1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
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Hearing Research xxx (2015) 1e5
Contents lists available at ScienceDirect
Hearing Research journal homepage: www.elsevier.com/locate/heares
Research paper
Q4 Q3
Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism Rocco Bruno a, Tommaso Aversa b, Mariaausilia Catena b, Mariella Valenzise b, Fortunato Lombardo b, Filippo De Luca b, *, Malgorzata Wasniewska b a b
Department of Otorhinolaryngology, University of Messina, via Consolare Valeria, 98124 Messina, Italy Department of Pediatrics, University of Messina, via Consolare Valeria, 98124 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 January 2015 Received in revised form 15 April 2015 Accepted 28 April 2015 Available online xxx
Only few studies have focused on neurosensory hearing function of patients with congenital hypothyroidism (CH) identified by CH screening programs and treated early and, therefore, this issue remains still controversial. The aim of this study was to ascertain whether an early and adequate replacement treatment may be able to prevent sensorineural hearing loss in 32 screened children with CH and no associated risk factors for neuro-otologic alterations. These patients were recruited according to highly selective criteria aiming to preliminarily exclude the negative interference of both treatment variables and other underlying risk factors. All the selected patients underwent, at a median age of 15.4 years, an audiologic investigation, which evidenced a mild and subclinical hearing loss in 25% of them. The poorest hearing scores were recorded in the individuals with athyreosis and in those with absence of distal femur bony nucleus at CH diagnosis. The prevalence of hearing impairment was significantly higher in CH patients than in 32 agematched control subjects with no CH (c2 ¼ 6.3, p < 0.025). In light of these findings, we concluded that: a) 25% of CH patients detected by CH screening may show, at a median age of 15.4 years, a mild and subclinical hearing impairment, despite early and adequate replacement treatment; b) the risk of hearing loss is higher in CH young patients than in agematched control subjects without CH; c) the risk of hearing loss is closely associated with the severity of CH; d) this risk is particularly relevant in the children with pre-natal onset of hypothyroidism. © 2015 Elsevier B.V. All rights reserved.
1. Introduction An association between thyroid function disorders and impaired auditory function has long been recognized in patients with either Pendred syndrome (Bizhanova and Kopp, 2010) or thyroid hormone (TH) resistance (Brucker-Davis et al., 1996) or endemic
Abbreviations: CH, congenital hypothyroidism; dB, decibel; FT4, free thyroxine; Hz, Hertz; LT4, L-thyroxine; TH, thyroid hormone; TSH, thyrotropin; c2, chi-square * Corresponding author. Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Policlinico Universitario di Messina, Via Consolare Valeria, 98124 Messina, Italy. Tel.: þ39 090 2213157; fax: þ39 090 2212143. E-mail addresses: [email protected] (R. Bruno), [email protected] (T. Aversa), [email protected] (M. Catena), mariella.valenzise@ unime.it (M. Valenzise), [email protected] (F. Lombardo), filippo. [email protected] (F. De Luca), [email protected] (M. Wasniewska).
