Hearing Research xxx (2015) 1e5. Contents lists available at ScienceDirect. Hearing Research. journal homepage:

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1 HEARES_proof May 0 / Q Research paper Even in the era of congenital hypothyroidism screening mild and subclinical sensorineural hearing loss remains a relatively common complication of severe congenital hypothyroidism Q Rocco Bruno a, Tommaso Aversa b, Mariaausilia Catena b, Mariella Valenzise b, Fortunato Lombardo b, Filippo De Luca b, *, Malgorzata Wasniewska b a Department of Otorhinolaryngology, University of Messina, via Consolare Valeria, Messina, Italy b Department of Pediatrics, University of Messina, via Consolare Valeria, Messina, Italy article info Article history: Received January 0 Received in revised form April 0 Accepted April 0 Available online xxx. Introduction abstract An association between thyroid function disorders and impaired auditory function has long been recognized in patients with either Pendred syndrome (Bizhanova and Kopp, 00) or thyroid hormone (TH) resistance (Brucker-Davis et al., ) or endemic Abbreviations: CH, congenital hypothyroidism; db, decibel; FT, free thyroxine; Hz, Hertz; LT, L-thyroxine; TH, thyroid hormone; TSH, thyrotropin; c, chi-square * Corresponding author. Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Policlinico Universitario di Messina, Via Consolare Valeria, Messina, Italy. Tel.: þ 00 ; fax: þ 00. addresses: rocco.bruno@unime.it (R. Bruno), tommaso.aversa@unime.it (T. Aversa), mariaausiliacatena@hotmail.com (M. Catena), mariella.valenzise@ unime.it (M. Valenzise), fortunato.lombardo@unime.it (F. Lombardo), filippo. deluca@unime.it (F. De Luca), malgorzata.wasniewska@unime.it (M. Wasniewska). 0-/ 0 Elsevier B.V. All rights reserved. Hearing Research xxx (0) e Contents lists available at ScienceDirect Hearing Research journal homepage: 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 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. years, an audiologic investigation, which evidenced a mild and subclinical hearing loss in % 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 agematched control subjects with no CH (c ¼., p < 0.0). In light of these findings, we concluded that: a) % of CH patients detected by CH screening may show, at a median age of. 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. 0 Elsevier B.V. All rights reserved. cretinism (DeLong et al., ). Such association has been sporadically reported also in children and adolescents with central hypothyroidism (De Luca et al., ; Wasniewska et al., 00) and, more recently, in patients with TH monocarboxylate transporter abnormalities (Dumitrescu et al., 00). 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 the age of six months but outside the neonatal period (Crifo et al., ; De Luca et al., ; Vanderschueren-Ladeweyckx et al., ). 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 hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (0), 0.0/j.heares.0.0.0

2 HEARES_proof May 0 / R. Bruno et al. / Hearing Research xxx (0) e 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., ; Rovet et al., ). Even in the last few years subtle hearing problems concerning high or very high frequencies have been reported to be possibly observed in screened patients with primary CH (Leger et al., 0; Lichtenberger-Geslin et al., 0; Leger et al., 0) and these findings highlight the need for careful monitoring of sensorineural hearing function and treatment adequacy throughout childhood and adolescence (Leger et al., 0). Other studies, in contrast, documented no hearing impairment in patients with screened CH (Francois et al., ; Hashemipour et al., 0). However, only a few studies have focused on neurosensory function of CH patients identified by neonatal CH screening programs and treated early (Leger, 0) 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.. Material and methods.. Study population It includes caucasian patients ( females) who were diagnosed in many CH screening centers of two southern regions of Italy (Sicily and Calabria) during the period e00. From the time of diagnosis (median age days, range e0) all these patients were provided with L-thyroxine (L-T) replacement therapy and followed up as outpatients in our clinical center of pediatric endocrinology. The 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-T therapy onset 0 days; b) initial L-T dose between 0 and mg/kg/day; c) availability of both thyroid scanning and knee X-rays at the time of L-T treatment initiation; d) no thyrotropin (TSH) determination outside the normal limits of our laboratory reference range (0.e.0 mu/l) during the overall follow-up period, from L-T therapy start to the time of this study... Study design and methods At confirmation of CH diagnosis thyroid scanning had been performed by m Technetium, whilst skeletal maturation had been evaluated by X-ray assessment of the distal femur epiphyseal ossification center. During the last months of 0 all the selected children and young adults underwent, at the median age of. years (range.0e.