FW, Kreicher KL, Hatch JL, et al. International journal of pediatric otorhinolaryngology. 2016; 89: Weir FW, Wallace SA, White DR, et al. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2017; 38: RC T, R: A language and environment for statistical computing City, Bonapace G, Concolino D, Formicola S, et al. Journal of medical genetics. 2003; 40: Walenkamp MJ, Karperien M, Pereira AM, et al. The Journal of clinical endocrinology and metabolism. 2005; 90: Barrenas ML, Bratthall A, Dahlgren J. Hearing research. 2005; 205: Saunders CL, Elliott MN, Lyratzopoulos G, et al. Journal of the Royal Society of Medicine. 2016; 109: Ghigo E, Bellone J, Aimaretti G, et al. The Journal of clinical endocrinology and metabolism. 1996; 81: Bess FH, Dodd-Murphy J, Parker RA. Ear and hearing. 1998; 19: Page 17 of 17