International Journal of Pediatric Otorhinolaryngology, 2 (1980) 347-355 0 Elsevier/North-Holland Biomedical Press

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A RETROSPECTIVE STUDY OF AUDIOLOGICAL FUNCTION IN A GROUP OF CONGENITAL HYPOTHYROID PATIENTS

S. CRIFb *, R. LAZZARI, G.B. SALAS& D. ARNALDI, M. GAGLIARDI and F. MARAGONI

Department of Otorhinolatyngology and Audiology; (R.L. and D.A.), Medical Psychology Institute, State University of Rome (Italy)

and

(G.B.S.) C.N.R. Thyroid Unit of Internal Medicine Department, Rome (Italy)

(Received November 21st, 1979) (Accepted December 14th, 1979)

SUMMARY

A retrospective survey has been carried out on audiological function in 46 congenital hypothyroid cases; mental and physical development were also assessed, as well as the adequacy of substitutive therapy. Using traditional audiometry it was found that 50% of the congenital hypothyroid patients were hypocusic. Severe and profound hearing loss (5 cases) was found in the group of hypothyroid patients with dyshormonogenesis, whereas only one- third of patients with thyroid agenesis presented a mild or moderate hearing loss not related to the time of diagnosis and treatment. The hearing loss was twice as frequent in the patients with clinical hypothyroidism. Using electro- physiological techniques, the early or slow potentials were comparable between hypocusic or normocusic patients; however a longer latency of the slow vertex responses was observed in the hypothyroid group as compared to the normal population. The mean estimated I.&. was about 2 standard devia- tions below the average; however 30% of subjects had normal or above nor- mal intellectual level, this percentage rises to 55% if only patients below 16 years are considered. The height was significantly shorter only in the Iate treated patients (1 year). No correlations were found among audiological and psychological variables, nor between these variables and height. All patients were on desiccated thyroid, but therapy was inadequate in 26% of cases and subclinical hypothyroidism was found in 33% of cases.

INTRODUCTION

It is well known that brain development is severely affected by lack of thyroid hormone in the perinatal period, leading to mental retardation and

* Deceased, June 16th, 1980.

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cretinism. The effect of congenital thyroid hormone deficiency on ear func- tion in early life has not been extensively studied.

Association of neural deafness with dyshormonogenetic goiter and, pos- sibly, cretinism has long been recognized, since an endemic report of “Pen- dred’s syndrome” [ 121. However, deafness is an inherited disease associated with a recessive autosomal gene [ 1,7] independent of thyroid deficiency.

Research carried out on different species of laboratory animals [3--5,10, 16-l&21,22] seems to point to the possibility that thyroxine may play an important role in the embryonic development of the inner ear. Furthermore, the effect of an experimental hypothyroidism provoked by propylthiouracil in fairly young animals would seem to be associated with morphological modifications of the tectorial membrane and of the respective structures, probably due to a modified synchrony of the production and the develop- ment of this structure, the distortion of which causes loss of receptors.

The first specific studies in the field of audiology were carried out on adults affected by acquired hypothyroidism [ 1,8,9,13,23]. Only recently have we seen audiological investigations on specific aspects of hypothyroid- ism. Rubenstein et al. [19] in a study carried out on 21 patients affected by congenital sporadic hypothyroidism, found that 8 manifested a sensori- neural hearing loss, 3 a mixed form and 2 a conductive hearing loss. Fur- thermore, they seem to have brought to light a correlation between the degree of hypothyroidism and the hearing loss, underlining the possibility that an early diagnosis and specific treatment may be able to restore hearing.

However, in some recent literature (e.g. ref. 6) the lack of valid data as to the incidence and degree of hearing loss was underlined along with the absence of specific interdisciplinary research linking the hearing loss to the degree of thyroid deficit and to the duration and effect of the specific hor- monal therapy. As far as this last aspect is concerned, the first observation of a regression of the hearing loss after opotherapy goes back to Rau in 1947 (see ref. 14).

Consequently, almost all of the authors who have carried out investiga- tions in this field noticed a variable improvement in some of their patients linked to the hormonal therapy, both in the acquired [8,9,17] and in the congenital form [ 191.

In the present paper a retrospective study has been carried out on a series of 46 congenital hypothyroid subjects with particular attention paid to the relationship between growth, audiological and mental damage and time of detection and treatment of the disease. This study could be particularly rele- vant for comparison with series of hypothyroid patients evaluated after the introduction of mass screening for congenital hypothyroidism.

MATERIALS AND METHODS

Patients The survey included 46 subjects; in 39 hearing was tested and in 33 psy-

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chometric tests were performed. Age ranged between 7 and 35 years and medians between 10 and 25 years. Most patients were from Rome, with 12 from Southern Italy. The group includes 4 brothers; one patient had a nor- mal homozygous twin. In 10 cases the congenital hypothyroidism was due to an organ defect and in the other cases to thyroid agenesis; an ectopic remnant was observed by scintigraphy in 10 cases.

Three out of 10 cases of dyshormonogenetic hypothyroidism could be defined as Pendred syndrome, in which deaf-mutism was associated with goiter.