cretinism (DeLong et al., 1985). Such association has been sporadically reported also in children and adolescents with central hypothyroidism (De Luca et al., 1985; Wasniewska et al., 2002) and, more recently, in patients with TH monocarboxylate transporter 8 abnormalities (Dumitrescu et al., 2004). Permanent sensorineural hearing loss has also been described in children with unscreened primary congenital hypothyroidism (CH) whose replacement therapy began late and even in some CH individuals treated before et al., the age of six months but outside the neonatal period (Crifo 1989; De Luca et al., 1986; Vanderschueren-Ladeweyckx et al., 1983). Neonatal screening programs of primary CH, which have been adopted over the last thirty years in most industrialized countries, have generally resulted in the prevention of severe cerebral damage and a large decrease of morbidity in these patients. Nevertheless, some mild hearing abnormalities were found to be still common
http://dx.doi.org/10.1016/j.heares.2015.04.018 0378-5955/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Bruno, R., et al., Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (2015), http://dx.doi.org/ 10.1016/j.heares.2015.04.018
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
HEARES6946_proof ■ 17 May 2015 ■ 2/5
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R. Bruno et al. / Hearing Research xxx (2015) 1e5
even in screened and early treated children with primary CH, although these abnormalities were much less severe than those detected before CH screening era (Bellman et al., 1996; Rovet et al., 1996). Even in the last few years subtle hearing problems concerning high or very high frequencies have been reported to be ger possibly observed in screened patients with primary CH (Le ger et al., 2014) et al., 2011; Lichtenberger-Geslin et al., 2013; Le and these findings highlight the need for careful monitoring of sensorineural hearing function and treatment adequacy ger et al., 2011). Other throughout childhood and adolescence (Le studies, in contrast, documented no hearing impairment in patients with screened CH (Francois et al., 1994; Hashemipour et al., 2012). However, only a few studies have focused on neurosensory function of CH patients identified by neonatal CH screening programs and treated early (Leger, 2014) and, therefore, this issue remains still controversial. In the present study, in order to shed further light on this topic, we have cross-sectionally investigated hearing function in a CH selected population consisting of only screened and adequately substituted children with no underlying risk factors for sensorineural hearing impairment. The aim of our study was to ascertain whether an early and adequate replacement treatment may be able to prevent sensorineural hearing loss in CH patients with no associated risk factors for neuro-otologic alterations. 2. Material and methods 2.1. Study population It includes 32 caucasian patients (21 females) who were diagnosed in many CH screening centers of two southern regions of Italy (Sicily and Calabria) during the period 1992e2006. From the time of diagnosis (median age 28 days, range 7e30) all these patients were provided with L-thyroxine (L-T4) replacement therapy and followed up as outpatients in our clinical center of pediatric endocrinology. The 32 recruited patients were members of a larger population of children with CH who were followed up during the same period in our center and were selected for this study according to the following exclusion and inclusion criteria. Exclusion criteria: a) transient CH; b) family history of congenital or childhood onset sensorineural impairment; c) prematurity and/or low for gestational age birth weight; d) neonatal distress; e) congenital infections of toxoplasmosis, rubella, cytomegalovirus and herpes; f) severe neonatal hyperbilirubinemia; g) history of meningitis, recurrent otitis or ototoxic medications; h) craniofacial abnormalities and/or clinical findings compatible with either middle ear pathologies or syndromes including sensorineural hearing loss. Inclusion criteria: a) age at L-T4 therapy onset 30 days; b) initial L-T4 dose between 10 and 14 mg/kg/day; c) availability of both thyroid scanning and knee X-rays at the time of L-T4 treatment initiation; d) no thyrotropin (TSH) determination outside the normal limits of our laboratory reference range (0.3e5.0 mU/l) during the overall follow-up period, from L-T4 therapy start to the time of this study. 2.2. Study design and methods At confirmation of CH diagnosis thyroid scanning had been performed by 99 m Technetium, whilst skeletal maturation had been evaluated by X-ray assessment of the distal femur epiphyseal ossification center. During the last months of 2014 all the selected children and young adults underwent, at the median age of 15.4 years (range