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 (FT) levels under L-T therapy. All hearing tests were carried out, in a double walled soundinsulated chamber fulfilling ANSI 00 criteria, using a Plus model Bell audiometer (Inventis, Padova, Italy) and TDH- earphones. In each audiogram, the hearing loss in decibels (db) was recorded, for both ears, for the frequencies, 0, 00, 000, 000, 000, 000 and 000 Hertz (Hz). Normal hearing sensitivity was defined as hearing acuity within 0 db Hearing Level (HL), whereas hearing was considered as abnormal when hearing loss exceeded 0 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 0 and 0 db HL, whilst it was considered as moderate or more severe when it exceeded 0 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-T dose at therapy start). The same investigation protocol was also applied in a sex- and age-matched control population consisting of healthy children and adolescents ( females) aged between. and.0 years (median age,). 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... 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 (c ) test. The level of significance was set at 0.0. The study design was approved by the ethical committee of our hospital and the children parents gave informed consent.. Results CH etiology, as assessed by the thyroid scanning performed before treatment start in all the cases, was: athyreosis in children, ectopic gland in and eutopic gland in. The distal femur bony nucleus was absent in / patients (.%) 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 (.% vs 0.%; c ¼., p < 0.0). Eight patients (%) exhibited, at audiometry, a mild sensorineural hearing impairment (between and 0 db HL), which was bilateral in cases and unilateral in the remaining cases (Table ). Including all the right and left ears tested, the percentage of ears for which hearing loss was recorded was 0.%. Assessments of hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (0), 0.0/j.heares.0.0.0

3 HEARES_proof May 0 / Table Main data at congenital hypothyroidism (CH) diagnosis and at the time of audiologic investigation in the CH patients with sensorineural hearing impairment (hearing loss exceeding 0 decibels db in at least one ear at frequencies between and 000 Hertz Hz). Patients At CH diagnosis At audiologic investigation Therapy onset (days) Thyroid scanning Distal femur nucleus hearing impairment for the various frequency ranges revealed that the majority of children (/) exhibited the max hearing loss at 000 Hz and only patients exhibited the most severe hearing impairment at lower frequencies (Table ). The audiologic data, the main thyroid test results and other clinical data of the hearing impaired patients are analytically reported in Table. None of these children had been previously suspected by both family pediatricians and parents to suffer from hearing impairment. For the remaining patients of this study population the audiogram data indicated normal hearing at all frequencies tested in both ears. If the hearing impaired patients were compared with those with normal hearing acuity, the only relevant differences between the 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 ). All the other considered parameters did not significantly differ in these patient subgroups (Table ). If the athyreotic patients of the entire CH series were compared with the 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 ). In the control population the only one individual who exhibited an appreciable hearing loss ( db HL in left ear and 0 db in right ear, both at 000 Hz) was a -year old girl, whereas all the remaining subjects (.%) 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 ( vs.%, c ¼., p < 0.0). Even though both ears were considered, the percentage of hearing impaired ears was significantly higher in CH cohort than in control group (0. vs.%, c ¼., p < 0.00). 