Circulating thyroid hormones Serum thyroxine (T4), triiodothyronine (T3) and thyrotropin (TSH) were

determined by radioimmunoassay using a double antibody technique [ 201. Normal values for thyroxine-iodine range between 3.5 and 8 pg/dl, for triiodothyronine between 80 and 220 pg/dl and for TSH < 10 ,uU/ml.

The determinations were carried out in two * laboratories with a coeffi- cient of variation of <5%.

Audiometric techniques We carried out a complete pure tone test (using Amplaid 207) evaluating

the results according to BIAP; a complete impedance test with analysis of the ipsi- and contralateral stapedial reflex (Madsen 20731) classifying the results according to Jerger and, in a certain number of patients, the recording of troncoencephalic (BSER) and slow (SVR) evoked potentials using Me- delec Amplaid MKIII apparatus.

Psychological techniques The following mental tests were used: (1) Bender Visual Gestalt test [2],

evaluated on a 5 point scale running from 1 (normal) to 5 (serious distur- bance) of the gestalt structure; (2) Progressive Matrices [ 151, adults or children form according to the age of the patient (the raw scores were trans- formed into a centile score); (3) Subtest Digit Symbol of the Wechsler-Bel- levue Scale [24 1, the raw scores were transformed into standard scores according to the age of the patient; (4) Subtest Digit Span of the Wechsler Bellevue Scale [ 241, the raw scores were transformed into standard scores according to the age of the patient; and (5) a rating scale for the evaluation of personal and economic self-sufficiency was filled out only for adults patients.

These tests were used in order to provide a rapid evaluation of mental capacity along with the possibility of giving non-verbal instructions. The Digit Span subtest was included mainly to obtain a direct reference to the audiometric tests.

* We wish to thank Prof. C. Beckers (Clinique Wniversitaires Saint-Lus, Universite Catho- lique Bruxelles, Belgium) for allowing the determination in his laboratory.

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Statistics Univariate analysis of variance and non-parametric correlations were used

to evaluate the relationships between audiological, mental and physical data. The subjects were subdivided in three groups: (1) diagnosed and treated

before 1 year, (2) later than 1 year and (3) dyshormonogenesis. The dyshor- monogenetic group was processed separately since the hearing function in these subjects can be affected independently of thyroid deficiency.

RESULTS

Traditional audiometry has shown that approximately 50% of congenital hypothyroids are hard of hearing, of sensorineural type.

Three cases of conductive deafness were found and confirmed by im- pedance measurements. The tympanogram showed effusion (Jerger type B) or atelectasia (Jerger type C) in the middle ear. Behavior of the acoustic reflex correlates with these results. The degree of the sensorineural hearing loss was classified, according to BIAP, as mild in 10 cases, moderate in 3, severe in 3 and profound in 2.

The impedance test of Metz revealed, in 6 out of 13 cases, the presence of recruitment at one or more frequencies.

The electrophysiological tests were carried in 8 patients: 3 of them were normal and 5 were affected by sensorineural hearing loss (2 cases mild, 1 moderate and 2 severe).

The early or slow potentials were compared in hard of hearing and normal hearing hypothyroid patients. The BSER profile (Fig. 2) showed 5 waves

-

l3S.SX)

- NORMAL l ILATERAL UNILATERAL CONWCTIVE

SEWS-U(AL SENSORINSURAL

Fig. 1. Pure tones test results obtained from 39 patients with congenital hypothyroidism.

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TABLE I

DEGREE OF SENSORINEURAL HEARING LOSS IN 18 CONGENITAL HYPO- THYROID PATIENTS

Hearing loss (BIAP)

Patients

With thyroid agenesia With enzymatic deficit

Mild 6 4 Moderate 3 0 Severe 0 3 Profound 0 2

corresponding to the activation of the tracts and nuclei of the subcortical acoustic pathway. Height and latency of the waves were the same in the two groups. However, a longer latency of the slow vertical responses was ob- served in the hypothyroid group in comparison to the results obtained in normal subjects.

Taking into consideration the distribution of hearing loss in the two groups, thyroid agenesis and dyshormonogenetic subjects (Table I), it is apparent that the severe and profound deafness is related to the group of dyshormonogenesis whereas, as shown in Table II, patients with mild or middle degree hearing loss are in the group of thyroid agenesis, no differ- ences being observed whether the treatment was early or late.

The thyroid remnant occurred in the late-treated group, therefore effects of the thyroid deficiency on hearing function in these subjects could have been attenuated by the residual thyroid activity.

Psychometric testing of patients gave mean values for the whole group as follows: Progressive Matrices (percentile), 31 + 33; Bender’s Visual Gestalt test 2 ? 1.06; and Digit Symbol and Digit Span subtests of the Wechsler Adult Intelligence Scale, 5.2 + 3.3 and 4.6 + 3.1, respectively. The mean I.&. was estimated at 2 standard deviations below the average; however 30% of

B Fig. 2. Brainstem Evoked Responses (BSER) obtained in a normacusic (A) and in a con- genitally hypothyroid patient (B) with mild sensorineural hearing loss. Stimulus: 70 dB SPL click.