8.0e22.0), an audiologic investigation that was conducted in the entire cohort by the same conventional pure tone audiometry and was carried out by the same audiologist (R.B.). Before the audiometric evaluation each patient received a routine otologic examination aiming to identify any abnormalities that may interfere with hearing, such as a perforated tympanic membrane or other middle ear pathologies. At the same time the patients underwent also a reevaluation of serum TSH and free thyroxine (FT4) levels under L-T4 therapy. All hearing tests were carried out, in a double walled soundinsulated chamber fulfilling ANSI 2004 criteria, using a Plus model Bell audiometer (Inventis, Padova, Italy) and TDH-39 earphones. In each audiogram, the hearing loss in decibels (dB) was recorded, for both ears, for the frequencies 125, 250, 500, 1000, 2000, 4000, 6000 and 8000 Hertz (Hz). Normal hearing sensitivity was defined as hearing acuity within 20 dB Hearing Level (HL), whereas hearing was considered as abnormal when hearing loss exceeded 20 dB HL in at least one ear. If hearing impairment degree differed between the two ears, then the category assigned was that for the ear for which the poorer results were obtained. Hearing loss was classified as mild when it ranged between 20 and 40 dB HL, whilst it was considered as moderate or more severe when it exceeded 40 dB HL. Hearing loss was classified as conductive or sensorineural, but only the cases with a sensorineural defect were taken into consideration in this study. Audiometric results were correlated with CH severity (etiology, TSH levels and bone maturation delay at diagnosis) and treatment variables (age and L-T4 dose at therapy start). The same investigation protocol was also applied in a sex- and age-matched control population consisting of 32 healthy children and adolescents (22 females) aged between 9.1 and 21.0 years (median age 13,5). These control subjects were recruited according to the following inclusion criteria: a) no personal history of CH screening positivity; b) no clinical evidence of perforated tympanic membrane or other middle ear pathologies at the time of the routine otologic examination which preceded audiometric evaluation. 2.3. Statistical analysis Results are expressed as mean ± SD or median and range values. Comparisons between groups were performed by Student's unpaired t test (normally distributed data) or ManneWhitney U test (non-normally distributed data), as appropriate. Frequency rates were compared by chi-square (c2) test. The level of significance was set at 0.05. The study design was approved by the ethical committee of our hospital and the children’ parents gave informed consent. 3. Results CH etiology, as assessed by the thyroid scanning performed before treatment start in all the cases, was: athyreosis in 9 children, ectopic gland in 15 and eutopic gland in 8. The distal femur bony nucleus was absent in 14/32 patients (43.7%) and the prevalence of children with absence of this nucleus was significantly higher in the subgroup with athyreosis than in that with either ectopic or eutopic gland (77.8% vs 30.4%; c2 ¼ 5.9, p < 0.025). Eight patients (25%) exhibited, at audiometry, a mild sensorineural hearing impairment (between 25 and 40 dB HL), which was bilateral in 5 cases and unilateral in the remaining 3 cases (Table 1). Including all the right and left ears tested, the percentage of ears for which hearing loss was recorded was 20.3%. Assessments of
Please cite this article in press as: Bruno, R., et al., Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (2015), http://dx.doi.org/ 10.1016/j.heares.2015.04.018
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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Table 1 Main data at congenital hypothyroidism (CH) diagnosis and at the time of audiologic investigation in the 8 CH patients with sensorineural hearing impairment (hearing loss exceeding 20 decibels dB in at least one ear at frequencies between 125 and 8000 Hertz Hz). Patients
1 2 3 4 5 6 7 8
At CH diagnosis
At audiologic investigation
Therapy onset (days)