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. L-T dose. Discussion Max hearing loss (db) Hearing loss (db) at other frequencies (Hz) Hearing loss presentation 0 athyreosis absent at 000 Hz at 000 bilateral athyreosis absent at 000 Hz e bilateral ectopy present at 000 Hz at 000 monolateral ectopy absent at 000 Hz e bilateral 0 athyreosis absent at 000 Hz at 000; at 000 bilateral 0 0 ectopy present at 000 Hz e monolateral 0 0 athyreosis absent at 000 Hz e bilateral 0 0 athyreosis absent 0.. at 000 Hz e monolateral The most salient fact which emerges from the present crosssectional study is that, in a cohort of children and adolescents with CH all detected by CH screening, a % of patients showed, at a median age of. 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., 0). 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-T 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., 0). 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 Mean (±SD) or median (and range) data at diagnosis of congenital hypothyroidism (CH) and at the time of audiologic investigation in the hearing impaired patients (Subgroup A) vs the patients with normal hearing acuity (Subgroup B). At CH diagnosis Athyreosis (%) Distal femur nucleus absence (%) R. Bruno et al. / Hearing Research xxx (0) e Therapy onset (days) L-T dose (mcg/kg/day) At audiologic investigation Serum FT (pmol/l) L-T dose (mcg/kg/day) Subgroup A 0 (0e)..0. (e0) 0. ± 0.. (.e.). (.e.). ±.0. ± 0. Subgroup B. (e).. (e0). ±.. (e). (0.e.). ±.. ± 0. p <0.00 <0.0 < hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (0), 0.0/j.heares.0.0.0

4 HEARES_proof May 0 / R. Bruno et al. / Hearing Research xxx (0) e Table Mean (±SD) or median (and range) data at the age of congenital hypothyroidism (CH) therapy start and at the time of audiologic investigation in the patients with athyreosis (Group A) and in those with either ectopic or eutopic gland (Group B). some role in conditioning the poor hearing outcome could not be completely excluded. Our present findings seem to support the view that CH children with athyreosis need more careful evaluation (Hanukoglu et al., 00) and that a closer monitoring schedule might be adopted in all the CH patients with delayed bone maturation at birth (Wasniewska et al., 00). This would imply that distal femur bony nucleus should be assessed in all CH infants before the start of treatment, a procedure which is not routine in most centers. We are aware that the cross-sectional nature of our study and the limited study population hamper the ability to draw firm conclusions about the significance of our findings. Nevertheless, we believe that this may be a useful contribution to the specific literature on the relationships between CH and hearing function development, since our data suggest that the risk of hearing impairment might be particularly relevant in the children with prenatal onset of hypothyroidism. It is well known that, in humans, the critical period for hearing maturation corresponds approximately to an interval ranging from the end of the first pregnancy trimester to the first year of postnatal life (Sohmer et al., ; Sininger et al., ). This implies that ear development in humans is TH sensitive not only during the first post-natal months, but also prior to birth (Chan and Kilby, 000) and explains why hearing abnormalities may be still relatively common even in screened and early treated CH children, provided that thyroid failure was already present during intrauterine life, as in the majority of the hearing impaired patients of the present study. The absence of distal femur bony nucleus in a full-term newborn, in fact, is generally considered as a sign of intrauterine delayed bone maturation, that is among the potential consequences of fetal hypothyroidism (Luton et al., 0). In all the eight patients of our series with sensorineural hearing abnormalities, hearing impairment was mild and subclinical. Nevertheless, because mild hearing loss is a lifelong problem which can be exacerbated with later age, it is mandatory that hearing function is longitudinally followed up over time (Rovet et al., ) and that patients and families are given advice about the importance of noise protection and of treating ear infections (Lichtenberger-Geslin et al., 0).. Conclusions At CH therapy start Age (days) Absence of distal femur nucleus (%) L-T dose At audiologic investigation i) % of CH patients detected by CH screening may show, at a median age of. years, a mild and subclinical hearing impairment, despite early and adequate replacement treatment; ii) the risk of hearing loss is higher in CH young patients than in age-matched control subjects without CH; iii) the risk of hearing