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220

Fig. 3. Slow-Vertical Responses (SVR) obtained in a normacusic (A) and in a congenitally hypothyroid patient (B) with mild sensorineural hearing loss. Stimulus: pure tone, 70 dB HTL.

subjects had an intellectual level normal or above the norm; this percentage rising to 55% if only patients below 16 years were considered. The Bender test demonstrated organic brain lesions in 3 cases.

All the tests employed were correlated at least at 5% level among them. Early-treated, late-treated and dyshormonogenetic groups were contrasted for intellectual level. No significant difference was found between the 3 groups although the late-treated subjects showed a tendency toward lower mental efficiency.

The height taken as a parameter of growth was compared in the 3 groups (early- or late-treated and dyshormonogenetic). The height of the early- treated group closely attained the mean of a normal population from Central Italy matched for age and sex (-1.8 + 7). The dyshormonogenetic group was, on the average, slightly but not significantly higher than the normal (+3.1 2 10). The height of the late treated group was significantly lower than normal (-14 f 13), particularly in the older subjects (-18 + 10). A case of

TABLE II

CORRELATIONS BETWEEN SENSORINEURAL HEARING LOSS AND THE BEGINNING OF OPOTHERAPY IN 31 CONGENITAL HYPOTHYROID PATIENTS WITH GLANDULAR AGENESIA

Age at beginning of therapy

Number of cases

Thyroid residue or captation 10%

Level of sensorineural hearing loss

Mild Moderate Severe or profound

6 months 6 0 2 1 0 6-12 months 5 1 2 1 0 l-5 years 12 7 1 1 0 5 years 7 3 2 0 0

dwarfism was found in a 45-year-old female who was diagnosed at the age of 30.

Audiological, mental and growth parameters were submitted to partial correlation analysis. The audiological and the psychological variables did not correlate statistically. A significant correlation was found only between audiometry and the Digit Span subtest in which verbal instructions were given. The height growth did not correlate with intellectual level or with hearing efficiency.

Statistical analysis confirmed that: (a) hearing loss is more frequent and severe in the dyshormonogenetic group; (b) height of the late-treated group is lower than that of the early-treated group, and (c) a thyroid remnant occurs mostly in the late-treated group.

At the time of the survey all patients were treated with desiccated thyroid powder. Five patients had interrupted the therapy for months (2 cases) or years (3 cases).

Elevated serum TSH and normal T3 and T4 values were found in 33% of patients with subclinical hypothyroidism. An evident hypothyroid serum profile (low T4, high TSH) was present in 26% of cases, but for only 13% of cases was sera T3 in the hypothyroid range. One-quarter of patients had T3 elevated above the normal values, suggesting in these cases a T3-toxicosis induced by the substitutive therapy.

Patients with normal levels of thyroid hormones were taking an average of 1 mg + 0.3 of desiccated thyroid powder/cm’/day, whereas the dosage in the inadequately treated patients was only 0.4 ? 0.3 mg/cm’/day.

We obtained a higher incidence of hearing loss in the hypothyroid subjects with low hormone levels in comparison with those with normal levels of cir- culating hormones (45%/20%).

DISCUSSION

In this study a high percentage of hearing loss has been found in congeni- tal hypothyroidism. Severe and profound deafness were diagnosed in the group of dyshormonogenetic cases; this deafness cannot be considered entirely a consequence of thyroid hormone deficiency, but an inherited defect ‘per se’. Taking into consideration thyroid agenesis, only one-third of the patients presented a mild or moderate hearing loss with frequency and severity not related to the time of diagnosis and onset of treatment. Mental development and height growth, on the contrary, were particularly affected in the group of adult patients.

The expected relationship between the onset of replacement therapy and development was only found for height, that was found to be lower in the group of late-treated subjects.

The relationship between mental development and onset of therapy seems to be only at a tendency level. The final hearing, mental and growth levels depend on variables other than the onset of therapy, i.e. ectopic gland and

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thyroid hormone in breast-fed subjects. A partial thyroid hormone supply in early life might prevent, in late-treated patients, a severe impairment of physical and mental development. In our patients the thyroid remnant, found mostly in the late-treated patients, could have been the factor mitigat- ing the effect of thyroid hormone deficiency.

In the central nervous system the thyroid hormones are needed in the perinatal period to accelerate the development of interneural connections by promotmg the synthesis of a factor (TAU) needed for polymerization of tubulin [ll].

Maturation and sensitivity to metabolites and hormones of the various structures and functions of the central nervous system occurs at different times in the course of ontogenesis and in the perinatal period.

The fact that in our patients cretinism was not associated with a marked hearing loss, suggests that the nervous structures involved in hearing func- tions might not have a specific need for thyroid hormone.

ACKNOWLEDGEMENTS

Supported by Grant 78.0058133 CNR, Italy, Program in Preventive Medicine, Subproject in Perinatal Preventive Medicine.

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