Serum TSH (mIU/l)
Thyroid scanning
Distal femur nucleus
L-T4 dose (mg/kg/day)
Age (years)
Max hearing loss (dB)
Hearing loss (dB) at other frequencies (Hz)
Hearing loss presentation
8 16 19 28 29 30 30 30
180 535 426 449 420 210 260 280
athyreosis athyreosis ectopy ectopy athyreosis ectopy athyreosis athyreosis
absent absent present absent absent present absent absent
10.00 10.08 10.02 10.56 11.00 10.05 12.00 10.63
19.6 17.5 15.5 9.3 16.7 15.4 15.6 17.9
35 30 30 30 40 30 30 25
25 at 6000 e 25 at 8000 e 25 at 4000; 35 at 6000 e e e
bilateral bilateral monolateral bilateral bilateral monolateral bilateral monolateral
hearing impairment for the various frequency ranges revealed that the majority of children (6/8) exhibited the max hearing loss at 8000 Hz and only 2 patients exhibited the most severe hearing impairment at lower frequencies (Table 1). The audiologic data, the main thyroid test results and other clinical data of the 8 hearing impaired patients are analytically reported in Table 1. None of these children had been previously suspected by both family pediatricians and parents to suffer from hearing impairment. For the remaining 24 patients of this study population the audiogram data indicated normal hearing at all frequencies tested in both ears. If the 8 hearing impaired patients were compared with those with normal hearing acuity, the only relevant differences between the 2 subcohorts regarded median TSH serum levels and the frequency of distal femur nucleus absence at CH diagnosis and also the prevalence of athyreosis, which were all significantly higher in the subgroup with sensorineural hearing loss (Table 2). All the other considered parameters did not significantly differ in these 2 patient subgroups (Table 2). If the 9 athyreotic patients of the entire CH series were compared with the 23 children with either eutopic or ectopic gland, the athyreotic subgroup differed from the other one in terms of median TSH levels and frequency of distal femur nucleus absence at therapy start and also in terms of hearing loss prevalence (Table 3). In the control population the only one individual who exhibited an appreciable hearing loss (25 dB HL in left ear and 30 dB in right ear, both at 6000 Hz) was a 21-year old girl, whereas all the remaining subjects (96.9%) showed normal hearing acuity at all frequencies tested in both ears. The prevalence of hearing impairment was significantly higher in CH patients than in control subjects (25 vs 3.1%, c2 ¼ 6.3, p < 0.025). Even though both ears were considered, the percentage of hearing impaired ears was significantly higher in CH cohort than in control group (20.3 vs 3.1%, c2 ¼ 9.1, p < 0.0025). In the control group the only one subject with an appreciable hearing loss had not been previously suspected by both family pediatricians and parents to suffer from hearing impairment.
at at at at at at at at
8000 8000 6000 8000 8000 4000 8000 8000
Hz Hz Hz Hz Hz Hz Hz Hz
4. Discussion The most salient fact which emerges from the present crosssectional study is that, in a cohort of 32 children and adolescents with CH all detected by CH screening, a 25% of patients showed, at a median age of 15.4 years, a mild and subclinical sensorineural hearing impairment, despite early and adequate substitutive treatment. Hearing loss concerned mostly high frequencies, was irrespective of other concomitant risk factors and was closely associated with the severity of CH. These findings as a whole confirm that, despite major improvements in prognosis, sensorineural hearing loss remains a significant problem for CH patients, particularly for those with a severe form of thyroid failure (Lichtenberger-Geslin et al., 2013). To the best of our knowledge, this is the first investigation on the relationships between CH and hearing function which was based on a study design aiming to evaluate the influence on hearing development of only one variable (CH severity), after having preliminarily excluded the interference of all the management variables (age and L-T4 dose at therapy start, treatment adequacy during the overall follow-up period) and of other concomitant risk factors. Such a study design gave us the opportunity of arguing that a relevant rate of CH patients are per se more exposed to the risk of developing over time a subtle sensorineural impairment, irrespective of treatment variables and concomitant predisposing factors. According to our results, the only variable that seems to be able to significantly