loss is closely associated with the severity of CH; iv) this risk is particularly relevant in the children with pre-natal onset of hypothyroidism. Contribution of each author in the research and/or article preparation Filippo De Luca (corresponding author) e analyzed results and wrote the article Malgorzata Wasniewska e set up the research project. Rocco Bruno e is the audiologist who otologic and performed all the audiologic investigations and interpreted all the audiograms. Tommaso Aversa and Mariaausilia Catena e organized the patients recruitment and the cross-sectional investigations and performed the statistical analysis of results. Mariella Valenzise and Fortunato Lombardo e followed up over time all the recruited patients from the time of diagnosis onwards and collected references. References Mean L-T dose Serum FT (pmol/l) Hearing impaired cases (%) Max decibel loss (db) Frequency at max db loss (Hz) Group A (e0).. ±.0.. (0.e.).0 ± 0.. ±...0 ±. 000 (000) (Nos ) (00e) (0.e.) Group B (Nos ) (e0) (e) ± 0.. (.0e.0). (0.e.). ± 0.. ± ± (000e000) p < <0.00 0, 0.0 Bellman, S.C., Davies, A., Fuggle, P.W., Grant, D.B., Smith, I.,. Mild impairment of neuro-otological function in early treated congenital hypothyroidism. Arch. Dis. Child., e. Bizhanova, A., Kopp, P., 00. Genetics and phenomics of Pendred syndrome. Mol. Cell. Endocrinol., e0. Brucker-Davis, F., Skarulis, M.C., Pikus, A., Ishizawar, D., Mastroianni, M.A., Koby, M., Weintraub, B.D.,. Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone. J. Clin. Endocrinol. Metab., e. Chan, S., Kilby, M.D., 000. Thyroid hormone and central nervous system development. J. Endocrinol., e. Crifo, S., Lazzari, R., Salabe, G.B., Arnaldi, D., Gagliardi, M., Maragoni, F.,. A retrospective study of audiological function in a group of congenital hypothyroid patients. Int. J. Pediatr Otorhinolaryngol., e. DeLong, G.R., Stanbury, J.B., Fierro-Benitez, R.,. 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Clin. Endocrinol. Metab., e. Hashemipour, M., Hovsepian, S., Hashemi, M., Amini, M., Kelishadi, R., Sadeghi, S., 0. Hearing impairment in congenitally hypothyroid patients. Iran J. Pediatr., e. Leger, J., Ecosse, E., Roussey, M., Lano e, J.L., Larroque, B., French Congenital Hypothyroidism Study Group.Leger, 0. Subtle health impairment and socioeducational attainment in young adult patients with congenital hypothyroidism diagnosed by neonatal screening: a longitudinal population-based cohort study. J. Clin. Endocrinol. Metab., e. Leger, J., 0. Endocrinology and adolescence: congenital hypothyroidism a clinical update of long-term outcome in young adults. Eur. J. Endocrinol. EJE-e0. [Epub ahead of print]. Lichtenberger-Geslin, L., Dos Santos, S., Hassani, Y., Ecosse, E., Van Den Abbeele, T., Leger, J., 0. Factors associated with hearing impairment in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study. J. Clin. Endocrinol. 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5 HEARES_proof May 0 / R. Bruno et al. / Hearing Research xxx (0) e 0 Luton, D., Azria, E., Polak, M., Carre, A., Vuillard, E., Delezoide, A.L., Guibourdenche, J., 0. Thyroid function in fetuses with down syndrome. Hormone Res. Paediatr., e. Rovet, J., Walker, W., Bliss, B., Buchanan, L., Ehrlich, R.,. Long-term sequelae of hearing impairment in congenital hypothyroidism. J. Pediatr., e. Sininger, Y.S., Abdala, C., Cone-Wesson, B.,. Auditory threshold sensitivity of the human neonate as measured by the auditory brainstem response. Hear. Res. 0, e. Sohmer, H., Freeman, S.,. Functional development of auditory sensitivity in the fetus and neonate. J. Basic Clin. Physiol. Pharmacol., e0. Vanderschueren-Lodeweyckx, M., Debruyne, F., Dooms, L., Eggermont, E., Eeckels, R.,. Sensorineural hearing loss in sporadic congenital hypothyroidism. Arch. Dis. Child., e. Wasniewska, M., De Luca, F., Siclari, S., Salzano, G., Messina, M.F., Lombardo, F., Valenzise, M., Ruggeri, C., Arrigo, T., 00. Hearing loss in congenital hypothalamic hypothyroidism: a wide therapeutic window. Hear. Res., e. Wasniewska, M., De Luca, F., Cassio, A., Oggiaro, N., Gianino, P., Delvecchio, M., Aiazzi, R., Stoppioni, V., Lombardo, F., Messina, M.F., Valenzise, M., Arrigo, T., 00. In congenital hypothyroidism bone maturation at birth may be a predictive factor of psychomotor development during the first year of life irrespective of other variables related to treatment. Eur. J. Endocrinol., e. 0 hearing loss remains a relatively common complication of severe congenital hypothyroidism, Hearing Research (0), 0.0/j.heares.0.0.0