affect the relationships between CH and hearing sensitivity prognosis is the severity of CH, with the poorest scores in terms of hearing acuity being observed in the individuals with athyreosis and in those with delayed bone maturation at birth. That athyreosis and delay in prenatal bone maturation are important factors influencing hearing function development in CH is a fact which had been just recently demonstrated for the first time (Lichtenberger-Geslin et al., 2013). In that study, however, the replacement treatment during the whole follow-up period was not always as adequate as in the present investigation and the possibility that other variables related to treatment may have played
Table 2 Mean (±SD) or median (and range) data at diagnosis of congenital hypothyroidism (CH) and at the time of audiologic investigation in the 8 hearing impaired patients (Subgroup A) vs the 24 patients with normal hearing acuity (Subgroup B). At CH diagnosis
Subgroup A Subgroup B p
At audiologic investigation
Serum TSH (mIU/l)
Athyreosis (%)
Distal femur nucleus absence (%)
Therapy onset (days)
L-T4 dose (mcg/kg/day)
Age (years)
Serum TSH (mIU/l)
Serum FT4 (pmol/l)
L-T4 dose (mcg/kg/day)
350 (180e535) 78.8 (35e517)
HEARES6946_proof ■ 17 May 2015 ■ 1/5
Hearing Research xxx (2015) 1e5
Contents lists available at ScienceDirect
Hearing Research journal homepage: www.elsevier.com/locate/heares
Research paper
Q4 Q3
Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism Rocco Bruno a, Tommaso Aversa b, Mariaausilia Catena b, Mariella Valenzise b, Fortunato Lombardo b, Filippo De Luca b, *, Malgorzata Wasniewska b a b
Department of Otorhinolaryngology, University of Messina, via Consolare Valeria, 98124 Messina, Italy Department of Pediatrics, University of Messina, via Consolare Valeria, 98124 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 January 2015 Received in revised form 15 April 2015 Accepted 28 April 2015 Available online xxx
Only few studies have focused on neurosensory hearing function of patients with congenital hypothyroidism (CH) identified by CH screening programs and treated early and, therefore, this issue remains still controversial. The aim of this study was to ascertain whether an early and adequate replacement treatment may be able to prevent sensorineural hearing loss in 32 screened children with CH and no associated risk factors for neuro-otologic alterations. These patients were recruited according to highly selective criteria aiming to preliminarily exclude the negative interference of both treatment variables and other underlying risk factors. All the selected patients underwent, at a median age of 15.4 years, an audiologic investigation, which evidenced a mild and subclinical hearing loss in 25% of them. The poorest hearing scores were recorded in the individuals with athyreosis and in those with absence of distal femur bony nucleus at CH diagnosis. The prevalence of hearing impairment was significantly higher in CH patients than in 32 agematched control subjects with no CH (c2 ¼ 6.3, p < 0.025). In light of these findings, we concluded that: a) 25% of CH patients detected by CH screening may show, at a median age of 15.4 years, a mild and subclinical hearing impairment, despite early and adequate replacement treatment; b) the risk of hearing loss is higher in CH young patients than in agematched control subjects without CH; c) the risk of hearing loss is closely associated with the severity of CH; d) this risk is particularly relevant in the children with pre-natal onset of hypothyroidism. © 2015 Elsevier B.V. All rights reserved.
1. Introduction An association between thyroid function disorders and impaired auditory function has long been recognized in patients with either Pendred syndrome (Bizhanova and Kopp, 2010) or thyroid hormone (TH) resistance (Brucker-Davis et al., 1996) or endemic
Abbreviations: CH, congenital hypothyroidism; dB, decibel; FT4, free thyroxine; Hz, Hertz; LT4, L-thyroxine; TH, thyroid hormone; TSH, thyrotropin; c2, chi-square * Corresponding author. Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Policlinico Universitario di Messina, Via Consolare Valeria, 98124 Messina, Italy. Tel.: þ39 090 2213157; fax: þ39 090 2212143. E-mail addresses: [email protected] (R. Bruno), [email protected] (T. Aversa), [email protected] (M. Catena), mariella.valenzise@ unime.it (M. Valenzise), [email protected] (F. Lombardo), filippo. [email protected] (F. De Luca), [email protected] (M. Wasniewska).
cretinism (DeLong et al., 1985). Such association has been sporadically reported also in children and adolescents with central hypothyroidism (De Luca et al., 1985; Wasniewska et al., 2002) and, more recently, in patients with TH monocarboxylate transporter 8 abnormalities (Dumitrescu et al., 2004). Permanent sensorineural hearing loss has also been described in children with unscreened primary congenital hypothyroidism (CH) whose replacement therapy began late and even in some CH individuals treated before et al., the age of six months but outside the neonatal period (Crifo 1989; De Luca et al., 1986; Vanderschueren-Ladeweyckx et al., 1983). Neonatal screening programs of primary CH, which have been adopted over the last thirty years in most industrialized countries, have generally resulted in the prevention of severe cerebral damage and a large decrease of morbidity in these patients. Nevertheless, some mild hearing abnormalities were found to be still common
http://dx.doi.org/10.1016/j.heares.2015.04.018 0378-5955/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Bruno, R., et al., Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (2015), http://dx.doi.org/ 10.1016/j.heares.2015.04.018
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
HEARES6946_proof ■ 17 May 2015 ■ 2/5
2
R. Bruno et al. / Hearing Research xxx (2015) 1e5
even in screened and early treated children with primary CH, although these abnormalities were much less severe than those detected before CH screening era (Bellman et al., 1996; Rovet et al., 1996). Even in the last few years subtle hearing problems concerning high or very high frequencies have been reported to be ger possibly observed in screened patients with primary CH (Le ger et al., 2014) et al., 2011; Lichtenberger-Geslin et al., 2013; Le and these findings highlight the need for careful monitoring of sensorineural hearing function and treatment adequacy ger et al., 2011). Other throughout childhood and adolescence (Le studies, in contrast, documented no hearing impairment in patients with screened CH (Francois et al., 1994; Hashemipour et al., 2012). However, only a few studies have focused on neurosensory function of CH patients identified by neonatal CH screening programs and treated early (Leger, 2014) and, therefore, this issue remains still controversial. In the present study, in order to shed further light on this topic, we have cross-sectionally investigated hearing function in a CH selected population consisting of only screened and adequately substituted children with no underlying risk factors for sensorineural hearing impairment. The aim of our study was to ascertain whether an early and adequate replacement treatment may be able to prevent sensorineural hearing loss in CH patients with no associated risk factors for neuro-otologic alterations. 2. Material and methods 2.1. Study population It includes 32 caucasian patients (21 females) who were diagnosed in many CH screening centers of two southern regions of Italy (Sicily and Calabria) during the period 1992e2006. From the time of diagnosis (median age 28 days, range 7e30) all these patients were provided with L-thyroxine (L-T4) replacement therapy and followed up as outpatients in our clinical center of pediatric endocrinology. The 32 recruited patients were members of a larger population of children with CH who were followed up during the same period in our center and were selected for this study according to the following exclusion and inclusion criteria. Exclusion criteria: a) transient CH; b) family history of congenital or childhood onset sensorineural impairment; c) prematurity and/or low for gestational age birth weight; d) neonatal distress; e) congenital infections of toxoplasmosis, rubella, cytomegalovirus and herpes; f) severe neonatal hyperbilirubinemia; g) history of meningitis, recurrent otitis or ototoxic medications; h) craniofacial abnormalities and/or clinical findings compatible with either middle ear pathologies or syndromes including sensorineural hearing loss. Inclusion criteria: a) age at L-T4 therapy onset 30 days; b) initial L-T4 dose between 10 and 14 mg/kg/day; c) availability of both thyroid scanning and knee X-rays at the time of L-T4 treatment initiation; d) no thyrotropin (TSH) determination outside the normal limits of our laboratory reference range (0.3e5.0 mU/l) during the overall follow-up period, from L-T4 therapy start to the time of this study. 2.2. Study design and methods At confirmation of CH diagnosis thyroid scanning had been performed by 99 m Technetium, whilst skeletal maturation had been evaluated by X-ray assessment of the distal femur epiphyseal ossification center. During the last months of 2014 all the selected children and young adults underwent, at the median age of 15.4 years (range
8.0e22.0), an audiologic investigation that was conducted in the entire cohort by the same conventional pure tone audiometry and was carried out by the same audiologist (R.B.). Before the audiometric evaluation each patient received a routine otologic examination aiming to identify any abnormalities that may interfere with hearing, such as a perforated tympanic membrane or other middle ear pathologies. At the same time the patients underwent also a reevaluation of serum TSH and free thyroxine (FT4) levels under L-T4 therapy. All hearing tests were carried out, in a double walled soundinsulated chamber fulfilling ANSI 2004 criteria, using a Plus model Bell audiometer (Inventis, Padova, Italy) and TDH-39 earphones. In each audiogram, the hearing loss in decibels (dB) was recorded, for both ears, for the frequencies 125, 250, 500, 1000, 2000, 4000, 6000 and 8000 Hertz (Hz). Normal hearing sensitivity was defined as hearing acuity within 20 dB Hearing Level (HL), whereas hearing was considered as abnormal when hearing loss exceeded 20 dB HL in at least one ear. If hearing impairment degree differed between the two ears, then the category assigned was that for the ear for which the poorer results were obtained. Hearing loss was classified as mild when it ranged between 20 and 40 dB HL, whilst it was considered as moderate or more severe when it exceeded 40 dB HL. Hearing loss was classified as conductive or sensorineural, but only the cases with a sensorineural defect were taken into consideration in this study. Audiometric results were correlated with CH severity (etiology, TSH levels and bone maturation delay at diagnosis) and treatment variables (age and L-T4 dose at therapy start). The same investigation protocol was also applied in a sex- and age-matched control population consisting of 32 healthy children and adolescents (22 females) aged between 9.1 and 21.0 years (median age 13,5). These control subjects were recruited according to the following inclusion criteria: a) no personal history of CH screening positivity; b) no clinical evidence of perforated tympanic membrane or other middle ear pathologies at the time of the routine otologic examination which preceded audiometric evaluation. 2.3. Statistical analysis Results are expressed as mean ± SD or median and range values. Comparisons between groups were performed by Student's unpaired t test (normally distributed data) or ManneWhitney U test (non-normally distributed data), as appropriate. Frequency rates were compared by chi-square (c2) test. The level of significance was set at 0.05. The study design was approved by the ethical committee of our hospital and the children’ parents gave informed consent. 3. Results CH etiology, as assessed by the thyroid scanning performed before treatment start in all the cases, was: athyreosis in 9 children, ectopic gland in 15 and eutopic gland in 8. The distal femur bony nucleus was absent in 14/32 patients (43.7%) and the prevalence of children with absence of this nucleus was significantly higher in the subgroup with athyreosis than in that with either ectopic or eutopic gland (77.8% vs 30.4%; c2 ¼ 5.9, p < 0.025). Eight patients (25%) exhibited, at audiometry, a mild sensorineural hearing impairment (between 25 and 40 dB HL), which was bilateral in 5 cases and unilateral in the remaining 3 cases (Table 1). Including all the right and left ears tested, the percentage of ears for which hearing loss was recorded was 20.3%. Assessments of
Please cite this article in press as: Bruno, R., et al., Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (2015), http://dx.doi.org/ 10.1016/j.heares.2015.04.018
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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3
Table 1 Main data at congenital hypothyroidism (CH) diagnosis and at the time of audiologic investigation in the 8 CH patients with sensorineural hearing impairment (hearing loss exceeding 20 decibels dB in at least one ear at frequencies between 125 and 8000 Hertz Hz). Patients
1 2 3 4 5 6 7 8
At CH diagnosis
At audiologic investigation
Therapy onset (days)
Serum TSH (mIU/l)
Thyroid scanning
Distal femur nucleus
L-T4 dose (mg/kg/day)
Age (years)
Max hearing loss (dB)
Hearing loss (dB) at other frequencies (Hz)
Hearing loss presentation
8 16 19 28 29 30 30 30
180 535 426 449 420 210 260 280
athyreosis athyreosis ectopy ectopy athyreosis ectopy athyreosis athyreosis
absent absent present absent absent present absent absent
10.00 10.08 10.02 10.56 11.00 10.05 12.00 10.63
19.6 17.5 15.5 9.3 16.7 15.4 15.6 17.9
35 30 30 30 40 30 30 25
25 at 6000 e 25 at 8000 e 25 at 4000; 35 at 6000 e e e
bilateral bilateral monolateral bilateral bilateral monolateral bilateral monolateral
hearing impairment for the various frequency ranges revealed that the majority of children (6/8) exhibited the max hearing loss at 8000 Hz and only 2 patients exhibited the most severe hearing impairment at lower frequencies (Table 1). The audiologic data, the main thyroid test results and other clinical data of the 8 hearing impaired patients are analytically reported in Table 1. None of these children had been previously suspected by both family pediatricians and parents to suffer from hearing impairment. For the remaining 24 patients of this study population the audiogram data indicated normal hearing at all frequencies tested in both ears. If the 8 hearing impaired patients were compared with those with normal hearing acuity, the only relevant differences between the 2 subcohorts regarded median TSH serum levels and the frequency of distal femur nucleus absence at CH diagnosis and also the prevalence of athyreosis, which were all significantly higher in the subgroup with sensorineural hearing loss (Table 2). All the other considered parameters did not significantly differ in these 2 patient subgroups (Table 2). If the 9 athyreotic patients of the entire CH series were compared with the 23 children with either eutopic or ectopic gland, the athyreotic subgroup differed from the other one in terms of median TSH levels and frequency of distal femur nucleus absence at therapy start and also in terms of hearing loss prevalence (Table 3). In the control population the only one individual who exhibited an appreciable hearing loss (25 dB HL in left ear and 30 dB in right ear, both at 6000 Hz) was a 21-year old girl, whereas all the remaining subjects (96.9%) showed normal hearing acuity at all frequencies tested in both ears. The prevalence of hearing impairment was significantly higher in CH patients than in control subjects (25 vs 3.1%, c2 ¼ 6.3, p < 0.025). Even though both ears were considered, the percentage of hearing impaired ears was significantly higher in CH cohort than in control group (20.3 vs 3.1%, c2 ¼ 9.1, p < 0.0025). In the control group the only one subject with an appreciable hearing loss had not been previously suspected by both family pediatricians and parents to suffer from hearing impairment.
at at at at at at at at
8000 8000 6000 8000 8000 4000 8000 8000
Hz Hz Hz Hz Hz Hz Hz Hz
4. Discussion The most salient fact which emerges from the present crosssectional study is that, in a cohort of 32 children and adolescents with CH all detected by CH screening, a 25% of patients showed, at a median age of 15.4 years, a mild and subclinical sensorineural hearing impairment, despite early and adequate substitutive treatment. Hearing loss concerned mostly high frequencies, was irrespective of other concomitant risk factors and was closely associated with the severity of CH. These findings as a whole confirm that, despite major improvements in prognosis, sensorineural hearing loss remains a significant problem for CH patients, particularly for those with a severe form of thyroid failure (Lichtenberger-Geslin et al., 2013). To the best of our knowledge, this is the first investigation on the relationships between CH and hearing function which was based on a study design aiming to evaluate the influence on hearing development of only one variable (CH severity), after having preliminarily excluded the interference of all the management variables (age and L-T4 dose at therapy start, treatment adequacy during the overall follow-up period) and of other concomitant risk factors. Such a study design gave us the opportunity of arguing that a relevant rate of CH patients are per se more exposed to the risk of developing over time a subtle sensorineural impairment, irrespective of treatment variables and concomitant predisposing factors. According to our results, the only variable that seems to be able to significantly affect the relationships between CH and hearing sensitivity prognosis is the severity of CH, with the poorest scores in terms of hearing acuity being observed in the individuals with athyreosis and in those with delayed bone maturation at birth. That athyreosis and delay in prenatal bone maturation are important factors influencing hearing function development in CH is a fact which had been just recently demonstrated for the first time (Lichtenberger-Geslin et al., 2013). In that study, however, the replacement treatment during the whole follow-up period was not always as adequate as in the present investigation and the possibility that other variables related to treatment may have played
Table 2 Mean (±SD) or median (and range) data at diagnosis of congenital hypothyroidism (CH) and at the time of audiologic investigation in the 8 hearing impaired patients (Subgroup A) vs the 24 patients with normal hearing acuity (Subgroup B). At CH diagnosis
Subgroup A Subgroup B p
At audiologic investigation
Serum TSH (mIU/l)
Athyreosis (%)
Distal femur nucleus absence (%)
Therapy onset (days)
L-T4 dose (mcg/kg/day)
Age (years)
Serum TSH (mIU/l)
Serum FT4 (pmol/l)
L-T4 dose (mcg/kg/day)
350 (180e535) 78.8 (35e517)
